Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Clc1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 59.8 %

Procedure:
The diaryl product was obtained using the same synthetic methods as shown in Example 25, step 5, using 2-(4-chlorophenyl)acetic acid (5 g, 29.2 mmol) and chlorobenzene (10.31 g, 91.2 mmol, 2.85 equiv) as reactants. The reaction was quenched by the addition of water/ice. The residue was dissolved in 3% HCl, extracted with 3×20 mL of dichloromethane, and the organic layers combined and concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:100)) yielded 4.63 g (54%) of 1,2-bis(4-chlorophenyl)ethanone as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH2:21]([NH2:24])[CH2:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[CH:7]=[C:2]([NH:24][CH2:21][CH2:22][CH3:23])[C:3]4[CH:19]=[N:18][N:17]([CH3:20])[C:4]=4[N:5]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CCCN
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CCCNc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C
Temperature: 190 °C
Yield: 11.7 %

Procedure:
A solution of 4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.04 g, 0.14 mmol) in acetonitrile (2 mL) was treated with propylamine (0.041 g, 0.7 mmol) in the presence of p-toluenesulfonic acid monohydrate (0.03 g, 0.14 mmol). The reaction mixture was heated at 190° C. in microwave for 2 h. Solvent were removed and the crude material was purified by mass directed purification to obtain 5 mg of 103 as a white solid. 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.11 (d, J=1.2, 1H), 7.63 (t, J=7.4, 2H), 7.50 (t, J=7.2, 1H), 6.72 (s, 1H), 4.04 (t, J=22.1, 3H), 3.40 (dd, J=20.2, 13.0, 2H), 1.79 (dd, J=14.5, 7.1, 2H), 1.07 (t, J=7.4, 3H). MS (ESI) m/z 307.2 (M+1)+
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1([CH2:36][NH:43][C:19](=[O:21])[CH2:18][N:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.21 g, 0.010 mole), 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), and anhydrous tetrahydrofuran (75 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of benzylamine (1.39 g, 0.013 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (50 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol-isopropyl ether, giving 2.8 g (68%). Recrystallization from isopropyl alcoholisopropyl ether gave 2.3 g of white flakes, mp 224°-225° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([C:48]1[NH:52][C:51]([C:53](O)=[O:54])=[C:50]([Cl:56])[CH:49]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:48]1[NH:52][C:51]([C:53]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=2[F:44])=[O:54])=[C:50]([Cl:56])[CH:49]=1)(=[O:47])[CH3:46]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Reaction time: 8 h
Yield: 16.4 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 5-acetyl-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0127 g, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.29 (s, 3H) 4.48 (d, J=5.36 Hz, 2H) 7.10 (s, 1H) 7.36-7.56 (m, 4H) 7.80 (s, 1H) 8.71 (t, J=5.22 Hz, 1H) 12.31 (br. s., 1H). LCMS: m/z 477.9 (M−1).
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]([Br:13])[CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:7]=2[CH:6]=[N:5]1)(=O)C>CO.Cl>[Br:13][C:10]1[CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[CH:6]=[N:5][NH:4][C:12]=2[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(Br)cc2[nH]ncc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a stirred solution of methyl 1-acetyl-6-bromo-1H-indazole-4-carboxylate (18 g, 61.0 mmol) in methanol (350 mL), 6N HCl (350 mL) was added and stirred it at 60° C. for 8 h. On completion of reaction, solvent was removed under reduced pressure then basified with saturated NaHCO3 solution till pH 8. The solid precipitate was filtered and dried under vacuum before being stirred in diethyl ether for 15 min, filtered and dried to afford methyl 6-bromo-1H-indazole-4-carboxylate (11 g, 71.7%).
Reaction SMILES: [CH:1]1([C@@:7]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[N:12]=[CH:11][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:27]1([C@@:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:8]2[N:12]=[CH:11][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:9]=2)[OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@](c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Yield: 96 %

