Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][O:15][C:16]1[NH:17][CH:18]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=2)[C:19]([C:23](=[O:25])[CH3:24])=[C:20]([CH3:22])[N:21]=1.N1C=CC=CC=1>C(Cl)Cl>[C:23]([C:19]1[CH:18]([C:26]2[CH:27]=[C:28]([F:34])[C:29]([F:33])=[C:30]([F:32])[CH:31]=2)[N:17]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[C:16]([O:15][CH3:14])=[N:21][C:20]=1[CH3:22])(=[O:25])[CH3:24]
Reactant: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was added to a solution of 1-[2-methoxy-4-methyl-6-(3,4,5-trifluorophenyl)-1,6-dihydro-5-pyrimidinyl]ethanone (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH2Cl2 (200 mL) at 0-5° C., and the resulting mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (dichloromethane/EtOAc, 1/9 to 3/20), to give the desired product as a white powder (4.00 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.N12CCCN=C1CCCCC2.[CH3:30][O:31][C:32]1[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39](C2C=CC=CC=2)[C:40](=O)[O-:41])[N:33]=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:15]([NH:18][C:40]([NH:39][C:34]2[N:33]=[C:32]([O:31][CH3:30])[N:37]=[C:36]([CH3:38])[N:35]=2)=[O:41])(=[O:16])=[O:17])[C:5]2[O:10][S:9](=[O:11])(=[O:12])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cc(Br)cc3c2OS(=O)(=O)C(C)=C3)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A reaction mixture of 3.54 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide, 1.61 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, 2.73 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate and 35 ml of absolute dioxan is stirred for 11/2 hours at room temperature. The solvent is evaporated and the oily residue is triturated with 10 ml of 1N hydrochloric acid and 5 ml of water. The precipitate is isolated by filtration, washed with ether and dried, affording 4.84 g of N-(6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8ylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea of m.p. 196°-198° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:33][C:31]([F:32])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:18][CH:19]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 63A. mp 145° C.; IR (KBr) cm−1: 2968, 1740, 1510, 1325, 1248, 1110; 400 MHz 1H NMR (DMSO-d6): δ 12.99 (br(s), 1H), 7.66-7.75 (m, 2H), 7.55-7.65 (m, 2H); 7.01-7.15 (m, 3H) 6.83-6.90 (m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.14 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 2.74 (t, 2H, t, J=7.6 Hz), 2.65 (t, 2H, J=7.4 Hz), 1.87 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C26H23F3O4S: C, 63.92; H, 4.75. found: C, 63.95; H, 4.65.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH2:17][CH:18]=[CH2:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH2:20](Br)[CH:21]=[CH2:22].O>CN(C)C=O>[CH2:17]([C:4]1([O:3][CH2:22][CH:21]=[CH2:20])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)[CH:18]=[CH2:19]
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC1(CC=C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 12 g, 0.3 mol) was added slowly to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-hydroxy-4-(2-propenyl)-1-piperidinecarboxylate (Description 129, 23.1 g, 0.096 mol) in dimethylformamide (200 mL) and the mixture was stirred at 0° C. for 10 minutes. Allyl bromide (25.4 ml, 0.3 mol) was added and the mixture was stirred at 0° C. for 5 minutes, then at room temperature for 45 minutes. The mixture was cooled to 0° C. and water (200 mL) was added. The mixture was extracted with diethyl ether (2×200 mL) and the combined organic fractions were washed with water (4×200 mL) and brine (150 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (9:1), to give the title compound (5.5 g, 20%). m/z (E) 226 (M+1-C4H8).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:22]=1.[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.O1CCCC1.O1CCCC1>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](/[CH:10]=[CH:11]/[C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)=[N:7][C:6]=3[CH:22]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc3cc(Br)ccc3o2)cc1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(/C=C/c2nc3cc(-c4ccccc4)ccc3o2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 54.7 %

Procedure:
Under an argon stream, a mixture of 5-bromo-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]benzoxazole (Compound of Reference Example 44) (129 mg), phenylboric acid (171 mg), tetrakis(triphenylphosphine)palladium(0) (61 mg), 2 M sodium carbonate (1.05 ml), toluene (3.15 ml) and tetrahydrofuran (1.05 ml) was stirred at 90° C. for 24 hours. The reaction mixture was subjected to distribution into ethyl acetate-tetrahydrofuran (3:1, v/v) and water. The organic layer was washed with water and dried over MgSO4, and the solvent was distilled off under reduced pressure. The residue was subjected silica gel column chromatography and the fraction eluted with ethyl acetate-hexane (1:6, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 5-phenyl-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]benzoxazole (70 mg, 55%). The compound was recrystallized from ethyl acetate-hexane.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].Br[C:11]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:14](=[O:23])[NH:15]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C:3]1([C:1]#[C:2][C:11]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:24]/[C:25]2[NH:26][CH:27]=[CH:28][C:29]=2[O:30][CH3:31])/[C:14](=[O:23])[NH:15]3)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: C#CC1(O)CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CC3(O)CCOCC3)c21

