Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-])=O)=[O:10])[CH3:2]>[Pd].C1COCC1>[NH2:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][O:7][C:6]1[CH:22]=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1
Reactant: CCOc1cccc(OCC(=O)Nc2ccc(O)cc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1cccc(OCC(=O)Nc2ccc(O)cc2N)c1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A 2 L hydrogenation vessel was charged with phenol 63b (12.1 g, 36.4 mmol) and THF (240 mL). To the resultant solution was added 10% Pd/C (1.2 g), and the mixture was hydrogenated at 49 psi for 2 hr. The catalyst was filtered off on glass fiber paper, and concentrated to a red oil. The crude oil crystallized with CH2Cl2 and was triturated with CH2Cl2:hexanes 1:1 (100 mL). The crystals were filtered, pressed with rubber dam, and rinsed with CH2Cl2:hexanes 1:1 (2×20 mL). The crystals were dried to give 10.1 g of 64 as yellow crystals (92%). HPLC analysis (10:10:80 H2O:A1:MeOH) showed a purity of greater than 99% with a retention time of 3.1 min.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (0.67 g, 2.01 mmol) in DCM (25 ml), were sequentially added triethylamine (0.84 ml, 6.04 mmol) and benzoyl chloride (0.28 ml, 2.42 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The crude was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-phenylacetate (310 mg; 42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12]C(C)([O-])C.[K+].CI>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 66 %

Procedure:
In a round-bottomed flask, 6-chloro-3-iodo-1H-indazole (167 mg, 0.57 mmol) was dissolved in THF (2 ml) and the solution was cooled to 0° C. Potassium tert-butoxide (90 mg, 0.80 mmol) was added and the reaction mixture was stirred at 0° C. for 1.25 h. Methyl iodide (0.045 ml, 0.72 mmol) was added dropwise then the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (gradient 0-5% EtOAc) to afford 110 mg (63%) of 6-chloro-3-iodo-1-methyl-1H-indazole as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3C(OC(C)(C)C)=O)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:8]3[CH:9]=[C:10]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc2c(N)ncnn12
Product: Nc1ncnn2c(C3CCCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12

Procedure:
Following the procedure described in Steps 3-5 (bromination, coupling, deprotection) of Example 1, the title compound was prepared using tert-butyl 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate and Intermediate C. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1 H), 7.85 (s, 1 H), 7.81 (d, 1 H), 7.64 (s, 1 H), 7.27-7.41 (m, 5 H), 7.22 (dd, 1 H), 6.73 (s, 1 H), 5.65 (s, 2 H), 4.27 (dd, 1 H), 3.08-3.18 (m, 1 H), 2.79-2.90 (m, 1 H), 1.51-2.14 (m, 6 H); ES-MS m/z 424.42 [M+H]+, HPLC RT (min) 2.14.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]([N:9]1[CH2:12][C@H:11]([NH2:13])[C:10]1=[O:14])=[O:8])(=[O:5])=[O:4].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[K+]>C(#N)C.C(N(CC)CC)C>[CH3:2][S:3]([NH:6][C:7]([N:9]1[CH2:12][C@H:11]([NH:13][C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:14])=[O:8])(=[O:4])=[O:5]
Reactant: CS(=O)(=O)NC(=O)N1C[C@H](N)C1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)NC(=O)N1C[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 5 °C
Reaction time: 3 h

Procedure:
(S)-N-Methylsulfonyl)-2-oxo-3-amino-1-azetidinecarboxamide, hydrochloride salt (189 mg; see example 6) was suspended in 8 ml of dry acetonitrile and 0.54 ml of triethylamine, and stirred at room temperature under nitrogen until solution occurred (about 15 minutes). The solution was cooled to 0°to 5° C., and then phenyl acetylchloride (153 μl) was added. The reaction was stirred at room temperature for 3 hours and then poured into 10 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer. The pH was adjusted to 7 (dilute potassium hydroxide) and the solution was extracted twice with ethyl acetate. The aqueous layer was covered with fresh ethyl acetate, and the pH was adjusted to 2 (3N hydrochloric acid). Repeated extraction with ethyl acetate gave an acidic ethyl acetate extract, which was dried (sodium sulfate) and evaporated to a residue (196 mg). Chromatography of this material on 20 g of SilicAR CC-4 using ethyl acetate/dichloromethane (1:1) provides 96 mg of crystalline product after removal of solvent. Recrystallization from ethyl acetate/dichloromethane provides an analytical sample having a melting point 168°-170° C., dec.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][C:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:60]2[CH2:65][CH2:64]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([O:24][C:22]([NH:21][C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16][N:11]([C:9]2[C:10]3[C:2]([CH:64]4[CH2:65][CH2:60]4)=[CH:3][N:4]([S:29]([C:32]4[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:12][CH2:13]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(C2CC2)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 218 %

