Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:42])=[C:16]4[C:27](=[O:28])[C:26]5[C:21](=[C:22]6[O:35][CH:34]7[O:36][C:30]([CH3:41])([CH:31]([OH:40])[CH:32]([NH:38][CH3:39])[CH:33]7[OH:37])[C:23]6=[CH:24][C:25]=5[OH:29])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:43]([O:45][CH3:46])=[O:44])[C:11]([OH:48])([CH3:47])[CH2:10]2)[CH:5]([O:49][CH3:50])[C:4]([O:52][CH3:53])([CH3:51])[CH:3]1[O:54][CH3:55].[C:56](OC(=O)C)(=[O:58])[CH3:57]>CO>[CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:42])=[C:16]4[C:27](=[O:28])[C:26]5[C:21](=[C:22]6[O:35][CH:34]7[O:36][C:30]([CH3:41])([CH:31]([OH:40])[CH:32]([N:38]([C:56]([CH3:57])=[O:58])[CH3:39])[CH:33]7[OH:37])[C:23]6=[CH:24][C:25]=5[OH:29])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:43]([O:45][CH3:46])=[O:44])[C:11]([OH:48])([CH3:47])[CH2:10]2)[CH:5]([O:49][CH3:50])[C:4]([O:52][CH3:53])([CH3:51])[CH:3]1[O:54][CH3:55]
Reactant: CC(=O)OC(C)=O
Reactant: CNC1C(O)C2Oc3c(cc(O)c4c3C(=O)c3cc5c(c(O)c3C4=O)C(OC3OC(C)C(OC)C(C)(OC)C3OC)CC(C)(O)C5C(=O)OC)C(C)(O2)C1O
Solvent: CO
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2OC(C)C(OC)C(C)(OC)C2OC)CC1(C)O)C(=O)c1c(O)cc2c(c1C3=O)OC1OC2(C)C(O)C(N(C)C(C)=O)C1O
Reaction time: 4 h

Procedure:
Eight hundred mg of N-demethylnogalamycin is dissolved in a mixture of 10 ml of methanol and 2 ml of acetic anhydride. After the solution has stood at room temperature for 4 hours, it is evaporated to dryness under reduced pressure. The residue is chromatographed on 90 g of silica gel using chloroform-methanol (19:1) and collecting 201 five-ml fractions. Fractions 100-201 are combined and evaporated to dryness in vacuo to give 470 mg of N-acetyl-N-demethylnogalamycin; homogenous by TLC, Rf 0.38 in CHCl3 --CH3OH (9:1); [α]D +485°; (c 0.286, CHCl3); UV (EtOH) 236 nm (ε38,400), 258 nm (ε19,200), 290sh nm (ε12,800); IR (Nujol) 3380, 1715, 1705, 1650, 1615, 1585, 1285, 1215, 1135, 1100, 1045, 1025, 1000, 915, 875, 820, 750 cm-1 ; 1H NMR (CDCl3) δ1.1-1.7 (m, 12H), 2.10 (s, 3H), 3.20 (s, 3H), 3.25, 3.53, 3.62, 3.68 (4s, 12H), 2.8-4.62 (m), 5.22, 5.55, 5.88 (3 broad s, 3H), 7.26 (s, 1H), 7.52 (s, 1H), 13C NMR (CDCl3) δ191.1, 179.8, 174.7, 171.6, 161.6, 155.8, 146.9, 143.8, 136.5, 133.5, 130.4, 125.2, 116.1, 114.2, 113.9, 100.7, 95.92, 84.3, 81.0, 77.8, 75.7, 74.0, 71.5, 69.4, 67.3, 61.1, 59.2, 58.7, 56.8, 52.2, 48.5, 40.0, 32.2, 29.4, 23.6, 22.4, 18.0, 14.6; mass spectrum m/e 815.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH:17]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Fc1ccc2onc(N3CCNCC3)c2c1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccc(F)cc34)CC2)CC1

