Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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:28]1[CH2:29][CH:30]=[C:31]([C:2]2[C:10]3[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=2)[CH2:32][CH2:33]1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C2=CCOCC2)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 2.23 mmol) in toluene/EtOH/H2O (4:2:1, 14 mL), was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.70 g, 3.3 mmol), sodium carbonate (0.70 g, 6.7 mmol) and Pd(PPh3)4 (0.13 g, 0.11 mmol). The resulting solution was stirred for 12 hours at 80° C., cooled, and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (×3) and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 1-50% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 5-(3,6-dihydro-2H-pyran-4-yl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid. LRMS (ESI) calc'd for C23H29N4O4Si [M+H]+: 453, found 453.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1C[O:14]CC1.C1CCC(N=C=NC2CCCCC2)CC1.[C:31]1([C:37]2[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[OH:14][N:7]1[C:6]([C:8](=[O:10])[NH:42][CH2:41][C:40]2[CH:39]=[CH:38][C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:44][CH:43]=2)=[CH:5][CH:4]=[CH:3][C:2]1=[O:1]
Reactant: O=C(O)c1cccc(O)n1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: C1CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2ccccc2)cc1)c1cccc(=O)n1O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Synthesis of benzyl protected 1,2-HOPO acid (1,2-HOPOBn acid) (1-benzyloxy-6-carboxypyridin-2-one), from 6-hydroxypicolinic acid was performed as reported by Raymond et al. (J. Med. Chem., 45, 3963 (2002)) (yield=80%). 1,2-HOPOBn acid (760 mg, 3.1 mmol) was added to 50 ml THF and dissolved immediately to a slightly yellow solution. NHS (360 mg, 3.1 mmol) was added to this solution (no color change) and stirred under N2 for 30 mins. DCC (640 mg, 3.1 mmol) was then added to the flask (no color change) and stirred for 3 hrs under N2. Solution was vacuum filtered to remove DCU and 4-phenylbenzylamine (568 mg, 3.1 mmol) was added to clear bronze filtrate. The solution stirred o/n at RT under N2. The creamy yellow solution was rotovaped to dryness; the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate. The organic layer was dryed over magnesium sulfate and then rotovaped to dryness to an off-white residue. The residue was sonicated in a minimal amount of MeOH to remove any remaining DCU. The sonicate was rotovaped to dryness and oven dried for 3 hours to a white solid with a 71% yield. Deprotection of the benzyl group was carried out in a 1:1 mixture of HCl (40 ml) to glacial acetic acid (40 ml) for 5 days. The milky white solution was then rotovaped to dryness and washed 3 times with MeOH. The final white residue (20) was oven dried to a 91% yield.
Reaction SMILES: Cl.O[C:3]1([C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][NH:28]3)[CH2:8][CH2:7][N:6]([CH2:9][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]=[CH2:23])[OH:11])[CH2:5][CH2:4]1.Cl.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH:28]1[C:29]2[C:25](=[C:24]([C:3]3[CH2:8][CH2:7][N:6]([CH2:9][CH:10]([CH2:12][O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH:22]=[CH2:23])[OH:11])[CH2:5][CH:4]=3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: C=CCOc1ccccc1OCC(O)CN1CCC(O)(c2cccc3[nH]ccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccccc1OCC(O)CN1CC=C(c2cccc3[nH]ccc23)CC1
Yield: 93.9 %

