Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:7]2)[N:6]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=4)[C:27]#[N:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1cccc(C2CC3(N=C(N)N(C)C3=O)c3cc(Br)ccc3O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cccc(C2CC3(N=C(N)N(C)C3=O)c3cc(-c4cccc(C#N)c4)ccc3O2)c1
Yield: 20.7 %

Procedure:
Pd(PPh3)2Cl2 (20 mg) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (46 mg, 0.11 mmol) in 1,4-dioxane (5 mL), Cs2CO3 (2 N, 0.5 mL) and 4-cyanophenylboronic acid (32.6 mg, 0.22 mmol). The mixture was refluxed under Ar for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-2-(3-methoxyphenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (10 mg, 20%). 1H-NMR (CDCl3): 2.26 (m, 1H), 2.48 (m, 1H), 3.72 (s, 3H), 5.62 (m, 1H), 6.79 (m, 3H), 6.94 (d, 1H), 7.12 (d, 1H), 7.20 (s, 1H), 7.29 (m, 1H), 7.36 (m, 1H), 7.41 (t, 1H), 7.61 (d, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C1COCC1>[CH:14]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][O:11][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:16])[CH3:15]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Reaction time: 0.08 h

Procedure:
To a solution of (1H-indol-5-yl)-methanol (1.00 g, 6.79 mmol) in THF (60 mL), cooled to 0° C., was added sodium hydride (60% in mineral oil; 1.36 g, 34.0 mmol) portionwise. After stirring for 5 min, triisopropylsilyl chloride (2.88 mL, 13.6 mmol) was added, and the resulting solution was stirred at RT for 2 h. The reaction was quenched by addition of a saturated aqueous NaHCO3 solution at 0° C. The aqueous layer was repeatedly extracted with EtOAc, and the combined organics were washed with H2O (1×) and brine (1×), dried (phase separator) and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane to c-hexane/EtOAc 9:1) afforded the title compound as a white solid. TLC, Rf (c-hexane/EtOAc 9:1)=0.72. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 7.61 (s, 1H), 7.49 (d, 1H), 7.32 (d, 1H), 6.93 (d, 1H), 6.57 (d, 1H), 4.92 (s, 2H), 1.60-1.85 (m, 3H), 1.01-1.12 (m, 39H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=[C:10]([S:12]([CH2:15][C:16]2C=C[CH:19]=[CH:18][CH:17]=2)(=O)=O)[N:11]=1)[CH3:4].[S:26]1C=CC=C1CS>>[OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=[C:10]([S:12][CH2:15][C:16]2[S:26][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:4]
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2ccccc2)nc2[nH]c(=O)sc12
Reactant: SCc1cccs1
Product: C[C@H](CO)Nc1nc(SCc2cccs2)nc2[nH]c(=O)sc12
Yield: 3 %

Procedure:
The title compound was prepared by the method described in example 16 step b) from the product of example 15 step e) (0.300 g, 0.79 mmol) and 2-thiophenemethanethiol (0.32 ml, 3.9 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][N:14](CC3C=CC(OC)=CC=3)[C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C1(S)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(-c3ccnc(Cl)n3)s2)C(=O)c2ccccc2)cc1
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2ccnc(Cl)n2)s1)c1ccccc1

Procedure:
A solution of N-[5-(2-Chloro-pyrimdin-4-yl)-thiophen-2-ylmethyl]-N-(4-methoxybenzyl)-benzamide (25 mg, 0.055 mmol) in 0.25 mL CH2Cl2 was treated with trifluoroacetic acid (0.25 mL) as co-solvent and PS-thiophenol resin (3 eq.) at 40° C. for 15 h. The material was filtered and concentrated to a yellow solid (16 mg, 88%). The crude material was used in the next step.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[S:11])[CH3:9])[NH:6][C:5]1=[O:19])[CH3:3].N1C=CN=C1.[CH2:25]([Si:27]([CH2:31][CH3:32])([CH2:29][CH3:30])Cl)[CH3:26]>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([Si:27]([CH2:31][CH3:32])([CH2:29][CH3:30])[O:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[S:11])[CH3:9])[NH:6][C:5]1=[O:19])[CH3:3])[CH3:26]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (477 mg, 1.51 mmol) is dissolved in dry N,N-dimethylformamide (3 ml), and thereto are added imidazole (260 mg, 3.79 mmol) and triethylchlorosilane (456 mg, 3.0 mmol), and the mixture is stirred at room temperature for five hours. The reaction solution is diluted with ethyl acetate (30 ml) and washed with water. The aqueous layer is extracted with ethyl acetate (20 ml), and the organic layers are combined, washed twice with brine, dried over sodium sulfate, and evaporated to remove the solvent. The resulting oily residue is purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-triethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (342 mg).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][CH2:14][NH2:15].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][CH2:14][NH:15][CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(O)CCl
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCNCC(O)C(=O)O)cc1OC
Temperature: 110 °C
Yield: 57.1 %

