Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(=O)[C@@H](O)CN[C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1.[F:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:10]3[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[CH:6][N:11]=3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1
Reactant: NC(=O)c1cc(NC[C@H](O)C(N)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1ccnc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C
Yield: 19.6 %

Procedure:
To a mixture of the (S)-6-((3-amino-2-hydroxy-3-oxopropyl)amino)-2-chloropyrimidine-4-carboxamide (0.372 g, 1.43 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.494 g, 1.57 mmol), 2M aqueous Na2CO3 (1.45 mL, 2.90 mmol), and PdCl2(dppf) (0.063 g, 0.077 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue triturated with 25 mL acetone. The insoluble solid was filtered off and washed successively with water, MeOH, 1N aqueous HCl, water, and MeOH. The solid was then dissolved in 3 mL DMSO with warming and diluted with 15 mL MeOH. Upon standing the solution deposited a solid that was filtered and rinsed twice with 5 mL MeOH and once with 2:1 acetonitrile/DMSO. The remaining solid was purified by reverse-phase chromatography using a 40-70% acetonitrile in water (+0.1% TFA) gradient. The product fractions were pooled and lyophilized to give (S)-6-(3-amino-2-hydroxy-3-oxopropyl)amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a cream-colored powder (0.115 g, 0.280 mmol, 20% yield). 1H NMR (400 MHz, DMSO-d6): 8.54 (2H, d, J=8.1 Hz), 8.26 (1H, s), 7.91-7.84 (1H, m), 7.73 (1H, s), 7.33-7.23 (4H, m), 7.19-7.13 (2H, m), 7.08-7.01 (3H, m), 5.78 (1H, br s), 4.14-4.07 (1H, m), 3.92-3.83 (1H, m), 3.53-3.45 (1H, m). LC/MS: m/z=412.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH3:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CO.I([O-])(=O)(=O)=[O:22].[Na+]>O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:16])=[O:22])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
4-chloro-4'-methylthiomethylbenzophenone (4.2 g) was added to methanol (150 ml). Sodium periodate (3.6 g) dissolved in water (20 ml), was added to this solution, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated, and water was added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with n-hexane to obtain the desired product (4.1 g, melting point: 116° to 118° C., yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]=[C:6]1[C:11]([O:13]C)=[O:12])=[O:4].[Li+].[OH-].C1(C)C=CC=CC=1.CO>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CC(O)CC1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Temperature: 0 °C
Yield: 24.4 %

Procedure:
To an ice-cold solution of 62 (3.4 g, 22 mmol) dissolved in dioxane and water (1:1, 110 mL), LiOH (0.52 g, 22 mmol) was added. After two and a half hours the mixture was co-evaporated with toluene and methanol. Purification by flash chromatography (toluene/Ethyl acetate 3:1+1% HOAc) gave the title compound (1.0 g, 27%) as yellow-white crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([NH:21]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[NH:50][C:49](=[O:54])[CH2:48][CH2:47]3)O1.BrC1C=C2C(=CC=1)NC(=O)CC2>>[NH2:21][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:8][NH:7][C:5]1[S:6][C:2]([C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[NH:50][C:49](=[O:54])[CH2:48][CH2:47]3)=[CH:3][N:4]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC(=O)N3)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1ncc(Br)s1
Agent: O=C1CCc2cc(Br)ccc2N1
Product: N[C@H](CNc1ncc(-c2ccc3c(c2)CCC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was synthesized using a procedure similar to that shown in Scheme 1 with a coupling reaction between (S)-tert-butyl 1-(N-(5-bromothiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate as shown in Scheme 10 and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one, which was prepared from commercially available 6-bromo-3,4-dihydroquinolin-2(1H)-one in a similar manner to the procedure shown in Scheme 1. MS m/z: 447 (M+1). 1H NMR (400 MHz, CD3OD): δ ppm 2.55-2.60 (m, 2H), 2.97 (t, J=7.63 Hz, 2H), 3.09 (dd, J=14.97, 7.34 Hz, 2H), 3.52 (d, J=6.85 Hz, 1H), 3.62 (d, J=3.72 Hz, 1H), 3.70 (m, 1H), 6.86 (d, J=8.22 Hz, 1H), 7.23-7.34 (m, 3H), 7.53 (d, J=8.02 Hz, 2H), 7.69 (d, J=8.02 Hz, 2H).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].[CH3:21]N(C)C=O.CI>O>[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Reactant: CN(C)C=O
Agent: [Na]
Solvent: O
Solvent: CI
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Reaction time: 2 h

