Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 94 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (2-methoxyphenyl)boronic acid (49 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 40%, hexane-ethyl acetate) to give 76 mg (90% yield) of the title compound. Purity 98%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18](Br)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH:36]1([Zn+])[CH2:38][CH2:37]1>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([CH:36]3[CH2:38][CH2:37]3)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(Br)nc2CCN1C(=O)OCc1ccccc1
Reactant: [Zn+]C1CC1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(C3CC3)nc2CCN1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of (±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (100 mg, 0.18 mmol, 1.00 eq.) and 0.5M cyclopropylzinc bromide in THF (0.7 mL, 0.35 mmol, 2.00 eq.) in THF (10 mL), tetrakis(triphenylphosphine) palladium (0) (10.2 mg, 9 μmol was added. The mixture was stirred at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was diluted with DCM (50 mL) and washed with water (2×25 mL). The org. layer was dried over MgSO4 and concentrated in vacuo. The residue was taken up in DMF, filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[B:17]1[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[O:21]1
Reactant: Cc1ccccc1N
Reactant: CC1(C)OB(c2ccccc2CBr)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NCc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 1.60 g (15 mmol) of 2-methylaniline, 3.00 g (10 mmol) of 2-[2-(bromomethyl)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 1.52 g (11 mmol) of K2CO3 in 75 ml of DMF was stirred for 12 h at 80° C. The resulting mixture was poured into 300 ml of water. The product was extracted with 3×50 ml of ethyl acetate. The combined extract was dried over Na2SO4 and then evaporated to dryness. An excess of 2-methylaniline was distilled off using Kugelrohr apparatus. The residue was re-crystallized from 20 ml of n-hexane. Yield 1.82 g (56%) of red crystalline powder. Anal. calc. for C20H26BNO2: C, 74.32; H, 8.11; N, 4.33. Found: C, 73.99; H, 8.02; N, 4.45. 1H NMR (CDCl3): δ 7.82 (m, 1H, 5-H in 2-MeC6H4), 7.36-7.41 (m, 2H, 3, 5-H in C6H4CH2), 7.26 (m, 1H, 4-H in C6H4CH2), 7.08 (m, 1H, 5-H in 2-MeC6H4), 7.02 (m, 1H, 3-H in 2-MeC6H4), 6.71 (m, 1H, 6-H in 2-MeC6H4), 6.61 (m, 1H, 4-H in 2-MeC6H4), 4.55 (br.s, 2H, CH2NH), 4.31 (br.s, 1H, NH), 2.13 (s, 3H, Me in 2-MeC6H4), 1.31 (s, 12H, Bpin).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:13](OCC)=[O:14].C[O-].[Na+].Cl>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]2[S:10][CH2:9][C:8](=[CH:13][OH:14])[C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCSc2c(Cl)cccc21
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1C(=CO)CSc2c(Cl)cccc21
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
A solution of 8-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one (10 g) in benzene (125 ml) was added dropwise to a mixture of ethyl formate (7.46 g) and sodium methoxide (5.44 g) in benzene (40 ml) with ice cooling and stirring over a period of 10 minutes. After being stirred for 1 hour at room temperature, 10% hydrochloric acid was added to the reaction mixture. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-chloro-2,3-dihydro-3-hydroxymethylene-4H-1-benzothiopyran-4-one (10.13 g).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.CS(O[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([F:37])[CH:31]=1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:19]2[CH:20]=[CH:21][C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH:6]4[CH2:7][CH2:8][O:3][CH2:4][CH2:5]4)[N:15]=3)=[CH:17][C:18]2=[O:22])=[CH:31][C:32]=1[F:37]
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Reactant: CS(=O)(=O)OCCc1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1CCc1ccc(Cl)c(F)c1
Reaction time: 0.25 h