Procedure:
A solution of 9.3 g of the free base of Example 10, 300 ml of lN hydrochloric acid and 100 ml of ethanol was refluxed for 3 hours and the mixture was diluted with water and made alkaline. The aqueous phase was saturated with potassium carbonate and was extracted with ethyl acetate. The organic phase was chromatographed over silica gel and eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 7.7 g of 4-(1H-indole-4-yl)-α-[[2-(2-propenyloxy)-phenoxy]-methyl]-1,2,3,6-tetrahydro-1-pyridine ethanol with an Rf=0.05.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:18]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.CCOCC>C1COCC1>[CH:11]1([CH2:10][CH2:9][C:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(CCC1CCCCC1)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)C1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3-Cyclohexyl-thiopropionic acid S-pyridin-2-yl ester (1.43 g, 5.74 mmol) from Step 1 above was dissolved in dry THF (28 mL) and cooled to −78° C. A solution of cyclopentylmagnesium bromide in Et2O (2.0 M, 3.01 mL, 6.02 mmol) was added dropwise. After stirring 1 h, the cooling bath was removed. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (1% EtOAc in hexanes) to give the product (0.99 g, 83%) as clear oil. 1H NMR (CDCl3) δ: 0.82-1.84 (m, 21H), 2.42-2.47 (m, 2H), 2.82-2.92 (m, 1H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([C:20](OCC)=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1.ClCCl.O>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:20](=[O:21])[C:15]=3[N:16]([CH3:19])[C:17]=2[CH:18]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
4 ml (40.6 mmol) of phenylhydrazine are added at room temperature to a solution of 4.6 g (13.6 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate in 120 ml of acetic acid. The reaction mixture is stirred for 30 min at room temperature and then for 4 hours at reflux. The mixture is cooled and 350 ml of dichloromethane and 100 ml of water are added. The organic phase is separated by settling, washed with a saturated aqueous sodium hydrogencarbonate solution and then with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 4.1 g (10.7 mmol) of product are isolated.
Reaction SMILES: [C:1]([CH:4]1[CH:18]2[CH:7]([CH2:8][C:9]3[C:17]4[C:16]2=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=3)[N:6]([CH3:28])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].O.ClCCl>C(O)C>[C:22]1([S:19]([N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[CH:18]5[CH:7]([CH2:8][C:9]([C:17]=34)=[CH:10]2)[N:6]([CH3:28])[CH2:5][CH:4]5[CH:1]([OH:3])[CH3:2])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12

Procedure:
To a stirred solution of the 9-acetyl compound (Example 4) (0.10 g) in ethanol (2 cm3) was added sodium borohydride (0.0075 g) with visible reaction. After 2 hours reaction was indicated to be complete. Water (20 cm3) and dichloromethane (20 cm3) were added and the mixture partitioned, the separated aqueous layer was re-extracted with dichloromethane (20 cm3) to give, after evaporating under vacuum, a yellow-white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:19].[C:20]([O:24]CC)(=O)[C:21]#[CH:22]>C(O)C>[C:1]1([CH:7]2[CH2:8][C:9]3[NH:19][C:20](=[O:24])[CH:21]=[CH:22][C:10]=3[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: C#CC(=O)OCC
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (1.0 g) and ammonium acetate (0.45 g) in ethanol (30 ml) was stirred at room temperature for 1 hour, refluxed for 6 hours and cooled. To the reaction solution was added ethyl propiolate (0.55 g), and the mixture was stirred at room temperature for 1 hour and refluxed 14.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from ethanol to give colorless crystals of 7-phenyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.19 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:25].[OH-].[Na+]>COCCOC.C(OCC)(=O)C.C(Cl)Cl>[I:1][C:2]1[C:10]2[N:9]([CH3:25])[C:8]3[CH2:11][CH2:12][NH:13][CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(I)cccc3c2C1
Reactant: CI
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1c2c(c3cccc(I)c31)CNCC2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
Tert-butyl 6-iodo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (6.8 g, 17 mmol) was dissolved in DME (50 mL), and potassium hydroxide (4.8 g, 85.4 mmol) and iodomethane (15.7 g, 110.5 mmol) were added and heated at 80° C. in a pressure vessel for 3 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The solids were removed by vacuum filtration. The filtrate was concentrated under reduced pressure to give a brown oil (5.5 g, 79% crude yield). The oil was dissolved in CH2Cl2 (30 mL). Trifluorocacetic acid (30 mL) was added in ten portions over 5 minutes and stirred for 30 minutes. The reaction was basified with 50% sodium hydroxide to pH 10. This mixture was extracted with CH2Cl2 (3×150 mL). The organics were collected, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 6-iodo-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.85 g, 73%). 1H NMR (CDCl3 300 MHz) δ 7.62 (d, 1H, J=7.6 Hz), 7.33 (d, 1H, J=7.7 Hz), 6.74 (t, 1H, J=7.5 Hz), 4.03 (s, 2H), 3.95 (s, 3H), 3.26 (t, 2H, J=5.6 Hz), 2.71 (t, 2H, J=5.6 Hz) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.CN([CH:25]=[O:26])C>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH:25]=[O:26])=[CH:3]1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c2ccn(C)c2c1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Product: Cc1cc(C)c2c(C=O)cn(C)c2c1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1,4,6-trimethyl-1H-indole (800 mg, 5 mmol) in DMF (0.9 mL) is cooled to 5° C. under nitrogen. Pyrophosphoryl chloride (1.4 mL, 10 mmol) is then slowly introduced. Upon complete addition the cooling bath is removed and the reaction is allowed to warm to ambient temperature. After a total of 45 minutes, the reaction is recooled to 5° C. and is slowly quenched with 2N NaOH. The pH of the solution is adjusted to 8. The precipitated solid is collected by filtration and is washed with water to afford 1,4,6-Trimethyl-1H-indole-3-carbaldehyde (875 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C([N:25]1[CH2:29][C:28](=O)[N:27]=[CH:26]1)(=O)C.P(Cl)(Cl)([Cl:33])=O>>[ClH:33].[NH:27]1[CH2:28][CH2:29][N:25]=[C:26]1[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][C:18]([F:21])([F:19])[F:20])[CH:14]=2)[NH:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)N1C=NC(=O)C1
Product: Cc1ccc(-c2[nH]c3ccc(OC(F)(F)F)cc3c2C2=NCCN2)cc1
Product: Cl
Temperature: 60 °C

