Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].C1C(=O)N([Br:19])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:19][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C#Cc1ccc(C(C)=O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(C#CBr)cc1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a stirring solution of compound 1.10 (12 g, 83.3 mmol) in acetone (200 mL) was added AgNO3 (1.34 g, 7.9 mmol) and the the reaction was stirred for 30 min. NBS (17.7 g, 99.96 mmol) was then added and the reaction mixture was stirred at 20° C. for 14 hr. Solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ethyl acetate in petroleum ether 5%-10% v/v) to give compound 1.11 as a white solid (14 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=8, 2H), 7.62 (d, J=8, 2H), 2.58 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.[CH3:19][C@H:20]1[CH2:25][C@H:24](OS(C)(=O)=O)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:19][CH:20]1[CH2:25][CH:24]([O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:4](=[O:18])[CH:3]=2)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32]
Reactant: C[C@H]1C[C@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CCN1C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 52.6 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (125 mg, 0.471 mmol), trans-tert-butyl 2-methyl-4-(methylsulfonyloxy)piperidine-1-carboxylate (138.2 mg, 0.471 mmol, Example 1) and potassium carbonate (163 mg, 1.178 mmol) in DMF (4.0 mL) was heated at 110° C. for 20 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined organic layers were washed with brine/water (1:1, 2×), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexane) to yield cis isomer of tert-butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (114.6 mg, 52% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3). δ 8.07 (d, J=8.80 Hz, 2H), 7.62 (d, J=8.25 Hz, 2H), 7.24 (d, J=7.70 Hz, 1H), 6.06 (dd, J=7.70, 2.75 Hz, 1H), 5.95 (d, J=2.20 Hz, 1H), 4.64-4.70 (m, 1H), 4.35-4.45 (m, 1H), 3.91-3.98 (m, 1H), 3.18-3.28 (m, 1H), 3.09 (s, 9H), 1.95-2.04 (m, 2H), 1.89-1.96 (m, 1H), 1.75-1.84 (m, 1H), 1.48 (s, 9H), 1.27 (d, J=7.15 Hz, 3H). MS (ESI) 463 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)[OH:19].[Cl-].[Na+]>>[C:13]([CH2:12][S:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2](=[O:1])[CH2:6][CH:5]([OH:19])[CH:4]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)CSCCCC1C(=O)C=CC1O
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2-[3-(carbethoxymethylthio)propyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][NH2:12]>C1COCC1.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:12][CH3:11])=[O:9])[CH:3]=1
Reactant: CN
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 3 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A 0° C. solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16 mol) in THF (100 mL) at was treated drop-wise with a solution of MeNH2 in EtOH, stirred at 3° C. for 4 h, then concentrated to dryness. The material was suspended in EtOAc, the solids removed via filtration and the filtrate was washed with brine (2×), dried and concentrated to yield 4-chloro-N-methylpicolinamide (16.4 g, 60%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (br s, 1H), 8.55 (d, J=5.2 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.66 (m, 1H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 171.0 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:17][CH3:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([N:11]1[CH2:10][C@@H:9]2[C@H:13]([CH2:14][CH2:15][C:16]3[C:4]([O:3][CH3:2])=[C:5]([O:17][CH3:18])[CH:6]=[CH:7][C:8]=32)[CH2:12]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1OC)CC[C@@H]1CNC[C@@H]21
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1OC)CC[C@@H]1CN(C(C)=O)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 114.7 %

Procedure:
A solution of trans-2,3,3a,4,5,9b-hexahydro-6,7-dimethoxy-1H-benz[e]isoindole hydrochloride (0.50 g, 1.9 mmole) and dry pyridine (9.5 mL) was stirred under N2 at room temperature as acetic anhydride (0.26 mL, 2.8 mmole) was added dropwise. The reaction mixture was stirred at room temperature for 0.75 hr, then was evaporated (in-vacuo). 2-Methoxyethanol was added and evaporated. The residue was dissolved in CH2Cl2 and was washed with 1N HCl, 1N KOH, water, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated to yield 0.60 g white solid; M+ 275.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].N[C:29]1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2[CH:30]=1.C(=O)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][CH2:29][CH3:30])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCC=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNc1cc2nc(-n3cc(C(=O)OCC)cn3)n(COCCOC)c2cc1Cl
Temperature: 23 °C
Reaction time: 22 h
Yield: 54 %

