Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]CCOCCO)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:16]([C:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:37]([CH3:38])=[CH:36][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:34][C:33]=2[CH3:45])[O:25][N:24]=1)[CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]>>[C:1]([O:5][C:6]([NH:8][CH:16]([C:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:37]([CH3:38])=[CH:36][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:34][C:33]=2[CH3:45])[O:25][N:24]=1)[CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOCCO
Reactant: COCCOCC(O)c1cc(CCCOc2c(C)cc(-c3ccccc3)cc2C)on1
Product: COCCOCC(NC(=O)OC(C)(C)C)c1cc(CCCOc2c(C)cc(-c3ccccc3)cc2C)on1
Yield: 91 %

Procedure:
Reaction of the bromomethyl compound of example 5 with 5-t-butyloxycarbonylamino-3-oxapentanol using essentially the same method as described in example 5 for Compound 7 gave the adduct, 3-(1-t-butyloxycarbonylamino-3,6-dioxaheptyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole in 91% yield. Trifluoroacetic acid (1 ml) was added to a solution of the adduct (240 mg, 0.46 mmol) in DCM (10 ml) and the reaction was allowed to stir under argon for 2 hours. The reaction was concentrated at vacuum then the crude product was partitioned between brine/sodium bicarbonate (1:1, 20 ml) and ethyl acetate (2×100 ml). The combined organic phase was dried (Na2SO4) and concentrated, the crude product was chromatographed on silica gel (20 g); eluent 92.5:7.5 DCM/(10% ammonia in methanol) to give 3-(1-amino-3,6-dioxaheptyl)-5-[3-[2,6-dimethyl-4-phenylphenoxy]-propyl]-isoxazole (Compound 14) in 71% yield. 1 H nmr (CD3OD): δ=7.5-7.15 (m, 7H); 6.24 (s, 1H); 4.55 (s, 2H); 3.81 (t, 2H); 3.61 (s, 4H); 3.46 (t, 2H); 3.03 (t, 2H); 2.72 (t, 2H); 2.26 (s, 6H) and 2.16 (m, 2H). MS (ES): (M+H)+ 425.2428 (Calc. C25H32N2O4H=425.2432).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:5][C:4]3[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=3)=[CH:14][CH:13]=1)[C:5]2=[O:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1c2ccc(O)cc2C(=O)N1c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(OCc3ccccc3)cc2C(=O)N1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 186 %

