Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.[I:18]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[I:18][C:9]1[N:8]2[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][C:7]2=[N:11][CH:10]=1
Reactant: COc1cc(-c2ccccc2)cc2nccn12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccccc2)cc2ncc(I)n12

Procedure:
To a solution of 5-methoxy-7-phenylimidazo[1,2-a]pyridine (397 mg, 1.77 mmol) in acetonitrile (30 ml) was added N-iodosuccinimide (478 mg, 2.12 mmol). After 1 h the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give 3-iodo-5-methoxy-7-phenylimidazo[1,2-a]pyridine. 1H NMR (600 MHz, DMSO-d6) δ 7.86 (d, 1H); 7.83 (d, 1H); 7.52-7.53 (m, 1H); 7.48-7.45 (m, 2H); 7.38-7.40 (m, 1H); 7.33-7.35 (m, 1H); 6.61 (d, 1H); 4.10 (s, 3H). LRMS (ESI) calculated for C14H12IN2O [M+H]+, 351.0 found 350.9.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:22]1[C:31](=[O:32])[C:30]2[NH:29][C:28]([C:33]3[N:37]([CH3:38])[N:36]=[C:35]([NH2:39])[CH:34]=3)=[N:27][C:26]=2[N:25]([CH2:40][CH2:41][CH3:42])[C:23]1=[O:24])[CH2:20][CH3:21]>>[CH3:42][CH2:41][CH2:40][N:25]1[C:23](=[O:24])[N:22]([CH2:19][CH2:20][CH3:21])[C:31](=[O:32])[C:30]2[C:26]1=[N:27]/[C:28](/[N:29]=2)=[C:33]1/[CH:34]=[C:35]([NH:39][C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)=[O:18])[NH:36][N:37]/1[CH3:38]
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(N)nn3C)nc2n(CCC)c1=O
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(NC(=O)Cc3ccc(OCc4ccccc4)cc3)NN1C)N=2

Procedure:
Using 4-(benzyloxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[I-].[CH3:13][S+](C)(C)=O.CC(C)([O-])C.[K+]>ClCCl>[O:10]1[C:7]2([CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH2:13]1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: C1COC2(CCC3(CC2)CO3)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 30.0 g (192 mmol) of 1,4-cyclohexanedione monoethlene acetal in 750 ml of dichloromethane was added to a homogeneous mixture of 50.7 g (231 mmol) of trimethylsulphoxonium iodide and 25.9 g (231 mmol) of potassium tert-butoxide, and the reaction mixture was stirred at room temperature for one hour. Ice-water was added, the phases were separated, the aqueous phase was extracted repeatedly with dichloromethane and the combined organic phases were washed repeatedly with water, dried over sodium sulphate, filtered and concentrated. This gave 28.3 g (87% of theory) of the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:25])[C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C([C:33]([O:35]O)=[O:34])C=1>ClCCl.O>[CH:33]([O:35][C:11]1[CH:14]=[C:15]([Cl:25])[C:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[C:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH:10]=1)=[O:34]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(OC=O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 69.1 %

