Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:27])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][CH:25]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:27])[CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(C)cc3C2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: Cc1ccc2c(c1)C(C)N(S(=O)(=O)c1ccc(O)cc1)c1ccccc1-2
Yield: 53.8 %

Procedure:
The title compound was prepared from 5-[(4-methoxyphenyl)sulfonyl]-6,8-dimethyl-5,6-dihydrophenanthridine (0.6 g, 1.58 mmol), cyclohexene (0.4 mL, 3.95 mmol), and 1.0 M boron tribromide in dichloromethane (9.5 mL, 9.49 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 4-[(6,8-dimethylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.31 g, 0.85 mmol, 54%) as a white solid, m.p. 111-113° C.;
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A 500-mL bottle was purged with nitrogen and charged with tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 101g (3.1 g, 10 mmol), 10% palladium on carbon (50% wet, 1.0 g) and ethanol (100 mL). It was evacuated, charged with hydrogen gas, and stirred for 16 h at room temperature. The hydrogen was then evacuated and nitrogen was charged into the bottle. The catalyst was removed by filtration through a pad of CELITE® and the filtrate concentrated under reduced pressure to afford 101h (2.7 g, 97%). MS: [M+H]+ 279
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])C.[C:10]1([NH:16][C:17]([NH:19][C:20]([NH2:22])=[NH:21])=[NH:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH3:7][C:6]1[N:21]=[C:20]([NH:19][C:17]([NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[NH:18])[NH:22][C:4](=[O:9])[CH:5]=1
Reactant: N=C(N)NC(=N)Nc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(=O)[nH]c(NC(=N)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxobutyric acid ethyl ester (2.6 grams, 0.020 mol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added at room temperature to a solution of 1-phenylbiguanide (3.5 grams, 0.020 mol, prepared as described in Part D of Example I) in anhydrous ethanol (15 milliliters). The mixture was heated at reflux and stirred for 4 hours. After a few minutes, all the components dissolved. Cooling the resulting yellow solution mixture to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with water, then with cold ethanol (0° C.), and finally with hexanes. The solid was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-phenylguanidine as a colorless solid (3.60 grams, 74 percent yield): mp=265° C.; 1H NMR (DMSO-d6, 303 K) δ: 11.19 (s, 1H), 9.05 (s, 1H), 9.5-6.5 (br, 2H), 7.65 (d, 2H, 3J=7.7 Hz), 7.26 (m, 2H), 7.00 (t, 1H, 3J=7.3 Hz), 5.60 (s, 1H), 2.09 (s, 3H); 13C NMR (DMSO-d6, 303 K) δ: 164.0, 163.2, 158.3, 156.2, 138.9, 128.8, 122.7, 120.7, 103.7, 23.6. Exact mass calculated for C12H13N5O=243.1120. Measured High Resolution Mass Spectrum (MAB/HR/N2)=243.1120. Anal. Calcd for C12H13N5O: C, 59.25; H, 5.39; N, 28.79. Found: C, 59.17; H, 5.39; N, 29.04.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1nccnc1N1CCNCC1
Solvent: ClC(Cl)Cl
Product: Clc1cnc(N2CCNCC2)c(Cl)n1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a suspension of 2-chloro-3-(1-piperazinyl)pyrazine (11.7 g, 58.7 mmol; from Example 90, Step 1) in CHCl3 (50 mL) was N-chlorosuccinimid (14.4 g, 108 mmol) added and the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and extracted twice with water. The combined aqueous phases were made alkaline (11M NaOH), saturated with NaCl, cooled, and extracted with EtOAc (×3). Concentration of the combined, dried (MgSO4), organic phases afforded 6.12 g (45%) of the title compound as a brown oil which crystallized upon standing: mp 89-97° C. Anal. (C8H10Cl2N4.⅓H2O)C, H, N.
Reaction SMILES: O.Br[C:3]1[S:13][C:6]2[NH:7][C:8](=[O:12])[C:9](=[O:11])[NH:10][C:5]=2[C:4]=1[Br:14]>C(O)(=O)C.[Zn]>[Br:14][C:4]1[C:5]2[NH:10][C:9](=[O:11])[C:8](=[O:12])[NH:7][C:6]=2[S:13][CH:3]=1
Reactant: O=c1[nH]c2sc(Br)c(Br)c2[nH]c1=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2scc(Br)c2[nH]c1=O
Reaction time: 24 h
Yield: 29 %