Procedure:
Methyl 1-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (Intermediate 62) (1.1 g, 1.81 mmol), potassium phosphate tribasic (1.343 g, 6.33 mmol), tricyclohexyl phosphine (0.101 g, 0.36 mmol) and cyclopropylboronic acid (0.438 g, 4.34 mmol) were taken up in toluene (10 mL) and water (0.400 mL). The mixture was purged with nitrogen for 30 minutes then palladium(II) acetate (0.041 g, 0.18 mmol) was added. The mixture was heated to 75° C. for 6 hours and then allowed to cool and stir at room temperature overnight. The reaction mixture was diluted with EtOAc (75 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (0.447 g, 43.4%) as a cream solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C(O)(=O)C.C(O)(=O)C.[CH:65]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH:68]=[CH:67][C:66]=1[Bi](C1C=CC2C(=CC=CC=2)C=1)C1C=CC2C(=CC=CC=2)C=1.C(O)(=O)C.C(=O)(O)O.C1C2C(=CC=CC=2)C=CC=1[Bi](C1C=CC2C(=CC=CC=2)C=1)C1C=CC2C(=CC=CC=2)C=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:67]3[CH:66]=[CH:65][C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)[CH:68]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: c1ccc2cc([Bi](c3ccc4ccccc4c3)c3ccc4ccccc4c3)ccc2c1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol, 1 eq) and Cu(OAc)2 (6 mg, 0.033 mmol, 0.17 eq) in CH2Cl2 (2.5 mL) in a round bottom flask equipped with a magnetic stir-bar was added tri(2-naphthyl)bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.075 ml, 1.31 mmol, 6.9 eq) to a suspension of tri(2-naphthyl)bismuth carbonate in CH2Cl2 (2.5 ml)]. The reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. After 4 hours the heating was discontinued and the mixture stirred at room temperature for 16 hours. The mixture was then diluted with saturated aqueous NaHCO3 and extracted 2 times with CH2Cl2. The extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (3:1 hexanes/acetone) to afford 32 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone. (1H NMR, 13C NMR, and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH:20]([C:30]3[C:31](=[O:37])[NH:32][C:33](=[O:36])[NH:34][CH:35]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:34]2[CH:35]=[C:30]([CH:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:25]=4[CH:24]=[CH:23][C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]3=4)[C:31](=[O:37])[NH:32][C:33]2=[O:36])[CH:5]=[CH:4][N:3]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(-c2ccnc(Cl)n2)cc1C1c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 2,4-dichloropyrimidine (1.49 g), cesium carbonate (3.26 g) and the product of example 1 step (iv) (3 g) in dimethylsulphoxide (40 ml) was stirred at room temperature for 3 hours and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The product was collected after trituration with 50% ethyl acetate in isohexane. Yield 2.55 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[I-].[K+].Br[CH:22]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24]>CO.C1C=CC=CC=1>[C:11]([C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[O:15][CH:22]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 5.16 g of 3,5-di-tert-butylphenol 1.188 g of sodium methoxide, and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The solution is heated at reflux overnight and worked up as described in Example 70 to yield a yellos oil which is purified by chromatography on 100 of silica gel (benzene, 400 ml) and pumped in vacuo at 120° C. (0.05 mm) to yield a yellow glass.
Reaction SMILES: ClC1C=C(C=CC=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[CH3:83][O:84][C:85]1[N:90]=[C:89]([O:91][CH3:92])[C:88](B(O)O)=[CH:87][N:86]=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[CH:9]=[C:8]([O:39][CH3:40])[CH:7]=[CH:6][C:5]=2[C:88]2[C:89]([O:91][CH3:92])=[N:90][C:85]([O:84][CH3:83])=[N:86][CH:87]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2cnc(OC)nc2OC)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 7 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 2,4-dimethoxypyrimidine-5-boronic acid (34 mg, 0.2625 mmol) to produce the title compound (8 mg, 7% yield).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Br[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu](I)I>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: Brc1nc2ccccc2s1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN1c1nc2ccccc2s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 28 mg (0.24 mmol) of L-Proline in N,N-dimethylformamide (3 mL) at ambient temperature was added 51 mg (0.24 mmol) of 2-bromobenzothiazole, 100 mg (0.72 mmol) of potassium carbonate, and 6 mg (0.03 mmol) of copper iodide. The reaction mixture was stirred at 100° C. overnight. It was then filtered and purified by reverse-phase HPLC (TMC Pro-Pac C18; 0-60% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give 35 mg 60% of the title compound as a light brown solid. 1H NMR (DMSO-d6): δ 7.78 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 4.48 (d, J=7.3 Hz, 1H), 3.52-3.61 (m, 2H), 2.37 (m, 1H), 2.01-2.11 (m, 3H). LC/MS 249.3 (M+1)
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:29][NH:30][O:31][CH3:32]>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25](=[O:27])[N:30]([O:31][CH3:32])[CH3:29])[CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
Add portionwise 1,1′-carbonyldiimidazole (4.14 g, 25.6 mmol) to a solution of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (5.0 g, 23.2 mmol) in dichloromethane (77 mL) at RT. Allow the mixture to stir for 15 min. Add slowly N,O-dimethylhydroxylamine hydrochloride (2.7 g, 27.9 mmol). Stir the reaction mixture at RT overnight. Dilute the mixture with dichloromethane (200 mL), wash with water (2×300 mL), brine (200 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatograph, eluting with 50-100% ethylacetate/hexane to give 5.36 g (89%) of the title compound. LC-MS/ES m/z 203.0 [M−tertBu+H]+.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([C:5]([O:7]CC)=O)=[O:4].[Na:14].[N+:15]([CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:17])=[O:16]>O1CCCC1.C(Cl)Cl>[C:1]([CH:2]1[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:18]([N+:15]([O-:17])=[O:16])[C:5](=[O:7])[C:3]1=[O:4])([O:11][CH2:12][CH3:13])=[O:10].[Na:14]
Reactant: CCCCCCCCCCCC=C[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCC1C(C(=O)OCC)C(=O)C(=O)C1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 4 h