Procedure:
A solution of 4.0 g. (0.014 mole) of the sodium salt of 2-amino-3-benzoylphenylacetic acid in 100 ml. of dry dimethylformamide was treated with 8.0 g. (0.057 mole) of methyl iodide. After stirring for two hours the solution was poured into water and the aqueous solution extracted several times with ethyl ether. The combined extracts were washed with water, dried over sodium sulfate and concentrated under vacuum to a yellow oil. The oil was crystallized from a chilled methanol-water solution to give 3.5 gms. (90%) of a yellow solid which melted at 52°-54° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26]C=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCNCC1)(OC(C)(C)C)=O.C(N)C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][CH2:22][C:23]3[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCCc3ccccc3)cn2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3ccccc3)cn2)CC1

Procedure:
In analogy to example 1 4-(5-phenethylcarbamoyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared starting from N-Boc-piperazine and using benzylamine in the last coupling step. Light yellow solid. MS (ISP): 397.5 ([M+H]+)
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)=[O:37])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), N-(tert-butoxycarbonyl)glycylglycine (0.232 g, 1.0 mmol), N,N-dicylohexylcarbodiimide (0.206 g, 1.0 mmol) and DMAP (0.122 g, 1.0 mmol) in 10 mL of CH2Cl2 was stirred overnight at ambient temperature. The reaction mixture was diluted with CH2Cl2 and filtered through a plug of silica gel. The gel was rinsed with additional CH2Cl2. The combined filtrates were concentrated in vacuo to give 0.35 g to the title compound as a white solid, mp 103–104° C.;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(N(CC)C(C)C)(C)C>ClCCl.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=3[Cl:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3ccc(Cl)cc3Cl)CC2)c1C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
To a light brown solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 110 mg, 0.35 mmol) and 2,4-dichlorobenzoyl chloride (110 mg, 0.53 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (183 μL, 1.05 mmol) at room temperature under a nitrogen atmosphere. The resulting light brown solution was stirred for 15 hours. The reaction mixture was diluted with water and brine and the resulting mixture was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution, dried over MgSO4, filtered, and concentrated to give the crude product. Flash chromatography (40 g ISCO column, eluting with 0-60% ethyl acetate/hexanes) provided {4-[1-(2,4-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (111 mg, 65%) as a white solid. MS cald. for C26H25Cl2FNO3 [(M+H)−] 488, obsd. 488.0.
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[Ru]>[CH:2]1([O:1][CH2:8][C@H:9]2[CH2:11][O:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: c1ccc(OC[C@H]2CO2)cc1
Reactant: [H][H]
Agent: [Ru]
Solvent: C1CCOC1
Product: C1CCC(OC[C@H]2CO2)CC1
Yield: 58 %

Procedure:
In two separate runs, dissolve (R)-2-phenoxymethyl-oxirane (1.410 g, 9.389 mmol) in tetrahydrofuran (50 mL). Add 5% ruthenium on carbon (0.71 g) and hydrogenate at 60 psi of hydrogen gas for 40 minutes. Filter through a filtering agent, wash with tetrahydrofuran, concentrate and purify (silica gel chromatography, eluting with 5:95 to 30:70 ethyl acetate:hexanes) to give the desired compound as a clear liquid (0.850 g, 57.9% combined yield).
Reaction SMILES: [CH:1]1([CH:4]([OH:6])[CH3:5])[CH2:3][CH2:2]1.[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:6][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH3:5])[CH3:14]
Reactant: CC(O)C1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)COC(C)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of cyclopropyl-1-ethanol (860 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 130° C. to give 1.11 g of the product 471. 1H NMR (CDCl3) δ 4.12 (s, 2H), 4.10 (q, 2H), 2.86 (m, 1H), 1.25-1.15 (m, 6H), 0.8-0.7 (m, 1H), 0.55-0.3 (m, 3H), 0.05-0.02 (m, 1H); MS: m/z 173 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]=O)[N:6]2[N:5]=[CH:4][N:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
To a suspension of Intermediate AW (N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (50 mg, 0.1 mmol)) and morpholine (0.01 ml, 0.12 mmol) in dichloroethane (3 ml) was added sodium triacetoxyborohydride (67 mg, 0.31 mmol). The reaction was stirred under N2 at rt for 16 h. The reaction mixture was diluted with CH2Cl2 and subsequently quenched with aqueous saturated NaHCO3. The organic phase was collected, dried (Na2SO4), concentrated and purified via column chromatography (95:5 v/v CH2Cl2-MeOH) to afford 26 mg of the title compound (yield 46%). 1H-NMR (DMSO-d6) δ9.32 (s, 1H), 8.96 (d, J=2 Hz, 1H), 8.64 to 8.61 (dd, J=8, 2 Hz, 1H), 7.90 (s, 1H), 7.59 to 7.34 (m, 6H), 4.29 (s, 2H), 3.86 (s, 2H), 3.55 to 3.50 (m, 4H), 3.14 (s, 3H), 2.47-2.41 (m, 4H); MS [M+H]+=573.9; LCMS RT=2.53 min.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[CH:25]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)c1
Yield: 6.3 %