Procedure:
6,7-Dibromothieno[2,3-b]pyrazine-2,3(1H,4H)-dione hydrate (0.50 g, 1.45 mmol) was dissolved in 113 ml 97% acetic acid at 100° C. and 0.11 g (1.68 mmol) of zinc dust was added in one portion. After stirring 24 h another 0.11 g (1.68 mmol) of zinc dust was added and the stirring was continued at 100° C. for 24 h. The reaction mixture was filtrated and evaporated to dryness under reduced pressure and 10 ml of water was added. The precipitate was filtered off and washed with water and dried. The crude material (0.215 g) was recrystallized from acetic acid to afford 0.104 g (29%) of the title compound. M.p. 295°-296° C. 1H-NMR (DMSO-D6, δ): 7.3 (s, 1H), 11.9 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=[C:7]([O:19][CH3:20])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH:33]=O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CN(C)C(=O)C>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][C:7]([O:19][CH3:20])=[C:3]2[C:2]=1[N:1]=[C:33]([C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]3)[CH:31]=1)[NH:6][C:4]2=[O:5])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)N1CCN(c2cccc(C=O)c2)CC1
Reactant: COc1ccc(OCc2ccccc2)c(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(OCc2ccccc2)c2nc(-c3cccc(N4CCN(C(C)C)CC4)c3)[nH]c(=O)c12
Temperature: 110 °C
Yield: 22.5 %

Procedure:
A solution of 2-amino-3-(benzyloxy)-6-methoxybenzamide (11, 0.267 g, 0.98 mmol) and 5-(benzyloxy)-2-methoxybenzaldehyde (3, 0.152 g, 0.65 mmol) in N,N-dimethylacetamide (10 mL) was treated with p-TsOH (0.30 g, 1.57 mmol) and NaHSO3 (0.204 g, 1.96 mmol) and then heated at 110° C. for 15 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% 95:4.5:0.5 CH2Cl2/MeOH/concentrated NH4OH in CH2Cl2 to afford the title compound (71 mg, 22%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.79 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.3 Hz, 2H), 7.42-7.33 (m, 5H), 7.14 (d, J=7.6 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 5.24 (s, 2H), 3.83 (s, 3H), 3.34-3.31 (m, 4H), 2.80-2.60 (m, 5H), 1.05 (br s, 6H); ESI MS m/z 485 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:22][C@@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]4[NH:30][N:29]=[N:28][N:19]=4)=[CH:20][CH:21]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:22][C@@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2ccnn2-c2ccc(C#N)cc2)cc1O[C@@H]1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccnn2-c2ccc(-c3nnn[nH]3)cc2)cc1O[C@@H]1CCOC1
Temperature: 110 °C
Yield: 39.6 %

Procedure:
4-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzonitrile (40.0 mg, 0.111 mmol), sodium azide (35.82 mg, 0.5510 mmol), ammonium chloride (29.5 mg, 0.552 mmol), and 1 mL of N,N-dimethylformamide were mixed in a 500 mL flask and heated under an atmosphere of N2 at 110° C. for 6 hours. The mixture was cooled to room temperature and poured into 5 mL of ice cold 3.0 M aqueous HCl. The precipitate was collected by vacuum filtration and washed with several portions of water. The solid was dried in vacuo overnight to give 20 mg (0.044 mmol, 40%) of 5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-tetrazole as a yellow solid. LC/MS (EI) tR 3.52, m/z 405.1 (M++1) 1H NMR (CDCl3 300 MHz) δ 2.0 (m, 2H); 3.7-3.9 (m, 4H); 3.9 (s, 3H); 4.8 (m, 1H); 6.6 (s, 2H); 7.0 (d, 1H); 7.1 (d, 1H); 7.4 (d, 2H); 7.8 (d, 2H); 7.8 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[S:37])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(C(=S)Nc2ccc(OCc3ccccc3)cc2)ccc1Cl
Yield: 77 %

