Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:42])([F:41])[C:22]1[CH:23]=[C:24]([C@@H:32](OC(=N)C(Cl)(Cl)Cl)[CH3:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>C(Cl)Cl>[F:20][C:21]([F:41])([F:42])[C:22]1[CH:23]=[C:24]([C@H:32]([O:19][C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH3:33])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](O)C1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g (3.8 mmol) (3R,4S) tert-butyl-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (Step B) and 3 g (7.6 mmol, 2 equiv) (S)-trichloroacetimidate (step C) in 40 mL dry heptanes and 10 mL dry methylene chloride under nitrogen atmosphere at 0° C. was added dropwise 0.092 mL (0.8 mmol, 0.2 equiv) HBF4-dimethyl ether complex. The resulting reaction mixture was stirred at 0° C. for 24 hr. The volatiles were removed under vacuum and the residue dissolved in 10 mL methylene chloride and purified by column chromatography on silica gel eluting with hexanes/EtOAc (8/2) to afford a mixture of two products. This mixture was further purified by preparative HPLC on ChiralPak OD column eluting with heptanes/ethanol (98/2) to obtain the minor isomer (epimeric at the benzylic methyl position) and the title compound. 1H-NMR (CDCl3): (rotamers): δ: 1.43-45 (2d, 3H, 6.5 Hz), 1.49-1.52 (2s, 9H), 3.3-3.5 (m, 3H), 3.73-3.97 (m, 3H), 4.53 (q, 1H, 6.5 Hz), 7.06-7.09 (m, 2H), 7.20-7.25 (m, 3H), 7.55 (m, 2H), 7.74 (s, 1H), 7.75 (s, 2H)ppm. MS: 447.9 (M-t-Bu)+ observed.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:27](S(C3C=CC=CC=3)(=O)=O)[C:13]3=[N:14][CH:15]=[CH:16][C:17](B4OC(C)(C)C(C)(C)O4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1.Br[C:39]1[C:40]([C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[N:41][N:42]([CH:44]([CH3:46])[CH3:45])[CH:43]=1>>[CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:27][C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:39]4[C:40]([C:47]5[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=5)=[N:41][N:42]([CH:44]([CH3:46])[CH3:45])[CH:43]=4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)n1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CN(C)Cc1ccc(-c2cc3c(B4OC(C)(C)C(C)(C)O4)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Product: CC(C)n1cc(-c2ccnc3[nH]c(-c4ccc(CN(C)C)cc4)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described in Intermediate 100 and Intermediate 21 using N,N-dimethyl-1-{4-[1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanamine and 4-bromo-1-(1-methylethyl)-3-(4-nitrophenyl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 481.4
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CCOCC.N#N.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3-Bromobenzonitrile (10.0 g, 55 mmol) was dissolved in dry THF (100 mL) and cooled to −100° C. (Et2O/N2). n-Butyllithium (24.2 mL, 2.5 M in hexane) was added over 30 minutes, maintaining the internal temp under −90°. After 20 minutes, triisopropylborate (18.0 mL) was added over 15 minutes, again maintaining the internal temperature. After the addition was complete, the reaction was allowed to warm slowly to room temperature over 1.5 hours. The reaction was stirred at room temp for 16 hours, then cooled to 15° C., after which 6 M HCl (25 mL) was added. After stirring vigorously for 3.5 hours, the reaction was partitioned between water and EtOAc. After extracting a second time with EtOAc, the combined organics were washed with 2 M NaOH. The aqueous extract was neutralized with 6 M HCl. The white precipitate was filtered, yielding the desired product (4.80 g, 60%). 1H NMR (DMSO-d6): δ8.37 (s, 2H), 8.10 (s, 1H), 8.03 (dt, 1H, J=7.3, J′=1.1), 7.83 (dt, 1H, J=7.6, J′=1.4), 7.53 (t, 1H, J=7.7).
Reaction SMILES: N1(N[C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.[NH2:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[C:47]2[OH:52]>>[OH:52][C:47]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:48]=1[CH:49]=[CH:50][CH:51]=[C:42]2[NH:41][C:8]([C:10]1[CH:40]=[CH:39][C:13]2[N:14]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=[N:20]4)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: Nc1cccc2c(O)cccc12
Product: O=C(Nc1cccc2c(O)cccc12)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 25 %

Procedure:
The general procedure described for Compound 574 was used with 5-amino-naphthalen-1-ol (15.9 mg), producing 7 mg of the title compound (25% yield). MS: 590.24 (M+H+) HPLC Procedure A, retention time=15.26 min.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.B(F)(F)F.[CH3:34]COCC>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[N:14]=[CH:34][O:16][N:15]=2)=[CH:17][CH:18]=1
Reactant: CCOCC
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: FB(F)F
Solvent: CCOC(OCC)OCC
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3ncon3)cc2)c(Cl)c1