Procedure:
To 5-hydroxy-2-(4-hydroxyphenyl)isoindoline-1,3-dione (2.08 g) in DMF (20 mL) was added potassium carbonate (4.62 g) and a solution of benzyl bromide (3.07 g) in DMF (3.0 mL) dropwise under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h then heated to 80° C. for 3 h. The mixture was cooled to room temperature, poured into water (250 mL) and let sit undisturbed for 2.0 h. The white solid was collected by filtration and washed with water. The solid was dried under high vacuum at 50° C. for 18 h yielding the title compound (3.30 g) as a white solid. 1H NMR (DMSO-d6): 7.87 (d, 1H, J=8.4 Hz), 7.48-7.35 (m, 12H), 7.32 (d, 2H, J=8.7 Hz), 7.13 (d, 2H, J=8.7 Hz), 5.35 (s, 2H), 5.17 (s, 2H); MS: 436 (MH+).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][CH:17]1[CH2:39][C:38]2[C:19](=[CH:20][C:21]3[N+:26]([O-:27])=[N:25][C:24]([CH2:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:23][C:22]=3[CH:37]=2)[CH2:18]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][CH:17]1[CH2:39][C:38]2[C:19](=[CH:20][C:21]3[N+:26]([O-:27])=[N:25][C:24]([CH2:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[N+:23]([O-:4])[C:22]=3[CH:37]=2)[CH2:18]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1Cc2cc3nc(CCCN4CCOCC4)n[n+]([O-])c3cc2C1
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1)[n+]([O-])c(CCCN1CCOCC1)n[n+]3[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
H2O2 (70%, 0.49 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 9.7 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 102 (320 mg, 1.0 mmol) and TFA (0.38 mL, 4.9 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 104 (148 mg, 44%) as a red solid: mp (MeOH/DCM) 119-121° C.; 1H NMR δ 8.27 (s, 1H, H-9), 8.23 (s, 1H, H-5), 3.45 (br t, J=4.5 Hz, 4H, 2×CH2O), 3.21-3.33 (m, 4H, 2×CH2), 2.68-2.81 (m, 3H, H-7, CH2), 2.48 (t, J=6.5 Hz, 2H, CH2N), 2.37 (br t, J=4.5 Hz, 4H, 2×CH2N), 2.06-2.13 (m, 2H, CH2), 1.20 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 155.2, 154.7, 150.2, 139.1, 133.8, 115.9, 113.9, 67.0 (2), 58.0, 53.5 (2), 41.4, 40.8, 35.0, 28.8, 21.8, 20.1. Anal. calcd for C18H24N4O3.¼CH3OH: C, 62.2; H, 7.2; N, 15.9. Found: C, 62.3; H, 7.0; N, 16.0%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][CH:14]([C:24]1[NH:28][C:27](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]3)=[C:33]([O:43][CH3:44])[CH:32]=2)=[N:26][N:25]=1)[C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=1)(=O)C.C(OCC)(=O)C>CO.[Cl-].[Na+].O>[CH3:44][O:43][C:33]1[CH:32]=[C:31](/[CH:30]=[CH:29]/[C:27]2[NH:28][C:24]([CH:14]([C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=3)[CH2:13][CH2:12][CH2:11][OH:10])=[N:25][N:26]=2)[CH:36]=[CH:35][C:34]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: COc1cc(/C=C/c2nnc(C(CCCOC(C)=O)c3cc(F)c(F)c(F)c3)[nH]2)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nnc(C(CCCO)c3cc(F)c(F)c(F)c3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
Potassium carbonate (210 mg) was added to a solution of 4-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}-4-(3,4,5-trifluorophenyl)butyl acetate (400 mg) in methanol (3 mL), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 325 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1.O1CCCC1>CN1CCCC1=O>[CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[S:12][CH:13]=[CH:14][N+:15]=2[CH2:18][CH2:17][CH2:23][S:20]([O-:22])(=[O:21])=[O:19])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(N=Nc2nccs2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CN(C)c1ccc(N=Nc2scc[n+]2CCCS(=O)(=O)[O-])cc1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
0.5 g (1.5 mmol) of N,N-dimethyl-4-[1,3-thiazol-2-yldiazenyl]aniline are dissolved in 1-methyl-2-pyrrolidinone (NMP), and 0.9 g (7.5 mmol) of 1,3-propane sultone is added. The reaction mixture is heated at, 100° C. for 4 hours. After cooling, 20 ml of tetrahydrofuran are added to the reaction mixture and the precipitated product is filtered off, washed with acetone and dried. The resulting dye is recrystallized from methanol/ethyl acetate. 0.53 g (45% of theory) of 3-(2-{[4-(dimethylamino)phenyl]diazenyl}-1,3-thiazol-3-ium-3-yl)-1-propanesulfonate is obtained as a dark blue powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH:11]([Si:13]([Cl:16])([Cl:15])[Cl:14])=[CH2:12]>[Cl-].[Al+3].[Cl-].[Cl-]>[Cl:14][Si:13]([CH2:11][CH2:12][C:10]1[C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[C:6]([CH2:12][CH2:11][Si:13]([Cl:16])([Cl:15])[Cl:14])[C:7]([CH2:12][CH2:11][Si:13]([Cl:16])([Cl:15])[Cl:14])=[C:8]([CH2:12][CH2:11][Si:13]([Cl:16])([Cl:15])[Cl:14])[C:9]=1[CH2:12][CH2:11][Si:13]([Cl:16])([Cl:15])[Cl:14])([Cl:16])[Cl:15]
Reactant: CCCCc1ccccc1
Reactant: C=C[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCc1c(CC[Si](Cl)(Cl)Cl)c(CC[Si](Cl)(Cl)Cl)c(CC[Si](Cl)(Cl)Cl)c(CC[Si](Cl)(Cl)Cl)c1CC[Si](Cl)(Cl)Cl
Yield: 102.2 %

Procedure:
In the same apparatus and by the same procedure described in EXAMPLE 1, n-butylbenzene 0.86 g (6.40 mmol), vinyltrichlorosilane 5.17 g (32.00 mmol) and aluminum chloride 0.047 g (0.35 mmol) were reacted at 80° C. for 6 hours under a dry nitrogen atmosphere. Recrystallization of solid product from THF gave 6.16 g (yield: 2.68%, mp: 228°-35° C.) of pentakis(trichlorosilylethyl)-n-butylbenzene. Distillation of the filtrate gave 2.20 g (yield: 36.59%, bp: 192°-8° C./0.6 mm), 1.81 g (yield: 30.0%, bp: 220°-5° C./0-6 mm), 0.63 g (yield: 10.15%), 0.12 g (yield: 2.05%) and 0.22 g (yield: 3.59%) of tris-, tetrakis(trichlorosilylethyl)-n-butylbenzenes, tetrakis(trichlorosilylethyl)dibutylbenzene, mono- and bis(trichlorosilylethyl)benzenes, respectively. isomeric mixtures were also obtained. NMR data of the polyalkylated products prepared as above are listed in Table 13.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (49 mg, 57%), MS (ISP) m/z=346.4 [(M+H)+], mp 276° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) (78.4 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH2:22][CH2:21][O:17][N+:18]([O-:20])=[O:19])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1cnccn1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1cnccn1
Temperature: 25 °C
Reaction time: 46 h
Yield: 26 %

