Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15].FC(F)(F)S(O[CH2:22][CH2:23][O:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[O:3][CH2:22][CH2:23][O:24][C:25]([F:28])([F:27])[F:26])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCOC(F)(F)F)c(OC)c1
Reaction time: 0.17 h

Procedure:
To sodium hydride (200 mg, 5.0 mmol) in DMF (6 mL) under N2 was added methyl 4-hydroxy-3-methoxy-benzoate (920 mg, 5.0 mmol) and the mixture was stirred for 10 min. 2-(Trifluoromethoxy)ethyl trifluoromethanesulfonate (prepared according to the procedure described by Blazejewski, et. al. JOC, 2001, 66(3), 1061-1063) (1.2 g, 4.6 mmol) was then added dropwise and the solution was stirred at room temperature for 2 h, then at 50° C. for 2 h. The mixture was concentrated to a solid, and the residue was taken up in 50 mL of DCM before it was washed with brine (20 mL), dried over MgSO4 and purified by column chromatography (0-25% EtOAc/hexane) to give methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate as a white solid. ESI-MS m/z calc. 294.1, found 295.3 (M+1)+; Retention time: 1.63 minutes (3 min run).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2=[O:20])=[CH:13][CH:12]=1.[NH4+].[Cl-].O>CCOCC.C1COCC1>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:20])=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(O)(c1ccccc1)CC2

Procedure:
A solution of 3.0 M phenylmagnesium bromide in Et2O (680 mL, 2.04 mole) under argon at ambient temperature was diluted with Et2O (700 mL) with stirring, and a solution of 6-methoxy-1-indanone (277 g, 1.71 mole) in THF (1400 mL) was added dropwise over 1 hr. The reaction mixture was stirred for 2 h at ambient temperature and then was poured with stirring into saturated NH4Cl (2.8 L). H2O (1.4 L) was added, and the organic phase separated. The aqueous phase was extracted with Et2O (2×1 L), and the combined organic extracts were concentrated to give crude 6-methoxy-1-phenyl-1-indanol (445 g) as a brown oil. This oil was dissolved in toluene (2.5 L), and p-toluenesulfonic acid monohydrate (12.3 g, 0.065 mole) was added. The solution was stirred and heated at reflux for 16 hr using a Dean-Stark trap with a condenser. H2O collection was minimal after 2 h and totaled 28 mL. The solution was cooled and extracted sequentially with 5% aqueous Na2CO3 (1 L) and H2O (2×1 L). The organic layer was concentrated to give a dark brown oil (400 g). This oil was distilled under vacuum to give the title compound (298.2 g, 79%) as a yellow oil: bp 152-190° C./2.0 Torr; TLC (10% EtOAc/hexanes) Rf0.75.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH2:21])[CH3:16]>>[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH:21][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13])[CH3:16]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c2c1CCCC2=O
Yield: 85.1 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and N1,N1-diethylpropane-1,3-diamine 0.27 g (2.1 mmol) was reacted to give 0.26 g (85%) of the titled compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[CH3:12][O:11][C:8]1[C:9]([CH3:10])=[C:2]2[C:3]([CH:4]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]([C:14]([F:13])([F:23])[F:22])[O:1]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: COc1ccc(C=O)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(OC)c(C)c2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of benzaldehyde from Step 1 (3.0 g, 18.07 mmole) and ethyl 4,4,4-trifluorocrotonate (4.5 g, 27.11 mmole) was dissolved in anhydrous DMF (20 mL), warmed to 60° C. and treated with anhydrous K2CO3 (4.99 g, 36.14 mmole). The solution was maintained at 90° C. for 24 hours. LCMS analysis indicated that the reaction was complete. After the reaction was cooled to room temperature, the solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford brown solid, that was dissolved in MeOH (40 mL) and was precipitated upon adding 13 mL water. The suspension was filtered and dried on vacuum yielding a light brown solid: (4.37 g, 76.6%): LCMS m/z339.10 (M+Na). 1H NMR (CDCl3/400 MHz) 7.68 (s, 1H), 7.03(d, 1H, J=8.7 Hz), 6.50 (d, 1H, J=8.7 Hz), 5.70 (q, 1H, J=6 Hz), 4.29 (q, 2H, J=7.2 Hz), 3.84 (s, 3H), 2.09(s, 3H), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:15]3[CH2:20][CH2:19][O:18][CH:17](C#N)[CH2:16]3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.C[CH2:24][N:25](CC)CC.[C:30](Cl)(=[O:32])[CH3:31]>CCOC(C)=O>[C:24]([C:15]1([C:11]2[CH:10]=[C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:7][CH:6]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)#[N:25]
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Reactant: N#CC1CC(c2cccc(Sc3ccc(N)cc3)c2)CCO1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Sc2cccc(C3(C#N)CCOCC3)c2)cc1
Temperature: 55 °C
Yield: 52 %