Procedure:
To a solution of 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol) and propionaldehyde (61.0 μL, 0.838 mmol) in THF (3 mL) was added sodium triacetoxyborohydride (0.226 g, 1.07 mmol) followed by acetic acid (40.9 μL, 0.762 mmol). The reaction mixture was stirred at 23° C. for 22 h. Molecular sieves (4 Å, 1.2 g) were added, and the reaction was kept at 40-50° C. for 24 h. Over the next 48 h, two additional portions of both propionaldehyde and sodium triacetoxyborohydride were added. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with EtOAc (3×35 mL) and the combined organic layers were washed with brine (25 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.178 g, 54% yield) as a 1:1 mixture of regioisomers. 1H NMR (400 MHz, CDCl3): 8.83 (s, 1H), 8.76 (s, 1H), 8.15 (s, 2H), 7.63 (s, 1H), 7.55 (s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 6.03 (s, 4H), 4.42 (br s, 1H), 4.35 (q, J=7.1 Hz, 4H), 4.27 (br s, 1H), 3.65-3.59 (m, 4H), 3.49-3.41 (m, 4H), 3.33 (s, 3H), 3.32 (s, 3H), 3.23-3.12 (m, 4H), 1.82-1.69 (m, 4H), 1.37 (t, J=7.1 Hz, 6H), 1.11-1.01 (m, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[K+]>CS(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 114.7 %

Procedure:
A mixture of 4-isopropylphenol (16.3 g), 4-chloronitrobenzene (15.8 g), dimethylsulfoxide (150 ml) and potassium hydroxide (5.6 g) was stirred at 90° C. for 48 hours. The reaction solution was poured into ice-water (500 ml), and extracted with ethyl acetate (250 ml), washed (3 times) with water, and d ried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give 4-(4-isopropylphenoxy)nitrobenzene (29.6 g). Further, it was dissolved in ethanol (300 ml), and thereto was added 5 % palladium/carbon (2.9 g) and the mixture was subjected to catalytic reduction at room temperature for 18 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 4-(4-isopropylphenoxy)aniline (24.6 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Nc1ccncc1
Reactant: O=Cc1ccc2occc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1cc(NCc2ccc3occc3c2)ccn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
Benzofuran-5-carbaldehyde (330 mg, 2.19 mmol, 1.0 equiv.) and 4-aminopyridine (227 mg, 2.41 mmol, 1.1 equiv.) were combined in 1,2-dichloroethane (22 mL) and treated with acetic acid (138 μL, 2.41 mmol, 1.1 equiv.) and sodium triacetoxyborohydride (969 mg, 4.34 mmol, 1.98 equiv.). The mixture was stirred at 60° C. overnight, and then quenched by addition of saturated NaHCO3 solution. The two phases were separated and the water layer was extracted twice with ethyl acetate. The combined organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with flash column chromatography on silica gel, eluting with ethyl acetate/dichloromethane/methanol to afford N-(benzofuran-5-ylmethyl)pyridin-4-amine as a white solid (62 mg, 13% yield). Mass: 225 (MH)+. Purity >99% (HPLC).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:19])[CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C1CCCCC1>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:19])[CH:11]([NH:18][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2
Reactant: Cc1ccc(C=O)cc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(CNC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a solution of amino-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (I76) (100 mg, 0.38 mmol) in dry THF (3.84 mL), are added 4-methylbenzaldehyde (68 mL, 0.57 mmol) and AcOH (0.5 mL, 8.73 mmol). The mixture is stirred at RT and sodium triacetoxyborohydride (163 mg, 0.77 mmol) is added. The reaction is stirred at RT for 1.5 hours then cyclohexane is added and the mixture is evaporated to dryness. The crude is purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.5) to obtain the title compound as a colorless oil (76 mg, 54% yield, mixture of diastereoisomers).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.Cl.[C:10](=N)(OCC)[CH2:11][CH2:12][CH2:13][CH3:14]>CN(C)C=O>[CH2:11]([C:10]1[NH:1][C:2]2[N:3]=[CH:4][N:5]=[CH:6][C:7]=2[N:8]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Nc1cncnc1N
Reactant: CCCCC(=N)OCC
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCc1nc2cncnc2[nH]1
Yield: 26.2 %