Procedure:
A mixture of 20 g (0.16 mole) of β-chlorolactic acid and 86 g (0.48 mole) of 3,4-dimethoxyphenethylamine was heated at 110° C. for 15 hours. The resulting product was dissolved in about 200 ml of water and the pH was adjusted to about 8 with Na2CO3. The aqueous solution was extracted with 2×500 ml of chloroform and neutralized to pH 7 with diluted HCl. The solution was evaporated to dryness and the residue was recrystallized in EtOH to give 24.6 g (61.6%) of crystals: m.p. 187.5°-188.5° C. The NMR, IR and mass spectra were consistent with the assigned structure, and the elemental analysis was consistent with the empirical formula, C13H19O5N.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:51]=[CH:50][C:29]2[N:30]3[C:34]([CH2:35][NH:36][CH2:37][C:28]=2[CH:27]=1)=[N:33][N:32]=[C:31]3[CH:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH2:40][CH2:39]1.C(N(CC)CC)C.[CH3:59][N:60]([CH2:62][C:63](O)=[O:64])[CH3:61]>CN(C)C(=O)C>[Cl:25][C:26]1[CH:51]=[CH:50][C:29]2[N:30]3[C:34]([CH2:35][N:36]([C:63](=[O:64])[CH2:62][N:60]([CH3:61])[CH3:59])[CH2:37][C:28]=2[CH:27]=1)=[N:33][N:32]=[C:31]3[CH:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH2:42][CH2:43]1
Reactant: CN(C)CC(=O)O
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CN(C)CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 50 °C
Yield: 57.8 %

Procedure:
A solution of HBTU (152 mg, 0.38 mmol) in N,N-dimethylacetamide (1.9 ml) was added to a solution of the amine of example 4 (97 mg, 0.26 mmol), triethylamine (1.5 μl, cat.) and dimethylamino-acetic acid (36 mg, 0.26 mmol) in N,N-dimethylacetamide (2.5 ml) and heated to 50° C. for 2 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was partitioned between dichloromethane (10 ml) and 2M aqueous sodium hydroxide solution (10 ml). The organic phase was dried over magnesium sulphate before being evaporated under reduced pressure and purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (7:1:93) as eluant to afford the title compound (70 mg) as a brown foam.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([NH2:8])=[O:7])[C:3]1([CH3:10])[CH3:9].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[C:18]([C:17]1[C:12]([NH:1][C@@H:2]2[CH2:5][C@H:4]([C:6]([NH2:8])=[O:7])[C:3]2([CH3:10])[CH3:9])=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=1)#[N:19]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)[C@H](N)C[C@@H]1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](C(N)=O)C2(C)C)n1
Yield: 78 %

