Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc([C@H](C)N)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: CCOc1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-ethoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 545 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[C:11]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:10]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]3=[O:7])=[CH:10][C:11]=2[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:22][CH2:21]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 62.4 %

Procedure:
Using piperidin-2-one (104 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 1, the title compound (293 mg) was obtained.
Reaction SMILES: [CH2:1]1COCC1.C[O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl>[CH3:1][N:13]1[C:8](=[O:7])[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:12]1
Reactant: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)cn1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Temperature: 85 °C
Yield: 53 %

Procedure:
To a stirred anhydrous THF (10 mL) mixture of N-({(5S)-3-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.10 g, 0.29 mmol) in a sealed tube, is added potassium carbonate (0.04 g, 0.58 mmol) and methyl iodide (0.1 mL, 1.7 mmol). The mixture is heated to 85° C. for 16 hours. The reaction is cooled to RT and diluted to 100 mL with CH2Cl2. The K2CO3 is filtered. The solution is concentrated to dryness, dissolved in MeOH (20 mL) and treated with saturated Na2S2O3. The solution is concentrated to dryness on silica. The residue is loaded onto a SIM and purified on a Biotage 12M column with 2–4% MeOH in CH2Cl2 to yield the desired compound (0.23 g, 53%). 1H-NMR (DMSO) δ: 8.26, 8.12, 7.82, 7.59, 6.47, 4.73, 4.14, 3.77, 3.50, 3.42, 1.84
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:5]([C:8]([NH:10][CH2:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:81]1[CH2:87][CH2:86][CH2:85][C@H:82]1[CH2:83][OH:84].C(=O)([O-])O.[Na+]>COCCOCCOC>[Cl:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][NH:18][C:4]1[C:5]([C:8]([NH:10][CH2:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=[C:2]([N:81]2[CH2:87][CH2:86][CH2:85][C@H:82]2[CH2:83][OH:84])[CH:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(CNc2cc(Br)cnc2C(=O)NCc2ncccn2)cc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Product: COc1ccc(CNc2cc(N3CCC[C@H]3CO)cnc2C(=O)NCc2ncccn2)cc1Cl
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In diglyme 2 ml are suspended 5-bromo-3-(3-chloro-4-methoxybenzylamino)-2-(2-pyrimidinylmethylaminocarbonyl)pyridine (prepared in the above (5)) 20 mg, trisdibenzylidene acetone palladium (0) 22 mg, 2,2′-bisdiphenylphosphino-1,1′-binaphthyl 4 mg, cesium carbonate 43 mg and L-prolinol 88 mg, and the mixture is stirred at 120° C. for 5 hours. An aqueous saturated sodium hydrogen carbonate solution is added to the reaction mixture cooled, and the mixture is extracted with ethyl acetate. The combined organic layer is washed, dried and the solvent is removed in vacuo. The residue is purified by silica gel preparative thin-layer chromatography (developing solution; ethyl acetate) to give (S)-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)-2-(2-pyrimidinylmethylaminocarbonyl)pyridine as a pale brown powder 5.2 mg. MS(m/z): 483(M+H)+
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2OC)CCCCC1.[NH2:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:43][CH:42]=2)=[N:39][C:38](Br)=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34].COC1C=CC(B(O)O)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:43][CH:42]=2)=[N:39][C:38]([C:16]2[CH:15]=[CH:14][C:19]([O:20][CH3:21])=[CH:18][CH:17]=2)=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OCc3ccccc3)cc2)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OCc3ccccc3)cc2)c1N
Yield: 392 %

Procedure:
A flask containing dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (132 mg, 0.322 mmol), methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate (665 mg, 1.61 mmol), 4-methoxyphenylboronic acid (293 mg, 1.93 mmol), palladium(II) acetate (36.1 mg, 0.161 mmol), and potassium phosphate tribasic (1025 mg, 4.83 mmol) was flushed with nitrogen. Tetrahydrofuran (16 mL) was added and the reaction was heated at reflux overnight. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried with sodium sulfate and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 0 to 10% EtOAc) afforded 556 mg of methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-(4-methoxyphenyl)-isonicotinate as a yellow oil. MS (ESI) m/z 441.2 (M+H). 1H NMR (CDCl3) δ ppm 8.01 (1H, s), 7.92 (2H, d, J=8.85 Hz), 7.67 (2H, d, J=8.85 Hz), 7.44-7.48 (2H, m), 7.40 (2H, t, J=7.63 Hz), 7.35 (1H, d, J=7.32 Hz), 7.10 (2H, d, J=8.85 Hz), 6.94 (2H, d, J=8.85 Hz), 5.94 (2H, br. s.), 5.13 (2H, s), 3.95 (3H, s), 3.83 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:25][NH2:26]>O1CCOCC1>[CH3:23][C:20]1[N:19]=[CH:18][C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:25][NH2:26])[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NN
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cn1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)cn1
Reaction time: 15 h
Yield: 27 %

Procedure:
There was suspended, in 1,4-dioxane (24 mL), 5-chloro-2-(6-methyl-pyridin-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine (0.79 g, 2.4 mM) prepared in the preceding step 1, then hydrazine monohydrate (1.2 mL, 24 mM) was added to the suspension and the mixture was stirred for 15 hours, while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and then the solvent was distilled off to thus give a crude product of the title compound (210 mg, yield: 27%).