Procedure:
150 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine and 15 mg of boron trifluoride ethyl etherate are stirred for 2 hours at 140° C. in 2 ml of triethyl orthoformate. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with water. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.14).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (2 g, 8.8 mmol) cooled at 0° C. was added a solution of Cs2CO3 (2.87 g, 8.8 mmol) in water (12.3 mL). After 30 min stirring, the resulting mixture was concentrated and the residue was suspended in DMF (41 mL). The suspension was cooled to 0° C. and benzylbromide (1.045 mL, 8.8 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. DMF was evaporated, the residue was poured in water and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Phase separator) and concentrated under reduced pressure. The residual oil was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 8:2) to give the title compound. TLC, Rf (c-hexane/EtOAc 8:2)=0.45; MS (UPLC-MS): 318 [M+H]+; tR (HPLC conditions d): 3.89 min.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.C(O)C.C(OCC)(=O)C.[C:23](#[N:25])C>>[NH:7]1[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:5]([CH2:4][C:23]#[N:25])=[CH:6]1
Reactant: CC#N
Reactant: CN(C)Cc1c[nH]c2ccncc12
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCc1c[nH]c2ccncc12
Yield: 26 %

Procedure:
Using essentially the same procedure described in Example 1, Step 5, hereinabove and employing N,N-dimethyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)methylamine as substrate and 1:2 ethanol:ethyl acetate as the chromatography eluent affords the title acetonitrile as a yellow solid, 0.160 g (26% yield), identified by NMR analysis.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([OH:42])[CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21].[CH:43]12[CH2:49][CH:46]([CH:47]=[CH:48]1)[CH2:45][CH:44]2O.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OC(=O)C)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][CH:48]4[CH2:47][CH:46]5[CH2:49][CH:43]4[CH:44]=[CH:45]5)[CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: OC1CC2C=CC1C2
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OC4CC5C=CC4C5)ccc3c2)CC1
Yield: 8 %

Procedure:
Triphenylphosphine was added to a solution of 1-(6-Hydroxy-naphthalen-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.4319 g, 0.001378 mol) and bicyclo[2.2.1]hept-5-en-2-ol (0.243 g, 0.00220 mol) in toluene (0.881 mL, 0.00827 mol) and the mixture was stirred for several minutes. Diisopropyl azodicarboxylate (0.434 mL, 0.00220 mol) was then added dropwise and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted in ethylacetate and washed with water, then brine. The organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography (0-40% EtOAc in heptanes) to give the title compound in 8% yield. ESI-MS (M+H+): 406.2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([O:17][CH3:26])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(O)nncc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3-(1-Hydroxyphthalazin-6-yl)-4-methylbenzoic acid (2.71 g, 9.67 mmol) was suspended in methanol (96.7 mL), thionyl chloride (2.12 mL, 29.0 mmol) was added and the mixture was stirred at 50° C. for 1.5 h and at RT overnight. The mixture was concentrated to give the title compound. MS (ES+): 295(M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NC1CCCCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and cyclohexylamine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[NH:12]1[C:20]2[C:15](=[C:16]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][N:12]4[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[CH2:23][CH2:24]2)[CH:29]=1)=[O:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: FC(F)(F)c1cccc(I)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(C(F)(F)F)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:54]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 55 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 284 mg mmole) of stearic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 305 mg (Yield: 55%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C(O)C>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][CH:38]=2)[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH2:27][NH:9][CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC1CCCCCCC1
Reactant: O=Cc1ccccc1C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(COc2ccc(C(c3ccc(OCc4ccccc4)cc3)c3ccccc3CNC3CCCCCCC3)cc2)cc1
Yield: 65.5 %

Procedure:
In 50 ml of ethanol was dissolved 3 g of cyclooctylamine. To the solution was added 11.41 g of 2-[bis-(4-benzyloxyphenyl)methyl]benzaldehyde obtained by Reference Example 8, and the mixture was heated under reflux for 2 hours. Thereafter, 1.78 g of sodium borohydride was added thereto, and the mixture was heated under reflux for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with ether, and the organic layer was separated. The aqueous layer was extracted with ether, and then the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized to afford 9.19 g of the desired product (Compound 82).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([NH:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])=[O:25])[N:5]=[CH:4][N:3]=1
Reactant: O=CNc1c(Cl)ncnc1Cl
Reactant: CCOP(=O)(CCCCON)OCC
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCCCONc1ncnc(Cl)c1NC=O)OCC
Yield: 77.2 %