Procedure:
The title compound, MS: m/e=447.1 (M+H+), can be prepared in accordance with the general method of example 1, step 1 from 5-fluoro-3-piperazin-1-yl-benzo[d]isoxazole hydrochloride and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate A).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:25]=[C:24]([F:26])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:27])[CH:17]=1)=O)(C)(C)C>ClCCl>[NH2:15][C:16]1[CH:17]=[C:18]([F:27])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:24]([F:26])[CH:25]=1
Reactant: COC(=O)c1c(F)cc(NC(=O)OC(C)(C)C)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(F)cc(N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At RT, 0.5 ml of TFA was added to a solution of 36 mg (0.125 mmol) of methyl 4-[(tert-butoxycarbonyl)amino]-2,6-difluorobenzoate in 1 ml of dichloromethane, and the mixture was stirred at RT for 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was co-evaporated repeatedly with dichloromethane and toluene and dried under reduced pressure. The crude product was used for the next step without purification. Yield: 24 mg (quant.)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH2:26][CH2:27][N:28]4[CH2:33][C:34]3([NH:42]C(=O)OC(C)(C)C)[CH2:39][O:38]C(C)(C)[O:36][CH2:35]3)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH3:18])=O)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:42][C:34]([CH2:33][N:28]1[C:29]2[C:25](=[C:24]([C:21]3[N:20]=[C:19]([C:11]4[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH3:18])=[C:9]([NH2:8])[CH:10]=4)[O:23][N:22]=3)[CH:32]=[CH:31][CH:30]=2)[CH2:26][CH2:27]1)([CH2:35][OH:36])[CH2:39][OH:38]
Reactant: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1NC(=O)OC(C)(C)C
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1N
Yield: 70 %

Procedure:
When the product of Step F was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 70% yield, as a creamy solid. 1H-NMR (DMSO-d6) 0.92-1.05 (m, 3H); 1.42 (broad s, 2H); 1.7-1.81 (m, 2H); 2.99 (s, 2H); 2.42-2.51 (m, 2H); 2.95 (s, 2H); 3.11-3.4 (m, 2H, +H2O); 3.53 (tr, 2H, J=9 Hz); 3.93-4.05 (m, 2H); 4.56 (m, 2H); 5.11 (s, 2H); 6.76 (d, 1H, J=6 Hz); 6.97 (d, 1H, J=9 Hz); 7.0 (d, 1H, J=6 Hz); 7.1-7.25 (m, 2H); 7.32-7.42 (m, 2H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34]>C1COCC1.O>[CH3:34][C:12]1[CH:13]=[C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])[CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:35])=[O:5]
Reactant: COC(=O)CCCCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
Lithium hydroxide monohydrate (120 mg, 2.86 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid methyl ester from Example E83.1 (410 mg, 0.95 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 24 h at room temperature and concentrated in vacuo. The residue was acidified with 1M HCl and extracted with chloroform. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% acetic acid:7% methanol:90% chloroform) to yield the title compound (105 mg, 26%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([N:22]1[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH2:30][CH2:31][CH2:32]Br)[C:23]1=[O:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl.O>[CH2:15]([N:22]1[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH2:30][CH2:31][CH2:32][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)[C:23]1=[O:34])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CCCBr)c1=O
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1cn(Cc2ccccc2)c(=O)n(CCCN2CCC(c3ccc(F)cc3)CC2)c1=O
Temperature: 25 °C
Yield: 60.9 %

Procedure:
A suspension of 4-(4-fluorophenyl)piperidine hydrochloride (105 mg, 0.49 mmol) and 1-benzyl-3-(3-bromopropyl)-5-methyl-1H-pyrimidine-2,4-dione (164 mg, 0.49 mmol) in 20 mL acetonitrile was treated with sodium iodide (134 mg, 0.97 mmol) and potassium carbonate (100 mg, 0.73 mmol) and the reaction was heated at reflux for 16 h. The mixture was cooled to ambient temperature and poured into a separatory finnel containing water (100 mL) and dichloromethane (100 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organics dried with magnesium sulfate, filtered and concentrated in vacuo to provide an oil. This crude material was purified by pressurized silica gel chromatography (5% methanol in ethyl acetate) to give 1-benzyl-3-{3-[4-(4-fluorophenyl)piperidin-1-yl]propyl}-5-methyl-1H-pyrimidine-2,4-dione (130 mg, 61%). The hydrochloride salt was prepared by conventional methods to provide a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH:24]=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:30]1([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][NH:35][C:33]([CH:30]4[CH2:32][CH2:31]4)=[O:34])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NC(=O)C1CC1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)C1CC1
Reaction time: 8 h