Procedure:
4-[3-(4-amino-phenyl sulfanyl)-phenyl]-tetrahydro-pyran-carbonitrile (93.57 g) and Et3N (53.1 mL) were dissolved in EtOAc (1.23 L) and heated to 50-60° C. To this solution was added acetylchloride (27.7 ml) in EtOAc (73 mL) over 30 minutes. The suspension obtained was filtered and the filter cake was washed with EtOAc (3×150 mL). The combined EtOAc solutions were washed with water (0.5 L), half saturated aqueous Na2CO3 (2×0.5 L), water (0.5 L) and saturated aqueous NaCl (0.25 L). The organics were dried with Na2SO4 and evaporated at 40° C. The crude product was recrystallized from refluxing EtOH (0.52 L) to give after cooling, filtration and drying at 40° C./20 mbar, N-{4-[3-(4-Cyano-tetrahydro-pyran-4yl)-phenyl sulfanyl]-phenyl}acetamide (55.27 g, 52% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[C:13]([C:17]([O-:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.[I-].[Li+].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:22][C:27]1[C:4]([C:5]#[N:6])=[C:23]([NH:10][C@H:9]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=[O:18])[N:12]3[C:8]=2[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:8])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C([O-])c1cccc2ncc(-c3cncc(F)c3)n12
Reactant: c1ccncc1
Agent: [I-]
Agent: [Li+]
Product: C[C@H](Nc1cccc(N)c1C#N)c1nc2cccc(C(=O)O)n2c1-c1cncc(F)c1

Procedure:
A solution of methyl 2-((1S)-1-(6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(5-fluoro-3-pyridinyl)imidazo[1,2-a]pyridine-5-carboxylate (0.060 g, 0.139 mmol) and lithium iodide (0.056 g, 0.416 mmol) in pyridine (0.73 mL) was stirred at 100° C. for 6 h. Volatiles were removed under reduced pressure to afford (S)-2-(1-((3-amino-2-cyanophenyl)amino)ethyl)-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylic acid as a dark residue. LC-MS (ESI) m/z 419.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:15]#[C:14][CH2:13][CH2:12][OH:16]
Reactant: Brc1ccc2ccccc2n1
Reactant: C#CCCO
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: OCCC#Cc1ccc2ccccc2n1
Reaction time: 5 h

Procedure:
A mixture of 2-bromoquinoline (0.44 g), 3-butynol (0.2 ml), N,N-dicyclohexylamine (0.46 ml), BTPC (30 mg), copper (I) iodide (5 mg) and acetonitrile (10 ml) was stirred at 22° for 5 h. Ether (50 ml) was added, and the mixture filtered and evaporated in vacuo. The residue was purified by FCC eluting with ether followed by ether-methanol (19:1), to afford the title compound as a colourless solid (0.41 g). A small sample recrystallised from ethyl acetate-hexane had m.p. 89°-91°.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[N:17][C:16]([N:19]3[CH2:23][CH2:22][NH:21][C:20]3=[O:24])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[H-].[Na+].I[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37].O>CN(C=O)C>[CH3:37][CH:36]([CH3:38])[CH2:35][CH2:34][N:21]1[CH2:22][CH2:23][N:19]([C:16]2[N:17]=[N:18][C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]4[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=4[C:2]([F:1])([F:29])[F:30])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)[C:20]1=[O:24]
Reactant: CC(C)CCI
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCN1CCN(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of 1-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}imidazolidin-2-one (0.080 g, 0.180 mmol), sodium hydride in 60% mineral oil (0.0035 g, 0.150 mmol) in DMF (10 mL) was stirred at room temperature for 30 minutes. 1-Iodo-3-methylbutane (0.0376 g, 0.190 mmol) was added and the mixture was stirred at 60° C. for 24 hours, followed by the dilution with 50 mL of water, and then extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The title compound was obtained as a pale yellow solid in 32% yield (0.028 mg) after column chromatography purification. 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=9.9 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.48-7.65 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 6.98 (d, J=9.9 Hz, 1H), 3.82-4.12 (m, 4H), 3.42-3.64 (m, 6H), 3.24-3.34 (m, 4H), 1.38-1.66 (m, 3H), 0.92 (d, J=6.5 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 167.8, 157.3, 150.5, 134.8, 132.6, 129.7, 127.5, 127.1, 125.8, 122.1, 120.4, 116.6, 46.8, 46.3, 45.9, 42.5, 42.1, 41.5, 36.5, 26.1, 22.8. MS (ES+) m/z 491 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=O)N[C:9]2[CH:13]=[CH:14][CH:15]=C[C:8]=2[O:7]1)=[O:5])[CH3:2].[H-].[Na+].IC.C(OCC)(=O)C.[CH3:27][N:28]([CH3:31])[CH:29]=[O:30]>>[CH3:11][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:15]=[CH:14][CH:13]=[CH:9][C:8]=2[O:7]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1Oc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)Oc2ccccc2N(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.5 mmol (1.2 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazin-3-one (described in C.R. Acad. Sci. Paris Series C, 1969, 269, 154) in 5 ml of dimethylformamide are added at 0° C. to a suspension of 11 mmol (0.44 g) of 60% sodium hydride in 5 ml of dimethyformamide. The reaction mixture is stirred at 0° C. for 30 minutes. 22.2 mmol (1.38 ml) of iodomethane are then added, and the reaction mixture is stirred at room temperature for 1 hour. After hydrolysis and extraction with ethyl acetate, the organic phase is dried, concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (3/7) as eluant to yield the expected compound.
Reaction SMILES: C([C@H]1C2=NC=C(C(OC)=O)C=C2CN1)(C)C.[CH:17]([C@H:20]1[C:24]2=[N:25][CH:26]=[C:27]([C:29](=[O:42])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=3)[CH:28]=[C:23]2[CH2:22][N:21]1C(OC(C)(C)C)=O)([CH3:19])[CH3:18]>>[CH:17]([C@H:20]1[C:24]2=[N:25][CH:26]=[C:27]([C:29]([NH:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:37]=3)=[O:42])[CH:28]=[C:23]2[CH2:22][NH:21]1)([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Agent: COC(=O)c1cnc2c(c1)CN[C@H]2C(C)C
Product: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reaction time: 0.03 h