Procedure:
A mixture of (1S,3R)-3-amino-2,2-dimethylcyclobutanecarboxamide. (120 mg, crude), chloro-2-(methylthio)pyrimidine-5-carbonitrile (130 mg, 0.70 mmol) and DIEA (129 mg, 1.0 mmol) in isopropanol (5 mL) was stirred at 80° C. for 2 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (160 mg, 0.55 mmol, 78% yield for two steps). MS (ESI) m/z 292.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:17])[CH2:13][N+:14]([O-:16])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.N1C=CN=C1.[CH2:23]([Si:25](Cl)([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:17][Si:25]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:13][N+:14]([O-:16])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])CC(O)c1c(Cl)cnc2ccccc12
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1c(Cl)cnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a brown clear solution of 1-(3-chloroquinolin-4-yl)-2-nitroethanol (A275-4) (0.423 g, 1.68 mmol) in DMF (4.19 mL) at room temperature was added imidazole (0.342 g, 5.03 mmol) and triethylsilyl chloride (0.341 mL, 2.01 mmol). The mixture was stirred at room temperature. After 2 h, the mixture was quenched with water (50 mL) and extracted with EtOAc (2×50 mL). The organic extract washed with 1 M LiCl (1×50 mL) and brine (1×50 mL), and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexane, and dried under high vacuum to give 3-chloro-4-(2-nitro-1-((triethylsilyl)oxy)ethyl)quinoline (A275-5). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (1H, s), 8.67 (1H, d, J=7.4 Hz), 8.10 (1H, dd, J=8.4, 0.8 Hz), 7.84 (1H, td, J=7.6, 1.4 Hz), 7.71-7.79 (1H, m), 6.38 (1H, dd, J=9.8, 2.5 Hz), 5.14-5.23 (1H, m), 5.03-5.11 (1H, m), 0.65-0.74 (9H, m), 0.32-0.51 (6H, m); LCMS (ESI) m/z 367.1 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[F:17]C1C=C(NN)C=CC=1C>>[ClH:1].[F:17][C:14]1[C:3]([CH3:2])=[CH:4][CH:5]=[C:6]2[C:13]=1[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1ccc(NN)cc1F
Agent: Cl
Product: Cc1ccc2[nH]cc(CCN)c2c1F

Procedure:
4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 3-fluoro-4-methylphenylhydrazine hydrochloride (6.00 g) as starting material.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][CH:12]=[CH:11][C@H:10]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Br.C(=O)([O-])[O-:28].[Na+].[Na+]>C1COCC1>[CH2:1]([O:8][C@H:9]([C@@H:14]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:13])[C@H:10]([OH:24])[CH2:11][CH:12]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1C=CO[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CC[C@@H](O)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
4,6-di-O-benzyl-D-glucal (4.9 mmol) was dissolved in THF (60 mL). 48% Water solution of hydrobromic acid (0.4 mL) was added and the reaction mixture was stirred at room temperature. After reaction was completed, water (250 mL) was added, and pH of obtained solution was adjusted to 8 using saturated sodium carbonate. Water solution was then extracted with ethyl acetate (3×100 mL). Combined water extracts were washed with water until neutral, and dried over anhydrous sodium sulfate. Solids and solvents were removed and crude product was purified by column chromatography (SilicaGel 60) using hexanes:ethyl acetate as eluents. Pure 4,6-di-O-benzyl-2-deoxy-D-glucose (3.1 mmol, yield 63%) was obtained.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=1)[C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1CNCc1ccccc1
Product: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1ccccc1)C(C)=O

Procedure:
Benzyl-[2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-amine and acetyl chloride were reacted as described in Example 11, Step 2 to provide N-benzyl-N-[2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-acetamide.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[N+:27]([O-])([OH:29])=[O:28]>S(=O)(=O)(O)O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16](=[CH:15][C:14]=1[CH2:13]3)[C:17]([N+:27]([O-:29])=[O:28])=[CH:18][CH:19]=[CH:20]2)=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c([N+](=O)[O-])cccc3nc2-1
Reaction time: 36 h

Procedure:
Camptothecin (25 g) in concentrated sulfuric acid (500 mL) was cooled in an ice-bath. To it was then added 70% nitric acid (30 mL), drop-wise to control the reaction temperature. The reaction mixture was then stirred for 36 hours, poured into excess crushed ice and the organic portion was extracted out using chloroform. The combined organic fraction was washed with freshly prepared 10% sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. Solvent was removed and the residue was purified by flash silica gel column using hexane/ethyl acetate (1:1) as eluent to furnish 2.7 g of 9-nitrocamptothecin.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:17][CH:18](OC)OC)[CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:18]=[CH:17][N:15]([CH3:16])[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(C)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C=CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
A solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-methylglycinamide (1.9 Kg, 6.1 mol) and p-toluenesulfonic acid monohydrate (270 g) in toluene (29.4 L) was stirred at 80° C. for 4 hrs. The resultant reaction mixture was cooled to room temperature, washed with water (4×2 L), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluting with heptane-ethyl acetate. Concentration of appropriate fractions provide the cyclization product as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[C:13]([OH:15])=[O:14].[CH3:16]O>OS(O)(=O)=O>[CH3:16][O:14][C:13]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1)=[O:15]
Reactant: CO
Reactant: COc1cccc2c1CCC=C2C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C1=CCCc2c(OC)cccc21
Yield: 94 %