Procedure:
4,6-Dichloro-5-formamidopyrimidine (0.441 g, 2.3 mmol), diethyl 4-(aminooxy)butylphosphonate (0.4 g, 1.77 mmol) and N,N-diisopropylethylamine (0.8 ml, 4.6 mmol) in diglyme (15 ml) were stirred at 100° C. for 2.5 hr. The reaction mixture was then allowed to cool, the hydrochloride of N,N-diisopropylethylamine was filtered off and the filtrate was diluted with chloroform (150 ml). The resulting solution was washed with 4% aq. NaHCO3 (1×20 ml) and water (1×20 ml). The combined aqueous layers were extracted with chloroform (6×20 ml) and the combined chloroform solutions were concentrated to an oil. The residue was chromatographed on silica gel (eluted with chloroform: ethanol, 96:4) to yield the title compound (0.520 g, 77%). 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.68 (6H, m, CH2CH 2CH2P), 3.9 (2H, m, NOCH2), 3.97 (4H, m, (OCH2CH3)2), 8.14 (1H, s, H-2), 9.5 (1H, br.s, NHOCH2, D2O exchangeable), 11.0 (1H, NHCHO, D2O exchangeable).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](Cl)=[O:44])=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][C:43]([NH:21][C:18]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:44])=[CH:40][CH:41]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-phenylpyrazin-2-amine (7a) (504 mg, 1.33 mmol) and 4-(dimethylamino)pyridine (16.3 mg, 133 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 18 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=4/1) to give Compound 11a (630 mg, 1.01 mmol, 75.4%) as a yellow foamy solid. Rf=0.33 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.23 (s, 6H), 0.94 (s, 9H), 0.96 (s, 9H), 3.47 (s, 2H), 6.72-6.79 (AA′BB′, 2H), 6.96-7.02 (AA′BB′, 2H), 7.03-7.09 (AA′BB′, 2H), 7.29-7.39 (m, 3H), 7.66-7.74 (m, 2H), 8.05-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.54 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.9, 18.0, 25.50 (3C), 25.54 (3C), 41.7, 119.5 (2C), 120.3 (2C), 127.8 (2C), 127.9, 128.0 (2C), 128.2 (2C), 128.5, 128.9, 130.3 (2C), 130.5, 137.6, 142.8, 147.6, 148.0, 153.8, 156.7, 169.3; IR (KBr, cm−1) 523, 694, 781, 804, 839, 914, 1020, 1070, 1086, 1105, 1169, 1263, 1371, 1416, 1510, 1605, 1672, 2857, 2886, 2930, 2955, 3040, 3059, 3233; HRMS (ESI+)/z 648.3043 ([M+Na]+, C36H47N3NaO3Si2+ requires 648.3048).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O-:18].[Na+].Cl>CO>[Cl:8][C:6]1[N:7]=[C:2]([O:18][CH3:17])[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: O=c1c(Cl)nc(Cl)cn1-c1ccc(F)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)cn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3,5-dichloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (13.0 g, 50.2 mmol; prepared according to the general methods described by M. Tutonda, et al., Tetrahedron, 1990, 46, 5715) dissolved in absolute methanol (100 mL) was treated with NaOMe (6.78 g, 125 mmol). The reaction mixture was stirred at room temp for 1 hour, neutralized with 2N HCl (Et2O solution), and evaporated the solvent under reduced pressure. The residue was treated with EtOAc, washed with 0.5N HCl solution, dried over MgSO4, and concentrated under reduced pressure to give the desired product (12.8 g, 100%). LRMS (ESI pos) m/e 254.9, 256.9 (M+1, Cl pattern). 1H-NMR (400 MHz, CDCl3) δ 7.39 (m, 2H), 7.20 (t, 2H), 6.95 (s, 1H), 4.05 (s, 3H); 19F-NMR (376 MHz, CDCl3) δ −111.5.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:10][C:9]=1[F:24])=[O:6].[OH-].[NH4+:27]>>[F:24][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:12]([F:14])=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:27])=[O:2]
Reactant: COC(=O)CC(=O)Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Yield: 56 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and and ammonium hydroxide. Yield=56%. Colorless solid. MS: m/e=339.3 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[CH3:22][C:23]([CH3:34])([C:28](=O)[C:29](OC)=[O:30])[C:24]([O:26][CH3:27])=[O:25]>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:28]([C:23]([CH3:34])([CH3:22])[C:24]([O:26][CH3:27])=[O:25])=[C:29]([OH:30])[N:17]=2)=[N:6]1
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O

Procedure:
6.00 g (14.562 mmol) of the compound from Example 23A were dissolved in 70 ml of ethanol, and 2.740 g (14.562 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124(14), 3680-3691; 2002) were added. The mixture was heated at reflux overnight. After cooling, the solid was filtered off with suction and washed with a little ethanol, and the filtrate was concentrated and dried under high vacuum.