Procedure:
380 mg (1.3 mmol) of the indole from Step A was heated with 210 mg (1.6 mmol) of N-acetyl-2-imidazolinone in 1.3 ml of neat phosphoryl chloride at 60° C. for 20 h. The excess of phosphoryl chloride was removed under reduced pressure, and the residue was dissolved in 2 ml of absolute ethanol and heated at 60° C. for 5 h. The mixture was cooled, and the crystalline precipitate collected by filtration, washed with ethanol, and dried in vacuo.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.[F:29][CH:30]([F:36])[C:31](OCC)=[O:32]>>[F:29][CH:30]([F:36])[C:31]([NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:10]1)=[O:32]
Reactant: CCOC(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Product: O=C1C=CN(c2ccc(N3CC(CNC(=O)C(F)F)OC3=O)cc2)CC1

Procedure:
The compound is prepared from {3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (250 mg, 0.64 mmol) and ethyl difluoroacetate (120 mg, 0.96 mmol) following the method described for Example 5 (using ethyl difluoroacetate as starting agent). The product is purified by silica gel column chromatography (eluent 1% MeOH in EtOAc) and recrystallized from MeOH to provide the title compound. MS (m/z): 366 [M+1]. 1H NMR (300 MHz, DMSO) δ 9.16 (t, J=5.8 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.53 (d, J=9.1 Hz, 2H), 7.28 (d, J=9.1 Hz, 2H), 6.24 (t, J=53.0 Hz, 1H), 4.98 (d, J=7.7 Hz, 1H), 4.80–4.75 (m, 1H), 4.14 (t, J=9.1 Hz, 1H), 3.97–3.92 (m, 2H), 3.76 (dd, J=6.3 and 9.1 Hz, 1H), 3.52 (t, J=5.5 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1C(O)=C[CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[N+](=[CH2:30])=[N-].C[CH2:32][O:33][CH2:34][CH3:35]>CO>[CH3:32][O:33][C:34]1[CH:35]=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12](/[OH:13])=[CH:14]/[C:15](/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:30])=[C:24]([O:25][CH3:26])[CH:27]=2)=[O:16])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: C=[N+]=[N-]
Reactant: CCOCC
Solvent: CO
Product: COc1ccc(/C=C/C(=O)/C=C(O)/C=C/c2ccc(OC)c(OC)c2)cc1OC
Yield: 19.8 %

Procedure:
Curcumin (1) in Et2O and MeOH was treated with excess of diazomethane in ether for 24 h. The solvents were removed in vacuo and the residue was purified by silica gel column chromatography and PLC to yield yellow needles of 4 (yield 19.8%); mp 129-130° C. (MeOH) (Roughley et al., J. Chem. Soc. Perkin I, 2379-2388 (1973))(128-130° C.); 1H NMR (300 MHz, CDCl3): δ 3.93 (12H, s, OCH3×4), 5.82 (1H, s, 1-H), 6.48 (2H, d, 16 Hz), 6.88 (2H, d, J=8 Hz), 7.08 (2H, bs), 7.15 (2H, bd), 7.61 (2H, J=16 Hz); 13CNMR (300 MHz, CDCl3): δ 55.9, 56.0, 101.3, 109.8, 111.1, 122.0, 122.6, 128.1, 140.4, 149.2, 151.0, 183.2.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH2:46][CH2:47][CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:13]([C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:20]([NH:45][CH2:46][CH2:47][CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(CCN)OCC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCC
Yield: 91.7 %