Procedure:
NaH (11.1 mg, 0.277 mmol; 60% oil dispersion) neat as a solid was added to a stirred suspension of 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (75.4 mg, 0.277 mmol) in DMF (700 μL) at room temperature under nitrogen. After 15 minutes, a clear solution had formed. A solution of 4-chloro-3-fluorophenethyl methanesulfonate (105 mg, 0.416 mmol) in of DMF (700 μL) was then added dropwise. After stirring overnight, the reaction was quenched by addition of saturated ammonium chloride solution (1 mL). The mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organics were isolated and washed with water (3×30 mL) and with brine (30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12M column with 2.5/97.5 methanol/ethyl acetate and eluted. The undesired O-alkylated product eluted first and was not collected. Product containing fractions then eluted and were pooled and concentrated to an oil that eventually solidified, 1-(4-chloro-3-fluorophenethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 7.30 (dd, 1H), 7.18 (br s, 1H), 7.02 (d, 1H), 6.98 (dd, 1H), 6.90 (m, 2H), 6.66 (dd, 1H), 5.17 (br d, 1H), 4.16 (t, 2H), 4.12 (m, 1H), 4.00 (m, 2H), 3.57 (m, 2H), 3.08 (t, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=430.1.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH2:20])[CH2:14]2)[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:29](=[O:30])[O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)[CH2:14]2)[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CN)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C

Procedure:
Intermediate 33 (0.724 g) in dichloromethane (5 ml) was treated with triethylamine (1.14 ml), forming a slurry which was added portion-wise over 5 min to a solution of 4-nitrophenyl chloroformate (0.444 g) in anhydrous dichloromethane (5 ml) at 0° C. under nitrogen. The stirring solution was allowed to warm to room temperature over 2 h, then filtered; the filtrate was purified directly by chromatography on silica gel (Biotage 90 g column), eluting with 35–40% ethyl acetate in cyclohexane, and appropriate fractions evaporated in vacuo to give the title compound (Isomer I) as an opaque yellow film (0.202 g).
Reaction SMILES: Br[CH:2]1[CH2:16][C@@H:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@@H:4]2[C:3]1=[O:17].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CC(C)=O>[N:18]1([CH:2]2[CH2:16][C@@H:5]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@@H:4]3[C:3]2=[O:17])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(Br)C(=O)[C@H]2C1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(n3ccnc3)C(=O)[C@H]2C1

Procedure:
A solution of (3aR,6aS)-tert-butyl 5-bromo-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (300 mg, 0.986 mmol) from Step 1, 1H-imidazole (201 mg, 2.96 mmol), and acetone (0.5 mL) in a 4 mL vial was stirred for 1.5 h at 80° C. The reaction mixture was then concentrated. The crude product was purified chromatographically using a 12 g silica gel cartridge with a gradient of 0-10% CH3OH/CH2Cl2 over 20 min to give (3aR,6aS)-tert-butyl 5-(1H-imidazol-1-yl)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate: MS (ESI+) m/z 292 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2.C(N1C=CN=C1)([N:20]1C=CN=C1)=O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2nc3ccsc3c(=O)n2c1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2nc3ccsc3c(=O)n2c1
Reaction time: 2 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (2.5 g, 0.01 mol) and 1,1'-carbonyldiimidazole (1.7 g, 0.01 mol) in dimethylformamide (25 ml) is heated at 90°-95° C. for one hour under nitrogen. The solution is cooled in an ice bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice bath temperature for 2 hours and at room temperature for one hour. The reaction mixture is cooled and the precipitate is filtered off. The precipitate is washed with tetrahydrofuran and recrystallized from dimethylformamide to give the product (1.2 g.), mp 319°-320° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH:19]1[C:24]([O:26][C:27](=O)[CH:18]21)=[O:25]>C1(C)C=CC=CC=1>[C:7]([CH:2]([N:1]1[C:24](=[O:25])[CH:19]2[CH:18]([CH:17]3[CH2:23][CH:20]2[CH:21]=[CH:22]3)[C:27]1=[O:26])[CH:3]([CH3:4])[CH2:5][CH3:6])([OH:9])=[O:8]
Reactant: CCC(C)C(N)C(=O)O
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(C)C(C(=O)O)N1C(=O)C2C3C=CC(C3)C2C1=O
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a suspension of (dl)-isoleucine (2.03 g, 15.5 mmol) in toluene (40 mL) was added triethylamine (2.4 mL, 17.2 mmol). The mixture was heated to reflux temperature and bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic anhydride (2.53 g, 15.5 mmol) was added. The reaction mixture was kept at reflux temperature and allowed to react for 4 hrs. After cooling to room temperature, the solvent was evaporated and the residue dissolved in H2O. The aqueous solution was washed with EtOAc, acidified with conc. HCl until pH=1, and extracted with EtOAc. The organic phase was washed with 5% HCl and brine and dried over Na2SO4. Removal of the solvent gave a white solid (3.72 g) which was recrystallized from EtOAc/hexane to yield the pure product as colorless crystals: mp=109° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1>>[F:40][C:37]([F:38])([F:39])[C:32]([C:14]1[CH:15]=[C:16]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:26])[CH2:20][CH2:19]2)=[CH:12][CH:13]=1)([OH:41])[C:33]([F:36])([F:35])[F:34]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: OB(O)c1cccc(F)c1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2-c2cccc(F)c2)CC1