Procedure:
To a solution of 1.73 g (4.30 mmol) of 13 in 15 mL of dichloromethane under argon was added 2.03 g (6.50 mmol) of 55% m-chloroperbenzoic acid (MCPBA). After refluxing for 10 h, the solution was diluted with 30 mL of water and extracted three times with diethyl ether (50 mL each). The combined extracts were washed twice with saturated aqueous NaHCO3 (30 mL each), 30 mL of water, and 30 mL of brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using hexane as eluent to give 1.24 g (70% yield) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenyl formate. 1H NMR (CDCl3) δ 8.22 (s, 1H, CHO), 6.79 (d,J=3.2 Hz, 1H), 6.58 (d,J=3.2 Hz, 1H), 1.03 (s, 9H, t-Bu), 0.96 (s, 9H, t-Bu), 0.22 (s, 6H, Me), 0.19 (s, 6H, Me); 13C NMR (CDCl3) δ 159.0 (s, C═O), 148.8 (s), 143.0 (s), 142.4 (s), 127.1 (s), 115.5 (d), 113.1 (d), 26.2 (q, 6C, t-Bu), 18.8 (s, 2C, t-Bu), −3.3 (q, 2C, Me), −3.6 (q, 2C, Me).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9]C)[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)N[O:68][CH3:69])C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][O:68][CH3:69])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:46][C:47]([CH3:52])([CH3:53])[C:48]([CH3:50])([CH3:51])[O:49]5)[CH:42]=[N:41]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NOC)n2)c(OC)c1
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NOC)n2)c(OC)c1)OCCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Racemic Compound 46A was prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methoxycarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound KS11B, 50.0 mg, 0.0787 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 20.8 mg, 0.0826 mmol) to afford 45 mg of the desired material (28%). MS (ESI): m/z=869.25/871.23 [M+H]+. UPLC: tR=1.48 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:18](Cl)([CH3:21])([CH3:20])[CH3:19].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:18]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Cl
Reactant: Cc1ccc2ccc3cccc4ccc1c2c34
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2ccc3cc(C(C)(C)C)cc4ccc1c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Next, a mixed solution of 4.4 g of 1-methylpyrene, 2 g of t-butylchloride and 33 ml of dichloromethane was cooled to 0° C. under a nitrogen gas stream and then 2.7 g of aluminum chloride was added. This mixed solution was stirred at room temperature for 3 hours and 30 ml of water was poured into the solution, followed by extraction with 30 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 3 g of 7-t-butyl-1-methylpyrene.
Reaction SMILES: [H-].[Na+:2].[O:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH:9](OCC)=[O:10]>CCCCCC.CCOCC>[O:8]=[C:4]1[C:5](=[CH:9][O-:10])[CH2:6][CH2:7][O:3]1.[Na+:2]
Reactant: CCOC=O
Reactant: O=C1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C1OCCC1=C[O-]
Reaction time: 1 h
Yield: 102.9 %

Procedure:
Three-neck, round-bottomed flask equipped with mechanical stirrer, addition funnel, and reflux condenser was placed in a hood behind a shield. The condenser was fitted with a drying tube which was connected to a mineral oil bubble chamber so hydrogen evolution could be monitored. After NaH (4.4 g of 60% oil dispersion, 0.11 mol) was washed with n-C6H14 (2×50 mL), filtered with brief suction drying, and transferred to the flask, sufficient Et2O was added to cover the resulting solid. A catalytic amount of C2H5OH (ca. 2 drops) was added directly to the Et2O—NaH suspension and dropwise addition without stirring of a solution of dihydrofuran-2(3H)-one (8.61 g, 0.1 mol) and ethyl formate (7.41 g, 0.1 mol) in Et2O (10 mL) was started. As soon as the Et2O began to reflux, additional Et2O (50-60 mL) was rapidly added through the reflux condenser and stirring was started. Lactone-formate addition was complete in 1 hr, and stirring was continued for an additional 22 h. Filtration, washing with Et2O, and vacuum drying gave desired product (14.0 g) as a fine powdery solid.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:29][NH2:30]>O>[CH3:29][NH:30][C:19](=[O:21])[CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)NC
Temperature: 80 °C

Procedure:
A mixture of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.24 g, 16.5 mmol, prepared in Parts A and B of Example 16), THF (15 mL), and methylamine (available as a 40% solution in water, 8 mL) was scaled in a high-pressure vessel, heated at 80° C. overnight, and concentrated under reduced pressure to provide 4.7 g of N-methyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[C:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:18].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][C:17]#[N:18])=[CH:21][CH:22]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reaction time: 8 h

Procedure:
A suspension composed of 1.15 g (4.77 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 1.00 g (6.21 mmol) of [4-(cyanomethyl)phenyl]-boronic acid, 1.3 g (7.15 mmol) of copper(II) acetate, 1.16 ml (14.31 mmol) of pyridine and about 500 mg of 4 Å molecular sieve in 200 ml of methylene chloride is stirred overnight. The reaction mixture is diluted by adding a further 100 ml of methylene chloride and the suspension is filtered. The filtrate is concentrated and then directly placed on a silica column which is eluted with a methylene chloride/methanol 99/1 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in a small amount of ethyl ether. After filtering off the solid, the title product is obtained in the form of beige powder.
Reaction SMILES: COC1C=C([N+]([O-])=O)C=CC=1O.[OH:13][C:14]([CH3:34])([CH3:33])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][NH:26][C:25](=O)[C:24]2=[O:30])=[CH:19][C:18]=1[O:31][CH3:32].C(N(C(C)C)C(C)C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[N:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][CH2:84][SH:85]>CN(C=O)C>[OH:13][C:14]([CH3:34])([CH3:33])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:85][CH2:84][CH2:83][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][N:77]=3)[C:24]2=[O:30])=[CH:19][C:18]=1[O:31][CH3:32]
Reactant: COc1cc(-n2cc[nH]c(=O)c2=O)ccc1OCC(C)(C)O
Reactant: SCCc1ccccn1
Agent: COc1cc([N+](=O)[O-])ccc1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2ccnc(SCCc3ccccn3)c2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Yield: 68 %