Procedure:
5-Methoxy-3,4-dihydronaphthalene-1-carboxylic acid (100 g, 490 mmol) was dissolved in 800 mL of methanol and 20 mL of 96% H2SO4, and heated at reflux for 18 hours. The reaction was then cooled and evaporated under reduced pressure to a volume of 100 mL, and quenched on ice. The aqueous mixture was extracted with diethyl ether (3×100 mL), and the organic phase was washed with water, 5% aqueous NaHCO3, brine, and then dried (MgSO4) and evaporated to yield 101 g (94%) of the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 2.36 (m, 2H), 2.78 (t, 3H), 3.83 (s, 6H), 6.82 (d, 1H), 7.14 (t, 1H), 7.19 (t, 1H), 7.40 (t, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]1=[O:13].[Se](=O)=[O:15]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]=[O:15])[C:3]1=[O:13]
Reactant: Cc1nc2ccccc2n(C)c1=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C=O)nc2ccccc21

Procedure:
A mixture of 1,3-dimethyl-1H-quinoxalin-2-one (1 g) and selenium dioxide (1.33 g, 2.1 eq) in dry dioxane (60 mL) was stirred at reflux under nitrogen for 30 min. After cooling, the dark-brown mixture was concentrated under reduced pressure and the residue was purified by FC (AcOEt) to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1-boc-4-(2-aminophenyl)-piperazine (5.55 g, 20 mmol) and triethyamine (5.6 mL, 40 mmol) in 200 mL of CH2Cl2 was added methanesulfonyl chloride (1.55 mL, 20 mmol). After stirring for about 4 hours, the solution was concentrated, and the residue dissolved in 200 mL of EtOAc. The solution was washed with 1 M HCl (2×), water and brine, and then dried (Na2SO4), filtered and concentrated to afford about 6.68 g (18.8 mmol, 94%) of the title compound as a brown solid. LRMS: 356.1 (M+1)
Reaction SMILES: Br[C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:8]1[CH:7]2[CH:2]1[C:3]([CH3:20])([CH3:19])[O:4][C:5]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:9][C:6]=12
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)[C@@H](O)[C@H](Br)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.5 %

Procedure:
A mixture of trans-3-bromo-3,4-dihydro-4-hydroxy-N,N,2,2-tetramethyl-2H-1-benzopyran-6-sulfonamide (19.2 g), potassium carbonate (15 g) and dimethylformamide (153 ml) was stirred at room temperature for 24 hours and followed by at 35° C. for 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated to give 3,4-dihydro-3,4-epoxy-N,N,2,2-tetramethyl-2H-1-benzopyran-6-sulfonamide (4.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]([O:23]C)=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:21]([OH:23])=[O:22])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
To 4-(Methoxycarbonyl-phenyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester (151) (30.4 g, 87.25 mmol) in EtOH (200 mL) was added of 1N NaOH (192 mL) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture is then concentrated to dryness. The resulting residue is taken up in H2O and acidified slowly at 0° C. with 10% NaSO4 (pH=5–6). The desired product was then extracted into EtOAc. The organic phase was then concentrated to dryness yielding 24.3 g (86%) product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]#[N:9].[Al+3].[Cl-].[Cl-].[Cl-].[C:14](Cl)([CH3:16])=[O:15]>ClCCCl>[C:14]([C:6]1[C:2]([CH3:1])=[C:3]([C:8]#[N:9])[NH:4][C:5]=1[CH3:7])(=[O:15])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(C#N)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1c(C)[nH]c(C#N)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2-carbonitrile (1.2 g, 10 mmol) was dissolved in anhydrous 1,2-dichloroethane (15 mL) and AlCl3 (2.93 g, 22 mmol) was added proportion-wise. The reaction vessel was purged with N2 and was cooled in an ice-water bath. AcCl (0.71 mL, 10 mmol) was added dropwise and the mixture was stirred for 1 h with cooling and for a further 3 h at room temperature. The reaction mixture was quenched by careful addition of 2 M aq HCl. The acidity of the mixture was adjusted to approximately pH 6 by addition of NaHCO3. After separation of the organic phase, the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed (H2O, then brine), dried (MgSO4), and filtered. The solvent was evaporated to afford of 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.42 g, 88%) as a pale tan solid. 1H-NMR (CDCl3) δ: 2.44 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.54 (s, 3H, CH3), 8.75 (br. s, 1H, NH).