Procedure:
Following the procedure outlined for Example 69, 3-fluorophenylboronic acid (20.23 mg, 0.145 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3′-fluoro-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol. 1H NMR (300 MHz, CD3OD) δ 7.89 (d, J=4.2 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.53 (s, 1H), 7.42-7.31 (m, 1H), 7.27 (d, J=4.0 Hz, 3H), 7.17 (d, J=8.6 Hz, 1H), 7.09-6.97 (m, 1H), 2.96 (br. s, 8H). m/z (ESI, +ve ion) 568.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.67 μM; GK-GKRP EC50 (LC MS/MS)=1.84 μM.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=3)[N:15]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>ClCCl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1
Reactant: COc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)n2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
2-(dibenzo[b,d]thiophen-4-yl)-6-(3-methoxyphenyl)pyridine (3.8 g, 103 mmol) was dissolved in 120 mL dichloromethane. The solution was cooled to 0° C. under nitrogen. BBr3 (22.8 mL, 1M in hexane) was slowly added in at 0° C. and then was slowly brought up to room temperature. The mixture was stirred at room temperature overnight. A brown solid was observed to form. The reaction was quenched by adding 100 mL water slowly. The dichloromethane was removed by rotovap. Then the mixture was refluxed for three hours. Saturated sodium bicarbonate solution was added to neutralize the mixture, which was extracted by dichloromethane and ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 4 gram glassy dark brown solid. The product was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Cl:21]N1C(=O)CCC1=O.O>C(O)C>[Cl:21][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:2]=3[Cl:1])[C:7]2=[N:14][C:13]=1[CH3:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cn2cccc(OCc3c(Cl)cccc3Cl)c2n1
Solvent: CCO
Solvent: O
Product: Cc1nc2c(OCc3c(Cl)cccc3Cl)cccn2c1Cl
Yield: 56.6 %

Procedure:
To a solution of 8-(2,6-dichlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (100 mg) in ethanol (2 ml) was added in one portion N-chlorosuccinimide (65.3 mg) at ambient temperature. After stirring for 1 hour at the same temperature, water was added thereto, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with 1% solution of methanol in methylene chloride. The desired residue was recrystallized with a mixture of benzene and n-hexane to give 3-chloro-8-(2,6-dichlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (63 mg).
Reaction SMILES: [C:1]12([O:11][C:12](=[O:26])[C@@H:13]([CH3:25])[NH:14]C(OCC3C=CC=CC=3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:27].CCOCC>CO.[Pd]>[ClH:27].[C:1]12([O:11][C:12](=[O:26])[C@@H:13]([CH3:25])[NH2:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](N)C(=O)OC12CC3CC(CC(C3)C1)C2