Procedure:
Tert-butyl 4-({3-[(R)-cyclohexyl(hydroxy)phenylmethyl]-1H-1,2,4-triazol-1-yl}methyl)piperidin-1-carboxylate (Preparation 3a, 2.00 g, 4.40 mmol) was dissolved in dioxane (11 ml) and stirred vigorously to achieve solubilisation. 4M HCl in dioxane (5.54 mL, 22.1 mmol) was then added. After stirring at room temperature for 24 hours the solvent was removed in vacuo, and the residue partitioned between dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a colourless oil, in 96% yield, 1.5 g.
Reaction SMILES: [C:1]1([C@@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@@H](C)c3ccccc3)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (S)-1-phenyl-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-methyl-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[CH:8]=[C:9]([Br:26])[N:10]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nccn1COCC[Si](C)(C)C
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)cn1COCC[Si](C)(C)C
Temperature: 60 °C
Yield: 38.7 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (0.20 g, 0.74 mmol)(as prepared in the previous step) in 2 mL of CH3CN was added NBS (0.13 g, 0.74 mmol) and the mixture heated to 60° C. for 2 h. The mixture was concentrated and the title compound purified by elution from a 20-g SPE column with 20% EtOAc/hexanes to give 0.1 g (39%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H21BrN2O3Si, 349.0 (M+H). found 348.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Temperature: 38 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanone ((ii), 25.45 g, 74 mmol) and THF (4 L) was added methyl magnesium bromide (3 M, 43 mL) at 38° C. during 15 min. The mixture was stirred at 38° C. for 20 min. The RM was cooled to RT, quenched with 1M NaHCO3 and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The title compound was obtained after crystallization in DCM-TBME (1:2) as a beige solid (tR 3.30 min (conditions 1); MH+=346).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:29][CH3:30])[NH:11]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:29][CH3:30])[NH:11]1
Reactant: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a stirred solution of 80 mg (0.17 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH2Cl2 was added 1 mL (1 mmol) of 1 M boron tribromide in CH2Cl2. The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 tetrahydrofuran-EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford 77 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass Spec.: 449(M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.[CH3:12][N:13](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][C:7]=1[C:12]#[N:13]
Reactant: CC(C)c1cnc(F)c(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)c1cnc(F)c(C#N)c1
Temperature: 80 °C

Procedure:
To a mixture of 2-fluoro-3-iodo-5-isopropylpyridine and 485 mg (4.13 mmol) of Zn(CN)2 in 15 mL of DMF (degassed) was added 360 mg (0.312 mmol) of Pd(PPh3)4. The mixture was heated at 80° C. under Ar for 19 h. The mixture was diluted with EtOAc, and the organic layer was washed with 10% NH4OH (2×10 mL), H2O (3×), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% Et2O/hexanes) provided 384 mg of pure 2-fluoro-5-isopropylnicotinonitrile as a yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-phenethyl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[C@@H:24]([CH2:25]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH2:23][O:22][C:21]1([CH3:39])[CH3:38])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[C@@H:24](/[CH:25]=[CH:11]\[C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:23][O:22][C:21]1([CH3:38])[CH3:39])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CS(=O)(=O)c2nc3ccccc3s2)COC1(C)C
Reactant: O=CC1(c2ccc(Cl)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C\C2(c3ccc(Cl)cc3)CC2)COC1(C)C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a stirred, cooled (0° C.) solution of 1-(4-chloro-phenyl)-cyclopropanecarbaldehyde (0.36 g) in tetrahydrofuran (15 ml) was added under an argon atmosphere (R)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) followed by a 1 M solution of LiHMDS in THF (4.8 ml). After 1 h at 0° C. the cooling bath was removed and stirring was continued overnight. The mixture was quenched by the addition of sat. aqueous NH4Cl (15 ml) and H2O (15 ml) and extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: heptane ->heptane/EtOAc 2:1) to give (S)-4-{(Z)-2-[1-(4-chloro-phenyl)-cyclopropyl]-vinyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.72 g) as light yellow viscous oil. MS (ISP): 378.3 ([M+H]+))
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH2:10][CH3:11]>>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCCOc1ccc(B(O)O)cc1
Reactant: Clc1ccnc(Cl)n1
Product: CCCOc1ccc(-c2ccnc(Cl)n2)cc1