Procedure:
Using Method C above, 4-ethynyl-tetrahydro-pyran-4-ol (43.3 mg, 0.34 mmol) (Example 85A) was coupled with (Z)-1,3-dihydro-4-bromo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 7) using (Ph3P)4Pd (16 mg) and Cul (3.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85° C. for 18 h to give (Z)-1,3-Dihydro-4-[(4-hydroxy-tetrahydro-pyran-4-yl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 30 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]3)=[N:9][C:10]=2[C:11]2[CH:24]=[CH:23][C:14]([C:15]([NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:31](O)(=[O:35])[C:32]#[C:33][CH3:34]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31](=[O:35])[C:32]#[C:33][CH3:34])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)=[O:16])=[CH:23][CH:24]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ccon4)cc3)c12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccon3)cc2)c2c(N)nccn12
Yield: 6.6 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(isoxazol-3-yl)benzamide (intermediate 35) and 2-butynoic acid, to afford the title compound (2 mg, 6.6%). Data: UPLC(C) Rt: 2.23 min; m/z 470.3 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:11][N:12]([CH3:16])[CH:13]([NH2:15])[CH3:14].C(=O)(O)[O-].[Na+].[I-].[K+]>C(O)C>[CH3:11][N:12]([CH3:16])[CH:13]([NH:15][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:14]
Reactant: ClCCc1cccnc1
Reactant: CC(N)N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCO
Product: CC(NCCc1cccnc1)N(C)C
Yield: 56.1 %

Procedure:
11 g of 3-(2-chloroethyl)pyridine hydrochloride, 16.3 g of N,N-dimethylethane diamine, 18.5 g of sodium bicarbonate and 13 g of potassium iodide are heated in 150 ml of ethanol for about 30 hours at about 60° C. The solvent is evaporated and the residue is taken up in 100 ml of water before an aqueous solution of 10N NaOH is added to give pH 8; the aqueous phase is then extracted 3 times with 80 ml of ethyl acetate. The pooled organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residual oil is distilled to give 6.7 g of the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(=O)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C1(O)C=CC=CC=1.[CH3:26][O:27][CH2:28][CH2:29]Br>CN(C=O)C>[CH3:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: COCCOc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(4-(2-Methoxyethoxy)phenyl)piperazine is prepared from 4-(4-hydroxy-phenyl)-1-acetylpiperazine. To NaH (60% in mineral oil, 0.79 g, 20 mmol) in DMF (25 ml) add the phenol (3.0 g, 13.6 mmol), followed by 2-bromoethyl methyl ether (2.27 g, 16.3 mmol). Stir at RT 18 h, concentrate, and partition between EtOAc and 5% citric acid. Wash the organic with 1N NaOH, then brine. Dry over MgSO4, and concentrate to obtain the alkylated product as a white solid. Heat this material (2.2 g, 7.9 mmol) in 6N HCl (30 ml) at reflux for 1 h. Allow to cool and basify to pH=10 with NaOH. Extract with CH2Cl2 and wash with water and then brine. Dry the organic with MgSO4 and concentrate to give the piperazine as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][N:11]=1.[CH3:30][N:31]=[C:32]=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:30][NH:31][C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][N:11]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)c1ncc(-c2ccc3ccccc3c2)[nH]1
Reactant: CN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc3ccccc3c2)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a stirred solution (0.18 M) of the product from step 1 in DCM/DMF (2:1) at 0° C., methyl isocyanate (1 eq.) was added. The reaction mixture was stirred at 0° C. for 1 h. Then, NaHCO3 (saturated solution) was added and extracted with EtOAc. The combined organic layers were dried. Evaporation of the solvent gave a crude that was purified by flash chromatography on silica gel (95:5 DCM/MeOH) to yield (63%) the title compound as a solid.
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[CH2:3][CH2:4][N:5]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@@H:6]([C:8](OC)=[O:9])[CH3:7].C[Al](C)C.C(N(CC)CC)C>ClCCl>[CH3:7][C@@H:6]1[C:8](=[O:9])[NH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][N:5]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: COC(=O)[C@@H](C)N(CC[C@@H](C)N)C(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CCN(C(=O)OCc2ccccc2)[C@H](C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl N-[(3R)-3-aminobutyl]-N-[(benzyloxy)carbonyl]-D-alaninate (0.5 g, 1.6 mmol) in dichloromethane (65 mL) was added trimethylaluminum (0.8 mL, 2M in toluene) and triethylamine (0.025 mL, 0.16 mmol), and the reaction mixture was stirred overnight at room temperature. Celite was added and the reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride solution. The white granular solid formed was filtered and washed with dichloromethane. The filtrate was evaporated and purified by flash chromatography on a Biotage® system (silica gel, 5% methanol/dichloromethane) to yield the title compound. MS 277.2 (M+1).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[NH4+].[Cl-]>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([OH:11])=[C:4]([C:3]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[OH:12])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Oc1ccc(Cl)cc1C(O)(C1CCCCC1)C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 7.0 g of 5-Chloro-2-hydroxy-benzoic acid methyl ester in 38 ml of THF, 115.5 ml of a solution of cyclohexylmagnesium chloride in THF (2 M) was added slowly at room temperature. The reaction mixture was then heated to reflux for 5 h. After cooling to room temperature it was hydrolyzed with ice. Saturated aqueous NH4Cl was added until the white precipitate was dissolved. The aqueous phase was extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from n-heptane to yield a bright yellow product. Yield: 5.2 g.
Reaction SMILES: O=[C:2]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6]CC)=O.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18]>C(O)C>[O:10]([CH2:9][C:2]1[CH:3]=[C:4]([OH:6])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(=O)COc1ccccc1
Reactant: NNc1ccccn1
Solvent: CCO
Product: Oc1cc(COc2ccccc2)nn1-c1ccccn1
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Ethyl 3-oxo-4-phenoxybutanoate (5a, 1.2 g, 5.4 mmol) was charged in a 25 mL round-bottom flask and dissolved in 10 mL of ethanol. A solution of 2-hydrazinopyridine (0.55 g, 5.0 mmol) in 5 mL of ethanol at 100° C. was gradually added thereto over 30 minutes, followed by stirring for 20 hours. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated by evaporation, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (n-Hex/EtOAc=9/1 (v/v)) to afford the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([OH:30])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2].[N+](=[CH2:33])=[N-]>CO.C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:33])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(=O)O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2NC21
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Reaction time: 0.33 h

