Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[K].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[OH:25]>CS(C)=O.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([O:25][C:18]2[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][C:19]=2[Cl:24])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([O-:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2c(Cl)cc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A stirred solution of methyl 5-chloro-2-nitro-benzoate (17.0 g., 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90°C for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3 × 100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2 × 30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101°-103°C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 97 %

Procedure:
Method 1 was followed using 3-fluoro-4-nitrotoluene (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (2.0 eq) at 55° C. for 48 hours yielding tert-butyl 4-(5-methyl-2-nitrophenyl)piperazine-1-carboxylate (97%). LCMS (m/z): 322.1 (MH+); LC Rt=3.43 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH3:17])[C:10]=1[CH3:18])=[O:5])[CH3:2].B(Br)(Br)Br.CCO.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:17])[C:10]=1[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(C)c1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
2-(4-Methoxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.32 g, 1.29 mmol) obtained in Step B was dissolved in DCM (5 mL), and the reactant was cooled to 0˜5° C. BBr3 solution (3.90 mL, 3.87 mmol, 1M/DCM) was added dropwise thereto, and the mixture was stirred at 0˜5° C. for 2 hours. After the termination of the reaction, EtOH and saturated sodium bicarbonate solution were added thereto in turn, and the mixture was stirred. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.24 g, 79%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:7]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(C(=O)OC(C)C)c1
Reaction time: 0.08 h
Yield: 76 %

Procedure:
(Intermediate 136, 0.6 g, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) was treated with a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (4.6 mL, 4.6 mmol) and the resulting reaction mixture was stirred in an ice bath for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was purified by flash column chromatography using 5%-30% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.33 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[N:26]=[C:25]([NH2:36])[N:24]=1)[CH2:19][NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>C(#N)C>[NH2:36][C:25]1[N:24]=[C:23]([C:22]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:10])[CH2:19]3)=[CH:14][C:13]=2[CH3:12])[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[N:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CN(C(=O)Nc1ccc(Cl)cc1)CC2
Reaction time: 0.5 h

Procedure:
1-Chloro-4-isocyanatobenzene (4.1 mg, 0.026 mmol) was added to a mixture of 4-(6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (15 uL, 0.11 mmol) in acetonitrile (0.3 mL). After 30 min., the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=492.2/494.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5].[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH2:4][NH:5][C:11]([CH3:12])=[N:1]2
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NCc1c(N)cccc1F
Solvent: CCO
Product: CC1=Nc2cccc(F)c2CN1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A solution of 2-amino-6-fluorobenzylamine (1.1 g, 7.86 mmol) and triethylorthoacetate (1.58 mL, 8.64 mmol) in ethanol (30 mL) was heated at 80° C. for 14 h. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo. The yellow oil was triturated with diethyl ether to give the title compound as white solid (0.74 g, 57%). Mass spectrum (API+): Found 165 (MH+). C9H9N2F requires 164.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:13])[CH:9]=[C:10]([OH:12])[CH:11]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:16][NH:17][C:18](=[O:19])[O:12][C:10]1[CH:9]=[C:8]([CH3:13])[CH:7]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:11]=1
Reactant: COC(COc1cc(C)cc(O)c1)OC
Reactant: CN=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cc(C)cc(OCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,2-Dimethoxyethoxy)-5-hydroxytoluene (2.50 grams), benzene (50 ml) and triethylamine (4 drops) were charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (1.0 ml) was added to the vessel, and the resulting mixture was stirred at room temperature for a period of about 2 hours. The mixture was then allowed to stand at ambient temperature over the weekend. After this time the reaction mixture was stripped of benzene, leaving a viscous liquid residue. This residue was distilled under vacuum to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-methylphenyl] N-methylcarbamate as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[C:10]([NH:12][CH3:13])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[NH2:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CNC(=O)c1cc(N)cc(N2CCOCC2)c1

Procedure:
A solution of 3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide (Example 86d; 300 mg, 1.12 mmol) in ethanol (20 mL) is hydrogenated at atmospheric pressure over Raney nickel (0.2 g) at 25° C. The calculated amount of hydrogen is taken up in 19 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate to give the title compound as a beige crystalline solid, m.p. 201–204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10].[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[C:26](O)=[O:27])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:12]([NH:11][C:9](=[O:10])[NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:33]([CH3:34])([CH3:35])[CH3:36])[C:31]([OH:32])=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNC(=O)Nc1cnccc1N
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1cnccc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 15.6 %