Procedure:
N-Benzyloxycarbonyl-D-alanine 1-adamantyl ester (7.35 g, 20.6 mmol) was dissolved in 100 mL MeOH and 14.5 mL 1.25N HCl/ether. The solution was hydrogenated over 1.09 g of 10% Pd/C at 40 psi in a Parr apparatus at room temperature for 40 minutes. The solution was filtered through a Celite pad and the clear filtrate was evaporated to dryness to give a yellow oil, which was crystallized from EtOAc. A light yellow salt (4.2 g) was obtained. The crude product was recrystallized from MeOH-EtOAc; yielded 7.85 g (72%), mp 218°-219° (dec), 250 MHz nmr (CD3OD, ppm) 1.50 (d, 3H, J=7.35 Hz, β--CH3 of Ala), 1.72 (m, 6H, 1-adamantyl aliphatic protons of C's 2, 8 and 9), 2.18 (m, 9H, adamantyl aliphatic protons), 3.95 (q, 1H, J=7.35 Hz, α--H of Ala).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(O)C.[Pt]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)=[N:16][CH:17]=1
Reactant: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)cc1
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(N2CCN(c3ccc(N)cn3)CC2)cc1
Reaction time: 48 h

Procedure:
A suspension of the product of part (i) (4.0 g, 12 mmole) in ethanol (150 ml) was hydrogenated at 45 p.s.i. (310 kPa) over 5% platinum on carbon (0.1 g) for 5 hours. After this time an additional portion of the catalyst (0.1 g) was added and hydrogenation was continued at room temperature for a further 48 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The dark residue was purified by flash chromatography on silica gel eluting with ethyl acetate (97):methanol (3) to yield, after collection and evaporation of appropriate fractions, the desired product, m.p. 134°-135° (1.2 g, 33%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: COc1ccc(CO)cc1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Cl)nc(SC)n2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 658.1 %

Procedure:
To a solution of 4,6-dichloro-2-(methyl thio)pyrimidine (75 g, 38.4 mmol, Sigma-Aldrich) in DMF (750 mL) was added p-methoxybenzyl alcohol (58.38 g, 42.1 mmol) and K2CO3 (212.3 g, 1538 mmol). The reaction was stirred at 60° C. for 12 h, then cooled to RT. Water (500 mL) was added to the mixture and the resulting suspension was filtered. The solid was dried and triturated with Hexanes to give 4-Chloro-6-(4-methoxy-benzyloxy)-2-methylsulfanyl-pyrimidine (75 g, 66.4% yield) as a white solid. MS (ESI, pos. ion) m/z: 297.0 (M+1); 1H NMR (400 MHz, CDCl3): δ 7.30-7.37 (m, 3H), 6.89-6.93 (m, 2H), 5.36 (s, 2H), 3.82 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18]C(=O)OC(C)(C)C)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 23 °C

Procedure:
To a 0° C. solution of tert-butyl (2-(4-acetamidobenzamido)phenyl)carbamate 1.5 (3.5 g, 9.5 mmol) in dry dichloromethane (55 mL) was added trifluoroacetic acid (22 mL) dropwise. The mixture was allowed to slowly warm to 23° C. for 2 hours until the reaction was complete. The solvents were removed in vacuo. The reaction mixture was diluted with water and the pH was adjusted to ˜8 with a saturated aqueous solution of sodium bicarbonate. The resulting precipitate was filtered, washed with water and ether, and dried under vacuum to afford 4-acetamido-N-(2-aminophenyl)benzamide 1.6 as an off-white solid. Yield 1.6=2.4 g (96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1csc(-n2ccnc2)n1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1csc(-n2ccnc2)n1
Yield: 62.1 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and 3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H19) (235 mg, 0.8 mmol) according to the general procedure K. Obtained as an orange oil (162 mg).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(OCC2CO2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
In 120 ml of anhydrous N,N-dimethylformamide was dissolved 25.9 g of benzyl 4-hydroxybenzoate and 12.7 ml of epibromohydrin. To the solution was added 23.6 g of anhydrous potassium carbonate, and the mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 24.5 g of the title compound as an oil (yield 76%).