Procedure:
Following the procedures described in parts A-D of example 134, 2-methoxy-4-nitrophenol was converted to 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrazine-2,3(1H,4H)-dione. A solution of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrazine-2,3(1H,4H)-dione prepared in Part ? (2.28 g, 7.44 mmol), EtN(iPr)2 (3.9 mL, 22.3 mmol), PyBOP (6.78 g, 13.0 mmol) in DMF (35 mL) was stirred at ambient temperature for 1.5 h. After addition of 2-pyridylethyl mercaptan (1.24 g, 8.93 mmol), the reaction was stirred at ambient temperature. After stirring overnight the reaction mixture was partially concentrated under reduced pressure, quenching by addition of aq. NaHCO3 and extracted with EtOAc. The EtOAc extracts were washed with brine, dried over MgSO4 and concentrated. Chromatography on silica employing a gradient elution with 2.5-10% methanol/methylene chloride, followed by chromatography on silica eluting with EtOAc, and trituration with EtOAc/Hexanes afforded the desired product 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one (2.15 g, 68% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([Br:11])[CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[C:6]([Br:11])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(Br)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)c(Br)c1
Temperature: 80 °C

Procedure:
The crude 3-bromo-4-fluorobenzoic acid methyl ester is dissolved in 120 mL of N,N-dimethylformamide, 4.32 g (43.1 mmol, 2 eq.) of N-methylpiperazine and 4.46 g (32.3 mmol, 1.5 eq.) of potassium carbonate were added and the reaction mixture heated at 80° C. for 8 hours. The mixture was poured into 300 mL of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:38])[C@@H:25](/[CH:26]=[C:27](\[Br:34])/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([OH:37])=[O:36].[C:39]([C@@H:41](O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:43]=1)#[N:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:23]1([CH3:22])[C@@H:25](/[CH:26]=[C:27](\[Br:34])/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([O:37][C@H:41]([C:39]#[N:40])[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:43]=1)=[O:36]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
0.9 ml of pyridine and 2.1 g of dicyclohexylcarbodiimide were added to a solution of 2.9 g of the product of Step B in 40 ml of methylene chloride and the mixture was stirred for 15 minutes. A solution of 2.5 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 15 ml of methylene chloride and then 25 mg of 4-dimethylamino-pyridine were added to the reaction mixture which was stirred for 2 hours and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 4.26 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-2-propoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate melting at 64° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=2[CH3:26])=[O:19])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=2[CH3:27])=[O:19])[CH2:12][CH2:13]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:46](=[O:48])[CH3:47])=[CH:31][CH:30]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of the above phenol (45 mg, 0.087 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 138 as a white solid (43 mg, 80%) following work-up and purification. 1H NMR (CDCl3) δ 0.82-1.12 (m, 5H), 1.54-1.58 (m, 1H), 1.76-1.79 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.25 (s, 3H), 2.51 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.74-2.86 (m, 3H), 3.30-3.36 (m, 1H), 3.56-3.62 (m, 1H), 3.82-3.87 (m, 1H), 3.89 (s, 2H), 6.53 (d, 2H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 7.41-7.46 (m, 1H), 7.52-7.55 (m, 3H), 8.60 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 12.37, 20.06, 20.93, 28.06, 29.26, 29.75, 38.92, 42.58, 47.57, 50.96, 55.43, 59.14, 111.59, 113.16, 117.91, 121.16, 128.32, 128.89, 129.64, 129.83, 129.94, 140.71, 141.26, 145.13, 156.53, 162.07, 165.32, 169.07. ES-MS m/z 555 (M+H). Anal. Calcd. for C32H38N6O3.0.8CH2Cl2: C, 63.27; H, 6.41; N, 13.50. Found. C; 63.46; H, 6.39; N, 13.29.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: Clc1cccc(Oc2cncc(Cl)n2)c1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(Nc2cncc(Oc3cccc(Cl)c3)n2)cc(OC)c1OC
Yield: 43 %