Procedure:
A mixture of 1-(4-amino-3-pyridyl)-3-heptylurea (0.50 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.60 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (0.46 g) was stirred in dichloromethane (10 ml) at room temperature overnight. The reaction solution was washed with water, saturated saline and dried over anhydrous MgSO4. The solvent was distilled off and the residue was purified by a silica gel column chromatography (chloroform:methanol=20:1) to give N-[3-(3-heptylureido)-4-pyridyl]-3,5-di-t-butyl-4-hydroxybenzamide (0.15 g, 16%) as crystals.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1>CCO>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: C1CNCCNC1
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCO
Product: c1cc(CN2CCCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved in anhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution of homopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and a solution of 4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) in EtOH (40 mL) was added. The reaction mixture was heated to reflux for 16 h, cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with CH2Cl2 (300 mL) and was washed with 2N KOH (1×300 mL). The aqueous layer was extracted with CH2Cl2 (1×300 mL) and the organic phase was washed with 2N KOH (150 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 5% H2O-5% NH4OH—1PrOH) afforded the desired product (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC Rf 0.45 (5% H2O-5% NH4OH—1PrOH): 1H NMR (CDCl3, 300 MHz) δ 8.77 (d, J=5.9 Hz, 2H), 7.53 (d, J=5.7 Hz, 2H), 3.91 (s, 2H), 3,19 (m, 4H), 2.92 (m, 4H), 2.04 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: COc1cccc(COc2ccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)cc2)c1
Yield: 53.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3-methoxy-benzyl bromide (120 mg, 0.6 mmol) to afford the title product (110 mg, 53% yield); LCMS; 100% APCI+, Calcd: 413.56. Found m/z: 414.29 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 3.82 (s, 3H), 4.02-4.18 (m 2H), 4.99 (s, 2H), 6.82-6.90 (m, 5H), 6.96-7.05 (m, 2H), 7.26-7.30 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Cl.[Cl:24][C:25]1[N:29]([CH3:30])[C:28]([CH2:31]Cl)=[N:27][CH:26]=1.BrCC1CCCCO1>>[Cl:24][C:25]1[N:29]([CH3:30])[C:28]([CH2:31][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:27][CH:26]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cn1c(Cl)cnc1CCl
Agent: BrCC1CCCCO1
Agent: Cl
Product: Cn1c(Cl)cnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (94%) as a colorless solid: mp 91-95° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.39 (d, J=7.8 Hz, 1H), 7.27 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.14 (dd, J=7.2, 0.9 Hz, 1H), 7.05 (ddd, J=7.4, 7.4, 0.8 Hz, 1H), 6.94 (s, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.12 (d, J=15.6 Hz, 1H), 4.93 (d, J=15.6 Hz, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.4, 144.8, 141.9, 141.7, 138.5, 131.6, 129.3, 124.8, 124.0, 123.8, 120.7, 119.5, 111.5, 110.7, 99.6, 80.3, 64.6, 64.0, 58.1, 38.2, 31.0; MS (ES+) m/z 426.2 (M+1), 424.2 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)#[CH:17]>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.[Cu]I.C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#Cc1ccc(N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 354.1 %

Procedure:
1,4-Diiodobenzene (4.95 g, 1.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.07 g, 0.10 mmol), copper(I) iodide (0.019 g, 0.10 mmol), triethylamine (5 mL), THF (10 mL) and 4-ethynylaniline 0.585 g, 5.00 mmol) were used following the general procedure for couplings. For the synthesis of 4-ethynylaniline, please see Tour et al. Chem. Eur. J. 2001, vol. 7, pp. 5118-5134 incorporated herein by reference. The tube was capped and stirred room temperature for 12 h. Flash column chromatography (CH2Cl2—hexanes as eluent) afforded the desired product as light yellow needles (1.13 g, 71% yield). IR (KBr) 3441, 3356, 2210, 1612, 1515, 1281, 1135, 1003, 842, 811, 512 cm−1. 1H NMR (400 MHz, CDCl3)δ7.650 (m, AA′ part of AA′XX′ pattern, J=8.7, 2.4, 1.8, 0.7 Hz, 2H), 7.324 (m, XX′ part of AA′XX′ pattern, J=8.7, 2.4, 1.8, 0.7 Hz, 2H), 7.208 (m, AA′ part of AA′XX′ pattern, J=8.6, 2.4, 1.8, 0.6 Hz, 2H), 6.630 (m, XX′ part of AA′XX′ pattern, J=8.6, 2.4, 1.8, 0.6 Hz, 2H), 3.833 (s, 2H). 13C NMR (100 MHz, CDCl3) δ147.05, 137.60, 133.20, 133.07, 123.67, 114.95, 112.39, 93.45, 91.83, 86.69.
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[C:11]1=[O:23])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)(=[O:27])=[O:26].S1C=CC=C1B(O)O>>[OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25]([CH3:24])(=[O:27])=[O:26])=[CH:18][CH:17]=2)[C:11]1=[O:23])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(I)cc2)C1=O
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: OB(O)c1cccs1
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(-c3ccccc3S(C)(=O)=O)cc2)C1=O
Yield: 79.8 %