Reaction SMILES: [OH:1][C@H:2]([C@H:6]1[C@@H:11]([NH:12][C:13](=[O:28])[CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:10][CH2:9][C@@H:8]([NH:29]C(=O)OC(C)(C)C)[CH2:7]1)[CH:3]([CH3:5])[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C@@H:8]1[CH2:9][CH2:10][C@H:11]([NH:12][C:13](=[O:28])[CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C@H:6]([C@@H:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[CH2:7]1
Reactant: CC(C)[C@H](O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](O)[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
The entirety of tert-butyl(1R,3R,4S)-3-((S)-1-hydroxy-2-methylpropyl)-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate prepared in previous Step (1 eq) in CH2Cl2 (20 mL) was added TFA (4 mL) at RT. The reaction was stirred for 5 h and concentrated in vacuo. The residue was partitioned between 1N NaOH (30 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the organic phases were combined, washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give N-(2-((1S,2R,4R)-4-amino-2-((S)-1-hydroxy-2-methylpropyl)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS found: (M+H)+=416.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.ClCCl.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]>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:27]2[CH2:28][CH2:29][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH2:25][CH2:26]2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(c3ccccn3)CC2)c1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
A mixture of (S)-[1-(3-bromophenyl)ethyl]carbamic acid tert-butyl ester (5.0 g, 16.7 mmol), 1-pyridin-2-ylpiperazine (10.9 g, 67 mmol), Pd2(dba)3 (1.55 g, 10 mol %), di-t-butyl-biphenylphosphine (0.51 g, 10 mol %), potassium phosphate (7.2 g, 34 mmol) in ethyleneglycol dimethyl ether (40 mL) was refluxed for 4 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (100 mL) and the precipitate was filtered off. The filtrate was concentrated under vacuum. The crude product was purified by flash chromatography over silica with ethyl acetate/hexanes (1:2) to provide the title compounds as an oil (4.1 g, 64% yield).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([NH:11][CH3:12])=[O:10].[CH3:14]I.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C=O)C>[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([N:11]([CH3:14])[CH3:12])=[O:10]
Reactant: CNC(=O)c1cncc(Br)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cncc(Br)c1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in oil) (28 mg) was added to a DMF (2.4 ml) solution containing 5-bromo-N-methylnicotinamide (100 mg), followed by stirring at 45° C. for 1 hour. Methyl iodide (43 μl) was added under ice cooling, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. Hexane was added to the obtained residue, solid matter was collected by filtration, and a white solid of 5-bromo-N,N-dimethylnicotinamide (42 mg) was thus obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([CH2:33][O:34][CH2:35][C:36](O)=[O:37])[C:29]=3[CH:39]=2)[C:15]1=[O:40].[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[N:16]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][N:31]=[C:30]([CH2:33][O:34][CH2:35][C:36]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:37])[C:29]=3[CH:39]=2)[C:15]1=[O:40]
Reactant: CS(N)(=O)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(COCC(=O)O)c3c2)c1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(COCC(=O)NS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