Procedure:
A mixture of the title compound of Step B (127 mg, 0.29 mmol), cyclopropanecarboxamide (74 mg, 0.87 mmol), trifluoroacetic acid (0.07 mL, 0.87 mmol) and triethylsilane (0.14 ml, 0.87 mmol) in toluene (2 mL) was gently refluxed overnight. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to provide the title compound, a compound of this invention, as a white foamy solid (113 mg, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[CH3:19][C:20](N(C)C)=O.C(I)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(=O)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCI
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a dry 100 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet were added 3.00 g of 2-fluoro-4-nitrobenzoic acid, 3.00 g of NaHCO3, and 20 mL of anhydrous dimethylacetamide. The suspension was treated with 3.50 mL of ethyl iodide and stirred at RT under N2 for 18 h. The reaction mixture was filtered to remove solids and the filtrate concentrated in vacuo to give an orange residue which was dissolved in 100 mL of CH2Cl2. The solution was washed with saturated aqueous NaHCO3 (3×50 mL), water (1×60 mL), and dried over anhydrous Na2SO4. Removal of drying agent by filtration and passage through a silica gel plus (3×5 cm) gave a light yellow solution which was concentrated in vacuo to afford 3.10 g (90%) of ethyl 2-fluoro-4-nitrobenzoate as a light yellow crystalline solid, m.p. 70-73° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19](O)=[O:20])=O)=[CH:6][CH:5]=1.S(OC)(OC)(=O)=O.O>C1COCC1>[F:3][C:4]1[CH:23]=[CH:22][C:7]([CH:8]2[C:10]3[C:11](=[CH:12][C:13]([CH2:14][OH:15])=[CH:17][CH:18]=3)[CH2:19][O:20]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a suspension of sodium borohydride (15.0 g) dispersed in THF (130 ml) was added dropwise at 20-30° C. a solution of 4-(4′-fluorobenzoyl)isophthalic acid (26.0 g) synthesized in Example 4 in THF (260 ml) and the mixture was heated to 55° C. Dimethyl sulfate (51.0 g) was added dropwise at 55-65° C. After the dropwise addition, the mixture was refluxed for 5 hr, and hydrolyzed with water (130 ml) in an ice bath. THF was evaporated under reduced pressure. To the residue was added 85% phosphoric acid (52 g) and the mixture was stirred at 60° C. for 5 hr. Water (390 ml) was added and the mixture was cooled. The generated crystals were collected by filtration, washed with water and dried to give crude 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (20.4 g). This was recrystallized from a mixed solvent of ethyl acetate and heptane (2:3) to give nearly pure 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (18.9 g, 86%). The various spectrum data of the crystals were the same as those obtained in Example 12.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[CH:13]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[CH:13]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2s1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2sc(N)nc2c1
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To a solution of ethanol (36 mL) was added 5-nitro-benzothiazol-2-ylamine (Example 15, 78 mg, 0.35 mmol) and tin dichloride dihydrate (449 mg, 2 mmol). The resulting mixture was heated at 80° C. for 4 hours. The solution was cooled to room temperature and the solvent was removed. The residue was dissolved in ethyl acetate and poured onto 50 mL of 1.5 N NaOH solution and extracted using ethyl acetate (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a solid (43 mg, 66%). 1H NMR (DMSO d) δ: 7.23–7.19 (m, 3H), 6.59 (d, 1H, J=1.96 Hz), 6.32 (dd, 1H, J=2.18, 8.28 Hz), 4.88 (br s, 2H); MS (ESI) 166 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][P:40]([CH3:44])(=[O:43])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][P:40]([CH3:44])(=[O:43])[CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[BH4-].[Na+].Br[CH2:16][CH2:17][CH:18]1[O:24][C:23]([C:29]#[C:30][CH:31]2[CH2:33][CH2:32]2)([C:25]([F:28])([F:27])[F:26])[C:22]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:21]=2[NH:20][C:19]1=[O:39]>C1COCC1.C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:21]2[NH:20][C:19](=[O:39])[C@H:18]([CH:17]=[CH2:16])[O:24][C@:23]([C:29]#[C:30][CH:31]3[CH2:33][CH2:32]3)([C:25]([F:26])([F:27])[F:28])[C:22]=2[CH:34]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)OC1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=C[C@@H]1O[C@](C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1 h

Procedure:
To a room temperature solution of 409 mg (1.8 mmol) of 2-nitrophenylselenocyanate in 5.0 mL of THF was added 16 mL of ethanol and 90 mg of sodium borohydride. After stirring 1 h, a solution of 260 mg of rel-3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 8 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 2 h, at which time an additional 20 mg of sodium borohydride was added and stirring was continued for an additional 2 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 130 mg of the title compound as a pure solid: HRMS: Calcd. for C17H14NO2F3Cl (M+H)+ : 354.0508. Found: 354.0487.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20](COCC[Si](C)(C)C)COCC[Si](C)(C)C)=[C:18]([C:37]([O:39][CH2:40][CH3:41])=[CH2:38])[C:17]([CH:42]4[CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]4)=[N:16][C:15]=23)[CH:2]=1>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([NH2:20])=[C:18]([C:37]([O:39][CH2:40][CH3:41])=[CH2:38])[C:17]([CH:42]4[CH2:43][CH2:44][S:45](=[O:49])(=[O:48])[CH2:46][CH2:47]4)=[N:16][C:15]=23)[CH:2]=1
Reactant: C=C(OCC)c1c(C2CCS(=O)(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: CCO
Product: C=C(OCC)c1c(C2CCS(=O)(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N
Temperature: 60 °C
Yield: 49.7 %