Procedure:
N-(4-Benzyloxy-phenyl)-4-chloro-3-nitro-benzamide (19.15 g, 50 mmol), Lawesson reagent (11 g, 27 mmol, commercially available) and dioxane (150 ml) were stirred together and heated under reflux for 4 h. When no more starting amide was present, as showed by TLC, the reaction mixture was cooled and the solvent removed under reduced pressure. The crude product was dissolved in minimum boiling toluene to recrystallise. The purified product was filtered and washed with cold toluene and cold hexane to give the thioamide, in 77% yield.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)([O-])C.[K+].[O:17]1[CH2:20][CH2:19][C:18]1=[O:21]>C1COCC1>[Br:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:20][CH2:19][C:18]([OH:21])=[O:17]
Reactant: O=C1CCO1
Reactant: O=Cc1cccc(O)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1cccc(OCCC(=O)O)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-3-hydroxybenzaldehyde (1 eq.) in THF (1.2 M) was added sequentially potassium tert-butoxide (1.0 M THF solution, 0.8 eq.) and oxetan-2one at RT. The resulting yellow suspension was stirred at RT for 16 h. The reaction mixture was quenched with 10% aq. HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])(=O)C.[OH-].[Na+].Cl>CO.O>[OH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12]
Reactant: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a stirred solution of compound (48) (2.0 g, 5.9 mmol) in methanol (25 mL) was added a solution of NaOH (0.8 g, 20 mmol) in 20 mL of water. The reaction mixture was stirred at room temperature for 2 h (monitored by TLC). The reaction mixture was acidified to about pH 5.0 using 0.1 N HCl and then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (1:1) as eluant to provide 1.3 g (75%) of compound (49) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.36-1.78 (14H, m); 1.99-2.12 (2H, m); 2.34 (2H, s); 3.23 (2H, d, J=6.4 Hz); 4.09 (1H, m); 5.26 (1H, t, J=6.4 Hz); 5.89 (1H, m). MS (ESI): m/z=298.23 (M−H−).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.[CH3:45][Zn]C>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].C(Cl)Cl.O1CCOCC1>[F:43][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([F:42])[C:36]=1[S:33]([NH:32][C:28]1[C:27]([F:44])=[C:26]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:45])[N:7]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (167 mg, 0.251 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (10.24 mg, 0.013 mmol) and dimethylzinc (0.251 mL, 0.501 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to give the title compound (120 mg). MS (ESI): 646.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][N:22]([CH3:30])[CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCNCC12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 3.2 %

Procedure:
To a solution of 7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-1,3,4,10a-tetrahydro-2H,9H-2,4-a,5,9-tetraaza-phenanthren-10-one (139 mg, 0.337 mmol) in DMF (3.4 mL) cooled to 0° C. was added potassium carbonate (233 mg, 1.683 mmol) and methyl iodide (2 M in THF, 0.168 mL). The reaction was stirred 1 h at 0° C. and filtered through celite. The filtrate was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (4.6 mg, 3.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.15-7.28 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.85-6.97 (m, 2H), 4.17-4.30 (m, 1H), 3.88 (dd, J=10.6, 3.3 Hz, 1H), 3.37 (s, 2H), 3.14-3.20 (m, 1H), 3.06-3.14 (m, 4H), 2.84 (d, J=11.6 Hz, 1H), 2.74 (td, J=12.4, 3.0 Hz, 1H), 2.44-2.48 (m, 4H), 2.26 (s, 3H), 1.91-2.02 (m, 2H). [M+H] calc'd for C22H27ClN6O, 427; found, 427.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])(O)[CH2:9][CH2:10][CH2:11][OH:12])[CH3:2].Cl.O1CCCC1>C(O)C>[CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])=[CH:9][CH2:10][CH2:11][OH:12])[CH3:2]
Reactant: CCc1ccsc1C(O)(CCCO)c1sccc1CC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccsc1C(=CCCO)c1sccc1CC
Temperature: 50 °C
Yield: 69 %