1,1'-Carbonyldiimidazole (1.17 g, 0.00722 mol) is added to a solution of {{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}methoxy}acetic acid (1.50 g, 0.00361 mol) in tetrahydrofuran. The mixture is stirred one hour at reflux and cooled to room temperature. Methylsulfonamide (0.755 g, 0.00794 mol) is added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.19 ml, 0.00794 mol). The resultant mixture is stirred overnight at room temperature, poured into 10% hydrochloric acid, and filtered. The resultant white solid is triturated in tetrahydrofuran, and filtered to give the title compound as an off-white solid (1.00 g, 56.2%, mp >240° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:2].CCN(CC)CC.[SH2:20]>N1C=CC=CC=1>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[S:20])[NH2:2]
Reactant: S
Reactant: N#CCc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65 g, 10.24 mmol) and Et3N (5 ml) in pyridine, H2S was bubbled during 3 h. The reaction mixture was stirred 16 h at room temperature. Water was then added to the reaction mixture which was agitated for 1 h before acidifying to pH 6 with 1M HCl. The solvent was evaporated and the residue was triturated 30 min. in water (20 ml) and filtered to obtain the title compound 250 (2.08 g, 83%) as a white solid. 1H NMR (DMSO) δ (ppm): 12.85 (bs, 1H), 9.53 (bs, 1H), 9.43 (bs, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.44 (d. J=8.1 Hz, 2H), 3.88 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[C:11]3[C:6](=[C:7]([NH:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3c(Cl)nccc23)CC1
Reactant: COc1ccc(CN)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2nccc3c(NC4CCN(C(=O)OC(C)(C)C)CC4)cccc23)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of Intermediate 84 (235 mg), 4-methoxybenzylamine (110 μl), tris(dibenzylideneacetone)dipalladium(0) (30.4 mg), 2-(di-tert-butylphosphino)biphenyl (41.0 mg) and sodium tert-butoxide (93.6 mg) in toluene (4.5 ml) was stirred at 70° C. for 1 hour. The reaction mixture was filtered through a Celite layer, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (270 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=C[CH:7]=1.C([Mg]Cl)(C)C.[O:14]=[C:15]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]3([C:31]#N)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[CH:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:17][NH:16]1>C1COCC1>[C:33]1([CH:18]2[C:19]3([CH2:24][CH2:23][N:22]([C:25]4([C:31]5[CH:5]=[C:4]([CH3:8])[CH:3]=[CH:2][CH:7]=5)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:15](=[O:14])[NH:16][CH2:17]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N#CC1(N2CCC3(CC2)C(=O)NCC3c2ccccc2)CCCCC1
Reactant: Cc1cccc(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(C2(N3CCC4(CC3)C(=O)NCC4c3ccccc3)CCCCC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of 3-iodotoluene (388 mg, 1.8 mmol) in dry THF (6 mL) under argon at -60° C. was added isopropylmagnesium chloride (2 M solution in THF, 977 μL, 2.0 mmol) and the resulting solution allowed to warm up to 0° C. over 1 h and then to room temperature over 10 min. The resulting solution was then added dropwise to a solution of rac-1-(1-oxo-4-phenyl-2,8-diaza-spiro[4.5]dec-8-yl)-cyclohexanecarbonitrile (200 mg, 0.6 mmol) in dry THF (3 mL) and the solution stirred overnight at room temperature. The reaction was quenched by the addition of ammonium chloride solution (sat., 10 mL) and the product extracted with ethyl acetate (2×20 mL). The combined organic extracts were then washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with DCM:MeOH:NH4OH (95:4.5:0.5) to afford the title compound (170 mg, 71%) as a white solid. MS: m/e=403.6 (M+H).