Procedure:
To a solution of 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4-6-triene-4-carboxylic acid (12 mg) in methanol (2 ml) was added a solution of diazomethane (excess) in diethyl ether at room temperature. The mixture was allowed to stand at room temperature for 20 minutes and then evaporated to dryness in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (15:1 v/v) to afford methyl 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][C:5]=1[O:26][CH3:27])([O-])=O.C(O)C.O1CCCC1>C(Cl)Cl>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][C:5]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 0.91 g of 10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 4.51 g of SnCl 2.2H2O, 6 ml of ethyl alcohol, 6 ml of tetrahydrofuran and 16 ml of methylene chloride is stirred at 50° C. for 2 hours. The solvents are evaporated in vacuo and the residue dissolved in 80 ml of ethyl acetate. The solution is treated with 50 ml of 1N NaOH with stirring for 30 minutes. The resulting suspension is filtered through diatomaceous earth.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13]O)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:17])=O.N1C2C=CC=CC=2N=N1.[OH-].[Na+]>O.O1CCCC1.CN(C)C(=O)C>[Cl:17][CH2:13][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[O:12][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ncccc1-c1cc(CO)no1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc2[nH]nnc2c1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ncccc1-c1cc(CCl)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a mixture of [5-(2-aminopyridin-3-yl)isoxazol-3-yl]methanol (0.19 g, 1 mmol) and N,N-dimethyl acetamide (1 mL) was added a mixture of thionyl chloride (0.15 mL, 2 mmol), benzotriazole (0.26 g, 2.2 mmol) and tetrahydrofuran (1 mL) under an ice cooling, which was stirred at room temperature for 30 minutes. To the reaction mixture were added water and 5N aqueous sodium hydroxide to adjust basic, then extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride water. The solvent was evaporated under a reduced pressure to obtain the title compound (0.21 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:23]([O:25]CC)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:23]([OH:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Ethyl 3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,9,10-tetrahydro-4H-pyrimido[1,2-d][1,4]oxazepine-2-carboxylate (920 mg, 2.5 mmol) was dissolved in 5 mL of THF and to it was added with stirring LiOH (120 mg, 5 mmol) and 5 mL water. After 30 min, the THF was evaporated and the aqueous layer was acidified with dil HCl. This was extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. Trituration from Et2O gave the title compound (790 mg, 91%) as a solid: 1H NMR (300 MHz, CDCl3) δ: 1.40 (s, 6H), 3.60 (s, 2H), 3.65-3.95 (m, 2H), 4.10-4.90 (m, 2H), 5.41 (s, 2H), 7.25-7.42 (m, 3H), 7.45-7.58 (m, 2H). LC/MS (M+H): 345.
Reaction SMILES: C(O)CCC.[ClH:6].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[CH2:11][CH2:12][NH2:13].C(O[CH:21](OCC)[CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)C>Cl.O>[ClH:6].[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][CH2:22][CH:21]2[C:14]3[C:10](=[CH:9][C:8]([OH:7])=[C:16]([OH:17])[CH:15]=3)[CH2:11][CH2:12][NH:13]2)=[CH:25][CH:26]=1
Reactant: CCOC(CSc1ccc(C)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(SCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 106.9 %

Procedure:
To a mixture of n-butanol (10 ml), water (2.5 ml) and concentrated hydrochloric acid (1 drop) were added 3,4-dihydroxyphenethylamine hydrochloride (0.63 g) and (4-methylthiophenoxy)acetaldehyde diethyl acetal (1.0 g), and the mixture was refluxed for 5 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was crystallized by adding acetone, and the crystals were recrystallized by adding acetone, and the crystals were recryatallized from a mixture solvent of methanol and ether to give 1-(4-methylthiophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.2 g), mp 270°C (dec.).