Procedure:
According to the Step 22-1 in synthetic method for EXAMPLE 22, compound 105-1 (0.12 g) and 2-methylsulfonylphenylboronic acid (0.11 g) were used instead of 14-4 and 2-thiopheneboronic acid to obtain compound 105-2 (102 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Clc1ccc(I)cn1
Reactant: OB(O)c1ccccc1
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: O
Solvent: COCCOC
Product: Clc1ccc(-c2ccccc2)cn1
Yield: 70.5 %

Procedure:
A mixture of 2-chloro-5-iodopyridine (5.0 g, 20.9 mmol), phenylboronic acid (2.6 g, 20.9 mmol), Pd(Ph3P)4 (1.45 g 1.25 mmol), sodium carbonate (6.64 g, 62.6 mmol), DME (20 mL) and water (5 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then vacuum distilled to give 2-chloro-5-phenylpyridine (2.79 g, 14.71 mmol (70.5% yield).
Reaction SMILES: [N:1]1([CH2:5][C@@H:6]([NH2:10])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[CH3:12].[Na].O>C(Cl)Cl>[N:1]1([CH2:5][C@@H:6]([NH:10][CH2:11][CH3:12])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[C@H](N)CN1CCC1
Reactant: CC=O
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CCN[C@H](CN1CCC1)C(C)C
Yield: 19.9 %

Procedure:
(S)-1-(Azetidin-1-yl)-3-methylbutan-2-amine (Compound U) (0.420 g, 2.95 mmol) and acetaldehyde (0.166 mL, 2.95 mmol) was mixed in DCM (10 mL). Sodium triacetoxyhydroborate (0.813 g, 3.84 mmol) was added in small portions and the resultant mixture was stirred at rt for 5 h. Water was added and the pH was adjusted to pH9. The water phase was extracted with DCM (4×50 mL). The combined organic layers were combined and washed with brine, passed through phase separator and evaporated under reduced pressure to give the title compound (0.1 g, 20%). The obtained crude product was used without further purification. LCMS (M+H)+: 171.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([OH:37])[CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[C:44](Cl)(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:44](=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:21][C:22]([CH3:35])([CH3:36])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1ccc(COC(=O)C(C)(C)CC(O)COC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate (20.6 g, 40 mmol), Pyridine (31.6 g, 400 mmol) in CH2Cl2 (500 mL) at 0° C., was added dropwise a solution of stearoyl chloride (18.2 g, 60 mmol) in CH2Cl2 (100 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was extracted with a 10% aqueous solution of NaHCO2 (300 mL) and the aqueous phase was washed with CH2Cl2 (200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1→5% MeOH in CH2Cl2), to give 27.2 g of 4-metoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2C(=C(OS(C(F)(F)F)(=O)=O)N(C3C=CC=C(C(F)(F)F)C=3)N=2)CC1)=O)(C)(C)C.C1(B(O)O)C=CC=CC=1>>[C:28]1([C:12]2[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(C(F)(F)F)c3)c(-c3ccccc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(C(F)(F)F)c3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Agent: OB(O)c1ccccc1
Product: FC(F)(F)c1cccc(-n2nc3c(c2-c2ccccc2)CCNCC3)c1

Procedure:
3-Phenyl-2-(3-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The desired compound (172.0 mg) was prepared from 279.1 of mg of 3-trifluoromethanesulfonyloxy-2-(3-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made from (3-trifluoromethyl-phenyl)-hydrazine as in Example 176, Steps A and B) and 0.21 g of phenylboronic acid, as described in Example 177, Step C. MS (ESI): exact mass calculated for C25H26F3N3O2, 457.20. found, m/z 458.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28].N1C=CN=C1.CN(C)C=O>O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH2:2][O:1][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[O:12][C:13]=1[CH3:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
A mixture of 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (0.40 g), triisopropylsilyl chloride (0.75 g), imidazole (0.27 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile as a colorless oil (0.53 g, yield 95%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).