Reaction SMILES: C([NH:20][C:21]1[NH:22][C:23](=O)[C:24]2[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:28]=2[N:29]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.II.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:71]1[CH:75]=[CH:74][N:73]=[CH:72]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23]([N:71]2[CH:75]=[CH:74][N:73]=[CH:72]2)[N:22]=1
Reactant: c1c[nH]cn1
Reactant: O=c1[nH]c(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-n2ccnc2)c2[nH]cnc2n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 2-N,9-bistritylguanine (1.90 g, 3 mmol), I2 (3.88 g, 15 mmol), Ph3P (3.99 g, 15 mmol) and imidazole (1.10 g, 15 mmol) was stirred in toluene (150 mL) at 95° C. for 15 min, and DIPEA (2.9 mL, 2.15 g, 16.6 mmol) was added. The mixture was stirred at 95° C. overnight. After removal of volatiles, the residue was boiled with EtOAc (3×) and filtered hot. The combined EtOAc extracts were evaporated to dryness. The residue was dissolved in TFA/H2O (9:1, 60 mL), and the solution was stirred at 0° C. for 4 h. Volatiles were evaporated in vacuo, and the residue was dissolved in 0.1 N NaOH/H2O//CH2Cl2 (100 mL/100 mL). The organic layer was extracted with 0.1 N NaOH/H2O (50 mL×2), and the aqueous phase was combined, washed [CH2Cl2 (2×50 mL)], and neutralized with CO2. Volatiles were evaporated in vacuo, and the residue was washed (H2O, CH2Cl2) to give 2-amino-6-(imidazol-1-yl)purine (0.40 g, 69%): UV (MeOH) max 222, 320 nm (∈ 29 800, 8700), min 207, 280 nm (∈ 16 100, 1500); 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.94 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.18 (s, 1H), 6.67 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 160.7, 157.5, 145.4, 141.9, 137.2, 130.5, 117.7, 115.4; HRMS m/z 201.0753 (M+[C8H7N7]=201.0763).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:19]([C:22]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)[CH2:24][CH2:23]1)[CH:20]=O>C(O)C>[F:17][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]3[N:7]([C:19]([C:22]4([C:25]5[CH:26]=[C:27]6[C:32](=[CH:33][CH:34]=5)[N:31]=[CH:30][CH:29]=[CH:28]6)[CH2:24][CH2:23]4)=[CH:20][N:1]=3)[CH:6]=2)[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Nc1ncc(-c2ccc(C(=O)O)c(F)c2)cn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluorobenzoic acid (0.20 g, 0.86 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.21 g, 0.86 mol) in ethanol (8 mL) was stirred at 100° C. overnight. The reaction mixture was purified by RP-HPLC to afford the desired product. LCMS: (M+H)=425.0.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClC[CH2:34][S:35](C)(=[O:37])=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:34][S:35]([CH2:18][CH2:17][N:16]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)CCCl
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CS(=O)(=O)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-chloro-2-methanesulfonyl-ethane (Prepared as described in Chem. Ber. 1894, 27, 3048) and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([C:24]1[CH:29]=[C:28]([S:30][CH2:31][CH2:32][CH2:33]O)[CH:27]=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:25]=1[OH:39])([CH3:23])[CH3:22].C(Br)(Br)(Br)[Br:41]>CCOCC>[Br:41][CH2:33][CH2:32][CH2:31][S:30][C:28]1[CH:29]=[C:24]([C:21]([CH3:23])([CH3:22])[CH3:20])[C:25]([OH:39])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1cc(SCCCO)cc(C(C)(C)C)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(SCCCBr)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (17.54 g, 66.89 mmol) was added to a stirred solution of 2 (9.9 g, 33.44 mmol) and carbon tetrabromide (22.18 g, 66.89 mmol) in dry ether. After stirring at room temperature for 18 hours, the reaction mixture was concentrated and the crude product was chromatographed (silica gel; hexane/ethyl acetate 98/2) to give 3 in quantitative yield. The structural assignment was supported by the 1H-NMR spectra in CDCl3.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:17]([OH:19])=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[ClH:20]>CO>[ClH:20].[OH:8][C:9]1[C:10]([C:17]([OH:19])=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccnc(C(=O)O)c1OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccnc(C(=O)O)c1O
Yield: 54.8 %

Procedure:
3-Benzyloxy-4-methoxypicolinic acid (8.3 g) was dissolved in 100 ml of methanol. Concentrated hydrochloric acid (2 ml) was added to the solution. The mixture was heated under reflux for 30 min. The reaction solution was concentrated under the reduced pressure. The residue was recrystallized from water-ethanol to give 3.6 g (yield 54.8%) of title compound as colorless powder.