Procedure:
Methyl N-cyanopyrazinecarboximidate (0.49 g, 3.0 mmol) was dissolved in methanol (6 ml), 2-nitroxyethylamine nitrate (1.01 g, 6.0 mmol) and triethylamine (1.01 g, 10.0 mmol) were added. The mixture was stirred at room temperature for 46 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (300:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.18 g, 0.78 mmol, yield: 26%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31](B4OC(C)(C)C(C)(C)O4)[CH:32]=3)[N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.ClCCl.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[N:12]1([S:9]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[N:27]=[CH:26][CH:25]=[C:24]4[C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH:3]=2)(=[O:11])=[O:10])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)N1CCOCC1
Reactant: CC1(C)OB(c2ccc3nccc(-c4ccncc4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)N1CCOCC1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
A mixture of 5-bromo-3-(4-morpholinylsulfonyl)-2-pyridinamine (0.296 g, 0.92 mmol), 4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.306 mg, 0.92 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-complex with dichloromethane(1:1) (37.6 mg, 0.046 mmol), 2 M aqueous K2CO3 (5 mL) and dioxane (5 mL) was heated at 100° C. for 18 h. After cooling to room temperature, the organic layer was separated and the aqueous portion extracted three times with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified twice by silica gel chromatography (eluent: i) 1-5% MeOH in CH2Cl2 and ii) 0-20% MeOH in CH2Cl2) to provide the title compound as a white solid (150 mg, 37% yield). MS(ES)+ m/e 448.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28][CH2:29]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2ccccn2)CC1
Agent: Cl
Product: CC(C)N1C(=O)C(NC2CCN(c3ccccn3)CC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-pyridin-2-ylpiperidine-4-amine dihydrochloride in a similar manner as described for Example 24 with TEA as base. 1H NMR (500 MHz CDCl3): δ 8.14 (dd, 1H), 7.58-7.53 (m, 2H), 7.48-7.41 (m, 4H), 6.62-6.55 (m, 2H), 5.23 (d, 1H), 4.42 (sept, 1H), 4.10-4.02 (m, 2H), 3.22-3.12 (m, 1H), 2.49-2.41 (m, 2H), 1.80-1.72 (m, 2H), 1.59 (d, 6H), 1.42-1.33 (m, 2H); 13C NMR (125 MHz CDCl3): 159.2, 158.7, 148.1, 137.7, 134.5, 131.9, 130.2, 128.9, 125.3, 113.6, 107.5, 106.9, 50.8, 47.8, 44.1, 32.1, 20.4; Mass Spectrum: M+H+ 427
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([CH:17]3[C:18]([CH3:20])([CH3:19])[C:16]3([CH3:24])[CH3:15])=[O:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(Cl)ccc23)C1(C)C
Yield: 33.2 %

Procedure:
A mixture of 6-chloroindole (0.38 g, 2.5 mmol), ethylmagnesium bromide (1.0 M solution in THF, 3.0 mL, 3.0 mmol), zinc chloride (1.0 M solution in Et2O, 3.0 mL, 3.0 mmol) and the product of Example 1A (3.0 mmol) in 10 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.23 g, 0.83 mmol, 34% yield). MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(O)(C(F)(F)F)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](O)([CH3:21])[CH3:20])=[CH:15][C:14]=1[CH3:23].N>C(Cl)(Cl)Cl.O>[N:1]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([CH3:23])[CH:15]=1)([CH3:21])[CH3:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C(C)(C)O)ccc1Cl
Agent: N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C(C)(C)N=[N+]=[N-])ccc1Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A flask was charged with sodium azide (4.22 g, 65 mmol) and chloroform (250 mL). The mixture was cooled in an ice-salt bath to −5° C. TFA (12.52 mL, 162 mmol) was added over 3 minutes, followed by a solution of the alcohol INT 20 (6 g, 32.5 mmol) in chloroform (10 mL) while the temperature was kept below 0° C. The formed slurry was stirred for one hour, then allowed to warm up to room temperature overnight. After that time, the thick slurry had turned into a cloudy solution. The mixture was treated with concentrated ammonia (25 mL) and water (50 mL). The chloroform layer was separated and the aqueous layer was extracted once more with chloroform. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH2:21][OH:22])=[C:19]([C:23]5[CH:24]=[C:25]([NH:31][C:32]6[CH:37]=[CH:36][N:35]=[C:34]([N:38]7[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39]7)[N:33]=6)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O[N:58]1[C:62]2N=CC=C[C:61]=2[N:60]=N1>C(N(CC)CC)C.NCC#N.C1COCC1>[C:62]([CH2:61][NH:60][C:43]([CH:40]1[CH2:41][CH2:42][N:38]([C:34]2[N:33]=[C:32]([NH:31][C:25]3[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=[C:23]([C:19]4[CH:18]=[CH:17][N:16]=[C:15]([N:8]5[CH2:7][CH2:6][N:5]6[C:10](=[CH:11][C:12]7[CH2:13][C:2]([CH3:46])([CH3:1])[CH2:3][C:4]=76)[C:9]5=[O:14])[C:20]=4[CH2:21][OH:22])[CH:24]=3)[CH:37]=[CH:36][N:35]=2)[CH2:39]1)=[O:44])#[N:58]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccnc(N3CCC(C(=O)O)C3)n2)c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccnc(N3CCC(C(=O)NCC#N)C3)n2)c1=O
Temperature: 30 °C
Yield: 28.3 %