Procedure:
3-(quinolin-3-yl)-5-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-6-(1-ethoxyvinyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-2c, 169 mg, 0.23 mmol) in a 1:1 mixture of EtOH/4 N HCl (6.0 mL) was heated at 60° C. for 3 h and concentrated. The residue was purified by PrepLC to give 53 mg (53%) of the title compound (HCl salt) as a light yellow solid. LC/MS RT=2.95 min (10 min method). Mass calculated for, M+H 436.14, observed 436.14.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]#[N:19].O.[OH-].[Li+]>CS(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]#[N:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: N#Cc1ccsc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccsc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
Combine 1,4-dichloro-2-nitro-benzene (3.87 g, 20.13 mmol), 2-aminothiophene-3-carbonitrile (2.50 g, 20.13 mmol), and DMSO (25.0 ml). Add lithium hydroxide monohydrate (1.69 g, 40.27 mmol) all at once and then stir the mixture at ambient temperature for 24 hours. Pour the mixture onto ice chips and stir it for 1.5 hours. Remove the resulting orange precipitate by vacuum filtration and then dry it under vacuum to give 4.85 g (86%) of the title compound: mass spectrum (ion spray): m/z=279.1 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)#[N:18].C1C(O)=CC=CC=1C>>[O:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[NH:18])[CH2:12][CH2:11]1
Reactant: Nc1ccccc1CN1CCOCC1
Reactant: N#CN1CCOCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: N=C(Nc1ccccc1CN1CCOCC1)N1CCOCC1

Procedure:
A mixture of 4(2-aminobenzyl)morpholine dihydrochloride (6.8 g), 4-cyanomorpholine (4.3 g) and m-cresol was heated at 90°-95° C. for 12 hours to yield N-(2-morpholinomethylphenyl)morpholine-4-carboxamidine (m.p. 118°-119° C.) which was recrystallised from hexane and then converted into its difumarate salt (m.p. 166°-167° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=2)=[C:11]1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH:40]2[CH2:42][CH2:41]2)[CH:30]=1)C1C=CC=CC=1.C(OCN1C2C=NNC(=O)C=2C(CC2C=CC=CC=2F)=C1C1C=CC(OC(F)F)=C(OC2CC2)C=1)C1C=CC=CC=1>>[CH:40]1([O:39][C:31]2[CH:30]=[C:29]([C:11]3[NH:10][C:14]4[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=4[C:12]=3[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=3)[CH:34]=[CH:33][C:32]=2[O:35][CH:36]([F:38])[F:37])[CH2:42][CH2:41]1
Reactant: COc1cccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)n(COCc3ccccc3)c3cn[nH]c(=O)c23)n1
Agent: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Product: COc1cccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)[nH]c3cn[nH]c(=O)c23)n1
Reaction time: 1 h
Yield: 21.7 %

Procedure:
Reaction was carried out in the same manner as in Example 22-(b) except for using 227 mg (0.396 mmol) of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(6-methoxy-2-pyridylmethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 28-(a) in place of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction suspension was filtered, the filtrate was concentrated under reduced pressure, methanol and 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred for 1 hour. Then, the solution was concentrated under reduced pressure and the obtained residue was applied to silica gel column chromatography (Eluent; chloroform:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 39 mg of the title compound as a white solid. (Yield: 22%)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[C:19]1([CH2:25][CH2:26][NH:27][CH2:28]/[CH:29]=[CH:30]/[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][C:5]=1[CH2:6][N:27]([CH2:26][CH2:25][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:28]/[CH:29]=[CH:30]/[C:31]([O:33][CH3:34])=[O:32])([O-:3])=[O:2]
Reactant: COC(=O)/C=C/CNCCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/CN(CCc1ccccc1)Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 2-nitro-4-(t-butoxycarbonyl)-benzylbromide (4.06 g, 12.8 mmol) in THF (50 mL), methyl 4-(phenylethylamino)-crotonate (3.4 g, 15.5 mmol) was added with stirring at RT. Triethylamine (2.2 mL, 15.7 mmol) was then added. After stirring for 16 h, the reaction was diluted with ethyl acetate and washed with 1N sodium carbonate, brine, dried (sodium sulfate) and concentrated. Flash chromatography (silica gel, 15% ethyl acetate/n-hexane) gave the title compound as an oil (5.16 g, 88%). 1H-NMR (CDCl3) δ1.60(9H, s), 2.74(4H, br s), 3.30(2H, dd), 3.74(3H, s), 4.00(2H, s), 6.00(1H, d, J=15 Hz), 7.02(1H, dt), 7.25(5H, m), 7.67(1H, d, J=8 Hz), 8.15(1H, dd), 8.45(1H, d, J=2 Hz).