Procedure:
2,4 dichloropyrimidine was coupled with 4-propoxyphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 249.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].CC(O)=[O:28]>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:28])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CCC(Cc1ccccc1)C2
Reactant: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCC(Cc1ccccc1)C2=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
Compound 02-3 (22.1 g, 62 mmol) was dissolved in AcOH (200 mL). The mixture was heated to 65° C. and a solution of Na2Cr2O7-2H2O (27.2 g, 93 mmol) in hot H2O (200 mL) was added over a period of 2 min. After complete addition the mixture was stirred for 3 h at 65-67° C. and 2 h at 75° C. The mixture was allowed to cool to RT and then quenched with saturated aqueous Na2SO3 (100 mL) and diluted with H2O (1.5 L). The aqueous mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with H2O (3×400 mL), brine (400 mL) and dried over Na2SO4. After removal of the solvent in vacuo the crude product was treated with Et2O (50 mL) and filtered off to give 02-4 (9.5 g, 25 mmol, 41%) as yellow powder containing about 8% of starting material 02-3 (HPLC).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:5]=1[O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:13]2[CH2:16][CH3:17])=[CH:9][N:8]=1.Br[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>C1COCC1.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]([C:12]1[N:13]([CH2:16][CH3:17])[C:14]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([O:6][C:5]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:4]=1[F:3])[N:15]=2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34]
Reactant: CNC(=O)CBr
Reactant: CCn1c(Nc2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(N(CC(=O)NC)c2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Reaction time: 1 h
Yield: 38 %

Procedure:
Sodium hydride (60% in oil, 0.010 g, 0.25 mmol) is added to a solution of [2-(2,6-difluorophenoxy)-9-ethyl-9H-purin-8-yl]-(2-chlorophenyl)-amine, 14, (0.1 g, 0.25 mmol) in THF (3 mL). After 5 minutes at room temperature 2-bromo-N-methyl-acetamide (0.06 mL, 0.37 mmol) is added and stirring is continued for 1 hour. The mixture is diluted with H2O (25 mL) and extracted three times with EtOAc (50 mL). The combined organic layers are washed with brine, dried over MgSO4, concentrated in vacuo and the residue purified by HPLC to afford 45 mg (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 7.54-7.59 (m, 2H), 7.15-7.36 (m, 4H), 7.04 (t, J=7.8 Hz, 2H), 4.53 (s, 2H), 3.61 (q, J=7.2 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H); ESI/MS: 473 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[N:13]([CH2:14]C(O)=O)[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56])[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:35])C=C>>[CH2:1]([C:8]1[N:13]([CH2:14][C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:56])[CH2:38][C:39]([OH:41])=[O:40])=[O:35])[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Product: O=C(O)CC(NC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O)C(=O)COCc1ccccc1Cl

Procedure:
N-2-(6-Benzyl-1,2-dihydro-2-oxo-3-(3-phenylpropionyl)amino-1-pyridyl)acetyl-3-amino-5-(2-chlorobenzyloxy)-4-oxo-pentanoic acid (90) was prepared from 52b and (3S) t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chlorophenylmethoxyl)-4-oxo-pentanoate (prepared by a similar method as 82) to give a white solid: 1H NMR(DMSO-d6) δ 9.2(s, 1H), 8.75(d, 1H), 7.7-7.1(m, 14H), 6.4(d, 1H), 4.65(d, 6H), 4.56(s, 1H), 4.6-4.35(dd, 1H), 3.9(s, 2H), 2.9-2.6(m, 6H) ##STR156##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:21][CH2:22]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(O)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(OS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To 16.3 g (0.05 mol) of 1-(1-tert-butoxycarbonyl-4-piperidylacetyl)-4-hydroxypiperidine [5], 147.1 g of toluene and 6.58 g (0.065 mol) of triethylamine were added. 6.30 g (0.055 mol) of mesyl chloride was added dropwise to the mixture at a temperature in the range of 0 to 5° C. and the reaction was allowed to proceed for 2 hours at the temperature in the range. Toluene was added to the reaction mixture. Thereafter, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride, and concentrated under a reduced pressure. 70.8 g of toluene was added to the concentrated residue, and the temperature of the mixture was increased. After the residue was dissolved in toluene, filtration was carried out. Thereafter, the filtrate was cooled to room temperature and the crystals which precipitated at room temperature were collected by filtration. The resultant wet crystals were dried under a reduced pressure, whereby 17.2 g of the title compound in the state of white crystalline powder was obtained (the yield was 84.8%). The values obtained by the analysis of 1HNMR, 13CNMR and mass spectroscopy were substantially the same as those obtained in Step 5a of Example 2.