Procedure:
By using an analogous procedure to that described for Reference Example 13, N-(carbobenzyloxy)-L-phenylalanine (2 g, 6.68 mmol), hydroxybenzotriazole (903 mg, 6.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 1.28 g, 6.68 mmol), 1-amino-3,3-diethoxypropane (935 mg, 6.36 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.68 mmol) were reacted in anhydrous tetrahydrofuran (32 mL) at room temperature for 16 h, to provide benzyl (1S)-1-benzyl-2-[(3,3-diethoxypropyl)amino]-2-oxoethylcarbamate (2.5 g, 92%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][C:3]1[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[N:4]=1
Reactant: COc1ccc2nc(OC)c(N)nc2c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 96.1 %

Procedure:
3-Amino-2,6-dimethoxyquinoxaline (616 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 799 mg of the titled compound (yield, 96%).
Reaction SMILES: C([C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10](N)[CH2:9]1)(OC(C)(C)C)=O.C([N:17](CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].C(O)(C(F)(F)F)=O>C(Cl)Cl.O.Cl>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([N:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([NH2:17])[CH2:9]1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(S(=O)(=O)c2ccccc2F)C1
Reaction time: 2 h
Yield: 64.4 %

Procedure:
(R)-3-Boc-aminopiperidine (1.05 g, 5.25 mmol) was dissolved in DCM (10 mL) and then triethylamine (1.10 mL, 7.89 mmol) was added. To this solution at room temperature was added 2-fluorobenzenesulfonylchloride (1.127 g, 5.79 mmol). After 2 h, reaction was deemed complete by LCMS and diluted with water and extracted with DCM (30 mL), and the organic layer was separated and dried over magnesium sulfate, filtered and concentrated and taken to the next step as such. The crude product from above was dissolved in DCM (25 mL) and TFA (10 mL) added in one portion. Reaction mixture followed by LCMS. After 1 h, TFA was stripped in vacuo and then the residue suspended in 3N HCl and washed with ether. The aq. layer was basified and extracted with DCM and the DCM layer separated and dried over magnesium sulfate, filtered and concentrated in vacuo to give 873 mg of (R)-1-((2-fluorophenyl)sulfonyl)piperidin-3-amine as the desired product as free base. LCMS (m/z): 255.5 (MH+), 0.49 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([N+](=O)[O-])cc1OCOCC[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
A mixture of 2-methoxy-5-nitrophenol (10 g, 59.1 mmol) in dichloromethane (150 mL) was treated with 2-(trimethylsilyl)ethoxymethyl chloride (10.5 mL, 59.3 mmol) and N,N-diisopropylethylamine (11.3 mL, 64.9 mmol) at room temperature and stirred for 1.5 hours. The reaction mixture was then concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum to provide the desired product.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[S:7][C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][NH:24][NH2:25])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15]4[C:14](=[N:25][N:24]([CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])[C:2]=4[CH:3]=[CH:4][C:5]=3[CH3:18])[C:13]=2[CH:12]=1
Reactant: Cc1ccc(Cl)c2c(=O)c3cc(Cl)ccc3sc12
Reactant: CCN(CC)CCNN
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccc(Cl)cc1-2

Procedure:
By condensation of 1,7-dichloro-4-methyl-9-thioxanthenone with 2-(diethylamino)ethyl hydrazine was obtained 9-chloro-2-(2-(diethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole. To 0.13 g. of this base in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.2 ml.). After 18 hours at room temperature the solution was evaporated to dryness under reduced pressure and the residue crystallized from acetone to give 9-chloro-2-(2-(diethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole N-oxide monohydrate, m.p. 134°-135° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C)nc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.05 g) in methylene chloride (100 mL) was added m-chloroperbenzoic acid (77%, 13.5 g). The reaction mixture was stirred at room temperature for 2 h and then diluted with chloroform (100 mL). The mixture was washed successively with aqueous sodium sulfite, saturated sodium bicarbonate, and brine. The organic later was then dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 6.21 g of methyl 6-methylnicotinate 1-oxide. A solution of methyl 6-methylnicotinate 1-oxide (4.35 g) in acetic anhydride (50 mL) was heated at 120° C. for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1:2 to 3:5 ethyl acetate/hexanes) provided 3.3 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 9.18, 8.31, 7.44, 5.29, 3.96, 2.19.