Procedure:
A suspension of 90% sodium diethyl oxalacetate (17.77 g., 76.1 mmol) in tetrahydrofuran (75 ml) was treated dropwise over a 15 minute period with a solution of 1-nitro-1-tridecene (17.30 g., 76.1 mmol) in methylene chloride (about 100 ml). After a complete solution was obtained the reaction mixture was heated in an 80°-90° C. oil bath and the solvent allowed to distill through a 10 cm vigreux column until the boiling point of the distillate reached 63° C. (100-120 ml of the solvent had distilled). Heating at reflux was continued, with no further distillations, for four hours and 150 ml of distilled water were added over a 5 minute period. The reaction mixture was allowed to cool to 30° C. and then cooled in an ice bath to 10° C. A precipitate began to form when the internal temperature reached about 35° C. and the mixture was stirred for one hour at 10° C. before the precipitate was collected by filtration. The solid was washed three times with 100 ml of isopropanol and then dried under vacuum over phosphorous pentoxide. About 23 g. of 3-carbethoxy-5-nitro-4-undecyl-1,2-cyclopentanedione, sodium salt, m.p. 166°-169° C. (dec) were obtained.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH3:15]O.Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH3:15])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1

Procedure:
Ferulic acid (4.85 g) and then methyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for 1 hour. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound. The product was crystallized from n-hexane to obtain a white crystal (5.09 g; 97.9%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[N:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C:6]([CH2:4][OH:3])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(Cc2cccc(OC)c2)c2cc(OC)c(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Yield: 84.5 %

Procedure:
The above 1-(3-methoxybenzyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (1.50 g, 3.94 mmol) was dissolved into 30 ml of THF. To this solution was added lithium aluminum hydride (240 mg, 6.49 mmol). The mixture was refluxed for 30 minutes and then poured into ice and extracted with methylene chloride and saturated ammonium chloride solution. The organic layer was dried with sodium sulfate and solvents were evaporated. The residue was washed with ether to give a white solid 1-(3-methoxybenzyl)-4-hydroxymethyl-6,7-dimethoxyisoquinoline (1.13 g, 85%). ES-MS calculated for C20H21O4N (m/e) 339.39, observed 340.5 (M+1). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Product: COC(=O)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
1-(Benzyloxycarbonyl)piperidin-4-ol and methyl 4-hydroxyphenylacetate were treated in the same manner as the one of Production Example 65 to thereby give the title compound as a pale green powder.