Procedure:
Procedure same as that for methyl(S)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate, using tert-butyl(S)-7-isopropyl-3-((4-(methoxycarbonyl)benzyl)carbamoyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as a starting material. LC-MS tR=0.73 min in 2 min chromatography, MS (ESI) m/z 354.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:29])[C:15]([CH2:25][CH2:26][CH2:27][CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:32](Cl)([CH3:35])(=[O:34])=[O:33].N1C=CC=CC=1>CC(C)=O>[CH2:25]([C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:30]=[CH:31][C:3]([NH:2][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 95.7 %

Procedure:
A solution of Example 33B (0.052 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.054 g, 96%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.N1CCCC1.Cl>CO>[O:10]=[C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[O:1][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(=O)c1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ncccc1O2
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A solution of 1-(3-hydroxy-2-pyridyl)ethanone (2.4 g, 18 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.5 g, 18 mmol) and pyrrolidine (1.5 mL, 18 mmol) in MeOH (12 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature 1M aqueous HCl was added until pH 4 was reached and the reaction mixture was stirred for further 30 minutes. Methanol was evaporated, the remaining mixture was poured into water, and the pH adjusted to pH 7 with saturated aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate (3×), washed with brine (3×), dried over sodium sulfate and evaporated to dryness. Purification by silica gel chromatography (50-100% ethyl acetate in hexane) afforded tert-butyl 4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (2.2 g, 40%) as an orange oil that solidified upon standing. ESI-MS m/z talc. 318.2, found 319.3 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](OCC)(OCC)(OCC)[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>>[CH3:10][C:11]12[O:7][CH2:6][C:3]([CH2:8][OH:9])([CH2:4][O:5]1)[CH2:2][O:1]2
Reactant: OCC(CO)(CO)CO
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC12OCC(CO)(CO1)CO2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of pentaerythritol (15 g, 110 mmol), triethyl orthoacetate (20.2 ml, 110 mmol), and p-toluenesulfonic acid monohydrate (947 mg, 5.5 mmol) was stirred at 100° C. for 30 minutes. The temperature of the mixture was further raised to 130° C. and the mixture was stirred for 30 minutes. To the reaction mixture, triethylamine (1.53 ml, 11 mmol) was added and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (8.5 g, yield: 48.2%) as a light yellow solid.
Reaction SMILES: S1C(C([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]([OH:12])=[O:11])=O)=CC2C=CC=CC1=2.[Cl:25][C:26]1[C:27]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=2[S:29][C:30]=1[C:31](Cl)=[O:32]>>[Cl:25][C:26]1[C:27]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=2[S:29][C:30]=1[C:31]([NH:8][C@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:32]
Reactant: O=C(Cl)c1sc2cc(F)ccc2c1Cl
Reactant: O=C(N[C@H](Cc1ccc(O)cc1)C(=O)O)c1cc2ccccc2s1
Product: O=C(N[C@H](Cc1ccc(O)cc1)C(=O)O)c1sc2cc(F)ccc2c1Cl