Procedure:
This oil consisting of 1,1-bis(3-ethyl-2-thienyl)-1,4-dihydroxylbutan was mixed with 75 ml 2N hydrochloric acid solution, 75 ml tetrahydrofuran and 75 ml ethanol and heated at 50° C. for 18 h. The solution was evaporated and the resultant oil was purified by "flash" chromatography on silica gel (Art 9385) eluting with heptane/ethylacetate (5:1) to give 4,4-bis(3-ethylthien-2-yl)but-3-en-1-ol (5.4 g, 69%) as an oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11](=[O:19])[C:12]2[CH:18]=[CH:17][CH:16]=[N:15][C:13]=2[N:14]=1.[OH-].[NH4+:23]>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:14][C:13]1[N:15]=[CH:16][CH:17]=[CH:18][C:12]=1[C:11]([NH2:23])=[O:19])=[O:10]
Reactant: [NH4+]
Reactant: O=c1oc(-c2ccccc2C(F)(F)F)nc2ncccc12
Agent: [OH-]
Product: NC(=O)c1cccnc1NC(=O)c1ccccc1C(F)(F)F
Yield: 33 %

Procedure:
2-(2-Trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.51 g) is stirred in 30% ammonium hydroxide (25 ml) at room temperature overnight. The resulting precipitate is filtered and rinsed with water and diethyl ether. The precipitate is dried under vacuum at 50 C overnight to give 2-(2-trifluoromethyl-benzoylamino)-nicotinamide (850 mg, 33% yield)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([C@@H:32]([C@@H:34]1[C@@H:38]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@@H:37]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35]1)[OH:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:40]([O:39][C@H:38]1[C@@H:37]([O:47][Si:48]([C:51]([CH3:53])([CH3:54])[CH3:52])([CH3:49])[CH3:50])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35][CH:34]1[C@@H:32]([OH:33])[C@@H:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41]
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 33.1 %

Procedure:
By using an analogous procedure to that described in Example 1, a solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (99 mg, 0.32 mmol, obtained from Reference Example 18), tert-butyl (2S,3S)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (165 mg, 0.229 mmol, obtained from Reference example 5), acetic acid (4 drops) and sodium triacetoxyborohydride (97 mg, 0.457 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under nitrogen for 4 hours. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(S)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (77 mg, 33%) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1nn(-c2ccc(N)c(C)c2)c(=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1nn(-c2ccc(NCc3ccc(Cl)cc3)c(C)c2)c(=O)o1

Procedure:
The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with 4-chlorobenzaldehyde/sodium borohydride in methanol/methylene chloride at room temperature and was purified by column chromatography (silica gel, ethyl acetate:n-heptane=1:1).
Reaction SMILES: [CH3:1][SH:2].C[O-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[C:13](\[NH:17][C:18]([CH:20]1[CH2:22][C:21]1([CH3:24])[CH3:23])=[O:19])/[C:14]([OH:16])=[O:15].N#N>CO>[CH3:23][C:21]1([CH3:24])[CH2:22][CH:20]1[C:18]([NH:17]/[C:13](=[CH:12]\[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][S:2][CH3:1])/[C:14]([OH:16])=[O:15])=[O:19]
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCCBr)C(=O)O
Reactant: CS
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Product: CSCCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Temperature: 25 °C

Procedure:
A stream of CH3SH gas was bubbled through a solution of 162 mg (3 mmoles) of sodium methoxide in 5 ml of methanol for 10 min. with cooling in an ice bath. The solution was allowed to warm to room temperature and 332 mg (1 mmole) of Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid was added. The solution was heated under reflux for 30 min. in a N2 atmosphere. Most of the methanol was evaporated under reduced pressure, the residue 2.5 N HCl. The precipitated oil was extracted with ether (3×). The ether extracts were washed with water, saturated brine and dried over MgSO4. Removal of the ether under reduced pressure gave a colorless oil that crystallized upon standing. It was recrystallized from ether-hexane to give 178 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-methylthio-2-octenoic acid, m.p. 82°-84° C. Homogeneous by TLC (toluene-acetic acid, 4:1). The NMR spectrum was in accord with the desired structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH3:26])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([C:17]1[C:18]([CH3:26])=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:16]=1[O:15][CH3:14])=[O:9]
Reactant: COc1ccc(Br)c(C)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2C)c(OC)c1OC

Procedure:
50B (240 g, 1.0 mol) is reacted with 3,4,5-trimethoxytoluene (182 g; 1.0 mol) in the presence of P2O5 (1.0 kg) and dichloromethane as described in Example 6 yielding white crystals, 220 g (54% ), mp 89-91° C.