Procedure:
Using Method EE with 2-chloro-6-(3-chlorophenyloxy)-pyrazine (200 mg, 0.83 mmol) and 3,4,5-trimethoxyaniline (183 mg, 1.00 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (165 mg). Yield: 43%. 1H NMR (250 MHz, DMSO-d6) δ 3.43 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.76 (s, 2H, Harom2′+6′), 7.18 (d, 1H, Harom 4, J=6.5 Hz), 7.28 (d, 1H, Harom 6, J=6.7 Hz), 7.36 (s, 1H, Harom 2), 7.43 (t, 1H, Harom 5, J=8.1 Hz), 7.79 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.62 (s, 1H, NH).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>C1COCC1>[C:16]1([CH:14]([C:11]2[S:10][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:13][CH:12]=2)[OH:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cnc(C#Cc2ccccc2)s1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)c1cnc(C#Cc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenylethynyl-thiazole-5-carbaldehyde (Example 205, 197 mg, 0.924 mmol) in THF (5.0 mL) was cooled at 0° C. and treated with a 3.0 M solution of phenyl magnesium bromide in Ether (340 μL, 1.0 mmol). After stirring for about 30 minutes at 0° C., the reaction was quenched with saturated aqueous ammonium chloride (25 mL), diluted with EtOAc (25 mL), transferred to a 125-mL separatory funnel and extracted. The layers were separated and the aqueous layer was extracted again with EtOAc (25 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with 25% EtOAc in hexanes to afford the titled compound, pPhenyl-(2-phenylethynyl-thiazol-5-yl)-methanol (190 mg, 71%), as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:18])[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
(a-1) To a stirred solution of 16 parts of phenyl (3-amino-4-nitrophenyl) methanone in 195 parts of dichloromethane were added 7.8 parts of acetyl chloride. After stirring for 17 hours at room temperature, the reaction mixture was evaporated. The residue was crystallized from a mixture of ethyl acetate and 2,2'-oxybispropane. The product was filtered off and dried, yielding 15 parts (81%) of N-(5-benzoyl-2-nitrophenyl)acetamide; mp. 97.8° C. (int. 48).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Cl)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N+](C1C=CC=CC=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].N[C:39]1[C:52]2[C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44](=[O:54])[C:43]=2[CH:42]=[C:41](Cl)[CH:40]=1>>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:42]4[C:43]5[C:44]([C:45]6[C:50]([C:51](=[O:53])[C:52]=5[CH:39]=[CH:40][CH:41]=4)=[CH:49][CH:48]=[CH:47][CH:46]=6)=[O:54])[C:15]=3[C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[O:17]
Reactant: Nc1cc(Cl)cc2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(Cl)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21

Procedure:
21 g of 6-chloro-2-(4-diphenyl)-anthrapyrimidine (obtained by reacting 1-amino-4-chloroanthraquinone with diphenyl-4-carboxylic acid N-methylamide in the presence of thionyl chloride (in accordance with D.R.P. 566,474)) are condensed, in accordance with Example 1, in 250 parts of nitrobenzene in the presence of 7.5 parts of sodium carbonate and 0.25 part of copper-1 chloride with 13.5 parts of 1-amino-3-chloroanthraquinone. 28 parts are obtained of the anthrimide of the formula ##SPC9##
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:33](=[O:34])[CH2:32][C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:27][CH:28]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-phenoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31 (dd, J=7.9, 0.7, 1H), 8.03 (d, J=7.7, 1H), 8.02-7.96 (m, 1H), 7.95-7.87 (m, 1H), 7.46-7.36 (m, 4H), 7.20-7.12 (m, 1H), 7.05-6.97 (m, 4H), 3.88-3.78 (m, 4H), 3.67 (s, 2H), 3.13-3.05 (m, 4H); MS (ESI−) M/Z 455 (M−H)−.