Procedure:
Following the 9a synthetic method, using 3-chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride (249.09 mg, 1.0 mmol) instead of 3 gave 7a as a colorless oil; (145.32 mg, 36.9%). [α]D25: +18.3 (c=0.37, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.97-7.87 (m, 2H), 7.73 (d, J=6.6 Hz, 1H), 7.45-7.38 (m, 1H), 7.18-7.15 (m, 2H), 6.80-6.77 (m, 2H), 4.96-4.90 (m, 1H), 3.34-3.16 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.56, 163.89, 160.62, 159.45, 156.42, 139.16, 133.55, 130.54, 127.03, 124.94, 118.51, 115.22, 114.80, 109.29, 108.95, 54.14, 35.98; HRMS (ESI): calcd for: C18H13ClFNO4S [M−H]−=392.0165, obsd [M−H]−=392.0174.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:33][C:34]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:39]4[C:34]([CH3:33])=[N:35][CH:36]=[CH:37][CH:38]=4)=[O:41])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ncccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a stirred solution of 1.0 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 3 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is slowly added 600 mg of 2-methylpyridine-3-carbonyl chloride dissolved in 15 ml of methylene chloride. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed well with water. The organic layer is dried(MgSO4), filtered and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give 800 mg of the desired product as a pale yellow residue. M+ =422.
Reaction SMILES: [S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH2:20])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].O>CO>[S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21](=[O:23])[CH3:22])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1
Solvent: CO
Solvent: O
Product: CC(=O)NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1

Procedure:
In one example, the primary amine group of compound B5 can optionally be acylated by contacting B5 with an excess of acetic anhydride in methanol containing a trace of water. Generally, this reaction is conducted at about 25° C. to about 30° C. for about 2 to about 24 hours to provide for 3-acetamidocycloheptyl 1-thio-β-galactopyranoside, C5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:21](=N)(N)[CH3:22].C([O-])(=O)C.[Na+]>O(CCOC)CCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[C:21]([CH3:22])=[N:19][NH:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=N)N
Reactant: COc1ccc(N2CCN(NC(=O)NN)CC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOCCOC
Product: COc1ccc(N2CCN(n3c(C)n[nH]c3=O)CC2)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A mixture of 13 parts of N-[4-(4-methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide, 14.2 parts of ethanimidamide hydrochloride, 12.3 parts of sodium acetate and 95 parts of 1,1'-oxybis[2-methoxyethane] is stirred for 3 hours at 130° C. The reaction mixture is poured onto water and the product is extracted twice with dichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 5.1 parts (35%) of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-5-methyl-3H-1,2,4-triazol-3-one; mp. 264.3° C.
Reaction SMILES: C(O[C:6](=[O:17])[NH:7][C:8]1[C:13]([CH:14]=[O:15])=[C:12]([Cl:16])[CH:11]=[CH:10][N:9]=1)(C)(C)C.[NH2:18][CH2:19][CH2:20]O.CC(O)=O>C1(C)C=CC=CC=1>[Cl:16][C:12]1[C:13]2[CH:14]3[O:15][CH2:20][CH2:19][N:18]3[C:6](=[O:17])[NH:7][C:8]=2[N:9]=[CH:10][CH:11]=1
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1Nc2nccc(Cl)c2C2OCCN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
tert-Butyl(4-chloro-3-formylpyridin-2-yl)carbamate (2.0 g, 7.79 mmol), 2-aminoethanol (0.57 g, 9.35 mmol), and AcOH (0.47 g; 7.79 mmol) were suspended in toluene (20 mL), and stirred overnight at room temperature. The reaction mixture was concentrated, and suspended in hexanes/ether (5/1, v/v). The resulting precipitate was filtered, suspended in NMP (3 mL) in 20 ml seal tube, and heated for 30 min. at 150° C. The crude product was purified directly via HPLC to provide 42 (270 mg, 10% yield) as a solid. LC-MS (M+H=226, obsd.=226).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)C.[ClH:27].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:27].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1cccc(F)c1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1cccc(F)c1
Yield: 81 %

Procedure:
N-benzyloxycarbonyl-m-fluoroanilinoacetaldehyde diethyl acetal (15 g) and 3,4-dihydroxyphenethylamine hydrochloride (5.75 g) were added to a mixture of n-butyl alcohol (150 ml) and water (20 ml) and then the mixture was refluxed for 11 hours in a stream of nitrogen. The reaction mixture was concentrated to dryness and the residue was in turn washed with ether and with a mixture of ether: ethyl acetate (2:1) and then crystallized with acetone. The crystals were collected by filtration to give 1-(N-benzyloxycarbonyl-m-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (11.27 g), mp 184° to 186° C. (dec).