Procedure:
A 50 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 102c (100 mg, 0.16 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 152 mg, 0.40 mmol), triethylamine (TEA, 8 drops), THF (10 mL), and 2-aminoacetonitrile (5 drops). The mixture was heated at 30° C. for 5 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 102 (30 mg, 28%) as a white solid. MS: [M+H]+ 663.2. 1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J=6.0 Hz, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.71 (s, 1H), 7.35 (d, J=4.5 Hz, 1H), 6.58-6.55 (m, 2H), 5.02 (s, 1H), 4.53-4.51 (m, 1H), 4.43-4.40 (m, 1H), 4.23-4.15 (m, overlap, 5H), 3.86-3.84 (m, 1H), 3.72-3.69 (m, 1H), 3.62 (s, 3H), 3.60-3.56 (m, 1H), 3.51-3.43 (m, 2H), 3.10-3.08 (m, 1H), 2.62-2.54 (m, 2H), 2.43 (s, 2H), 2.18-2.16 (m, 1H), 2.06-2.04 (m, 1H), 1.22 (s, 6H).
Reaction SMILES: Br[C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[NH:11][C:10]3[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=3[N:3]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Product: Cn1c(=O)c2[nH]c(N3CCOCC3)nc2n(C)c1=O
Yield: 80 %

Procedure:
0.3 moles of the 8-bromo-theophylline, prepared as in the previous paragraph, is refluxed in 1.5 moles of morpholine for two hours. The precipitate obtained is filtered, to give approximately 80% yield of 8-morpholino-theophylline.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:18]2[C:17]([O:19][CH3:20])=[CH:16][CH:15]=[C:14]([CH:21]=O)[C:13]=2[CH2:12][CH2:11][C:10]1=[O:23])=[O:7])(C)(C)C.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].N1C=CC=CC1>C1(C)C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[C:6]([CH2:8][N:9]1[C:18]2[C:13](=[C:14]([CH2:21][CH:28]3[S:24][C:25](=[O:30])[NH:26][C:27]3=[O:29])[CH:15]=[CH:16][C:17]=2[O:19][CH3:20])[CH2:12][CH2:11][C:10]1=[O:23])([OH:5])=[O:7]
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(C=O)c2c1N(CC(=O)OC(C)(C)C)C(=O)CC2
Agent: C1=CCNC=C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)O)C(=O)CC2
Yield: 44.9 %

Procedure:
4.16 g of 1-tert-butoxycarbonylmethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-carboxaldehyde and 1.66 g of 2,4-thiazolidinedione (1.00 eq.) were suspended in 40 ml of toluene, and two drops of acetic acid and two drops of piperidine were added, followed by heating and refluxing for 13 hours using a Dean Stark trap. After cooling, crystals were separated by filtration and washed with toluene. The crystals obtained were suspended in 3.15 g of silica gel, 2.09 g of dihydropyridine, and 60 ml of toluene, followed by heating and refluxing overnight. 3.15 g of silica gel was added, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), and recrystallized from ethyl acetate-hexane, giving 2.13 g (38% yield) of 5-(1-carboxymethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:37][C:36]3[CH:35]=[C:34]([F:33])[CH:41]=[C:40]([F:42])[CH:39]=3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3cc(F)cc(F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (50 mg, 0.11 mmol) in 1,2-dichloroethane (1.0 mL) was added 3,5-difluorobenzaldehyde (0.014 mL, 0.12 mmol) and sodiumtriacetoxyborohydride (31 mg, 0.14 mmol). The mixture was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 2-{5-[1-(3,5-difluoro-benzyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester and methyl ester. Calcd for C32H34F5NO2 (M+H) 560.61, Found 560.3 (methyl ester) and Calcd for C33H36F5NO2 (M+H) 574.64, Found 574.2 (ethyl ester).