Procedure:
The title compound (18 mg, 6%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (275 mg, 0.818 mmol, prepared in example 1), 3-methylbenzeneboronic acid (135 mg, 0.993 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water) and 1,4-dioxane (5.5 mL) was prepared in a manner analogous to the procedure described in Example 2. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 110 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase, chromatography on a Vydac C-18 column in a gradient of 5 to 70% of 0.1% trifluoroacetic acidlacetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnc(Nc2ccc(S(=O)(=O)NCCN3CCCC3)cc2)nc1
Solvent: CO
Product: Nc1cnc(Nc2ccc(S(=O)(=O)NCCN3CCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.5 %

Procedure:
Intermediate 44 (Example 92) (4.26 mmol, 1.0 equiv) dissolved in MeOH (0.05-1.0 M) was evacuated of air and placed under an argon blanket; Pd/C (10% by wt) was then added. The mixture was evacuated and then refilled with hydrogen and stirred at room temperature for 4 h. Filtration through CELITE with a MeOH wash, followed by concentration under reduced pressure afford the title compound as a white solid (100 mg, 7%). The crude amino-compound was used in the next step without purification. MS (ES+): m/z=363 (M+H)+. LC retention time: 1.34 min.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5](O)=[O:6].[Na+].Cl>>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:8]([OH:10])=[O:9]
Reactant: N[C@@H](CCC(=O)O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=C1CC[C@@H](C(=O)O)N1

Procedure:
20 g of monosodium glutamate (Aldrich) was mixed with 11 mL of HCl 32% and the pH was adjusted to about 2.5 (using HCl). The mixture was heated to above 100° C. in an autoclave for 10 hours. Then the solution was evaporated to dryness to obtain the L-pyroglutamic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].N12CCN(CC1)CC2.CCCCCCC>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC1(C)CCN(c2ccc(O)nc2)CC1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CCCCCCC
Product: CN(C(=O)Oc1ccc(N2CCC(C)(C)CC2)cn1)c1ccccc1
Yield: 41 %

Procedure:
A solution of 4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ol (0.86 g, 4.17 mmol), N-methyl-N-phenylcarbamoyl chloride (0.71 g, 4.17 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.47 g, 4.17 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. Extra dichloromethane was added and the solution was washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. Crystallisation from ethyl acetate:heptane yielded the title compound (0.58 g, 41% yield)
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([S:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[N:1]1([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([S:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1cc2ncnc(Cl)c2cc1SC
Product: COc1cc2ncnc(N3CCCc4ccccc43)c2cc1SC
Yield: 35 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 35% yield from 1,2,3,4-tetrahydroquinoline and 4-chloro-7-methoxy-6-methylsulfanyl-quinazoline. (M.P. 193°-196° C.; LC-MS: 338 (MH+)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: BrCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: BrCCCCCCCSc1ccc(Br)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A mixture of 4-bromobenzenethiol (6 g), 1,7-dibromoheptane (16.37 g), and potassium carbonate (8.77 g) in dimethylformanide (30 ml) was stirred at room temperature for 5.5 Hours. The reaction mixture was pulverized with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-bromo-4-(7-bromoheptylthio)benzene (7.62 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]([CH3:18])[CH3:17]>CC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COc1ccc(Br)cc1
Yield: 60.2 %

Procedure:
4-Bromo-phenol (2 g, 11.6 mmol) is dissolved in acetone (40 mL). Potassium carbonate (8 g, 38.4 mmol) is then added followed by isobutyl bromide (4 g, 29.2 mmol). The reaction is heated to reflux for four days, refilling solvent as necessary. The reaction mixture is diluted with water and extracted with ether, the organic layer is separated and concentrated in vacuo. The residue is dissolved in hexane dried with magnesium sulfate, and filtered through a plug of silica gel. The solvent is removed in vacuo to afford 1.6 g (60% yield) of the title compound as a colorless non-viscous oil. 1H NMR (CDCl3) δ 1.01 (d, 6H, J=6.56 Hz), 2.05-2.08 (m, 1H), 3.67 (d, 2H, J=6.57 Hz), 6.77 (d, 2H, J=9.09 Hz), 7.36 (d, 2H, J=9.09 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].[C:15]([CH2:23][C:24]([CH3:26])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:5][C:24]([CH3:26])=[CH:23][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1ccccc1
Yield: 97.7 %

Procedure:
To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) is added 1-benzoylacetone (3.66 g, 22.56 mmol), then the mixture is heated to reflux for 24 h. The solvent is evaporated under a vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off under atmospheric pressure. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (6.80 g, 98%).