Procedure:
Using the procedure of Example 1, 5 g of 4,5-diaminopyrimidine and 10 g of ethyl pentanimidoate hydrochloride [J.A.C.S., Vol. 64, p 1827 (1942)] using dimethylformamide as solvent were reacted to obtain 2.1 g of the desired product which after crystallization from ethyl acetate melted at 166° C. The product was crystallized from ethyl acetate to obtain 1.8 g of the expected product melting at 168° C. 200 mg of an analytical sample was obtained by an additional crystallization of 300 mg of the product from ethyl acetate melting at 168° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]C(C)([O-])C.[K+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-Benzyl-3-methyl-piperidin-4-one (2.03 g, 10 mmol) in THF (10 mL) was added potassium t-Butoxide (1.1 g, 10 mmol) and methyl iodide (0.62 mL, 10 mmol). The solution was then stirred at room temperature for about 72 hours. The reaction was quenched with brine and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2].Br[CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>>[CH2:1]([O:3][C:4]([C:6]1([CH2:29][CH2:30][N:31]2[C:32](=[O:41])[C:33]3[C:34](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]2=[O:36])[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O
Product: CCOC(=O)C1(CCN2C(=O)c3ccccc3C2=O)CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O

Procedure:
The title compound was prepared from 5-oxo-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester and N-(2-bromoethyl)phthalimide as described in Example 1. 1H NMR (CDCl3) δ 7.85 (m, 4H), 7.75 (m, 4H), 7.55-7.45 (m, 2H), 7.4-7.35 (m, 1H), 7.25-7.2 (m, 1H), 4.2-4.0 (m, 6H), 3.9-3.85 (m, 1H), 3.65-3.55 (m, 3H), 3.4 (br s, 1H), 2.4 (s, 3H), 2.4-2.35 (m, 1H), 1.35-1.15 (m, 3H). MS (ES) m/z 583 (MNa)+
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[H-].[Na+].[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20]Br)(=[O:15])[CH3:14].O>CN(C=O)C>[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OCCOCBr
Reactant: Clc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2c(Cl)ncnc21
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 6-chloropurine (6 g, 38.8 mmoles) in DMF was added sodium hydride 60% (0.93 g) over 1.5 hour period. (2-acetoxyethoxy)methyl bromide was then added at room temperature; the reaction mixture was allowed to stir for 2 hours under N2 atmosphere. H2O was added and the product was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and evaporated in vacuo to give a light yellow solid 7.1 g, 68% yield of 9-[(2-acetoxy-ethoxy)methyl]-6-chloro-purine. The crude was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH:10]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:15]=3[CH:16]=2)[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>N1C=CC=CC=1>[C:26]([O:11][CH:10]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:15]=2[CH:16]=1)[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:25][CH:24]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccc2oc(C(O)COc3ccc(C(=O)O)cc3)cc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(COc1ccc(C(=O)O)cc1)c1cc2cc(C(C)C)ccc2o1
Temperature: 0 °C

Procedure:
2-[1-Hydroxy-2-(4-hydroxymethylphenoxy)ethyl]-5-isopropylbenzofuran (10 g) obtained in Example 6 was dissolved in 100 ml of pyridine, the mixture was stirred at room temperature for 24 hours with 10 ml of acetic anhydride, poured into ice water, the mixture was acidified with concentrated hydrochloric acid and the crystals separated out therefrom were filtered, dried and recrystallized from ethyl acetate/n-hexane to give 8.2 g of crystals. M.p. 135°-137° C.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[C:3]1=O.B>>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)[CH2:3]1
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Agent: B
Product: CN1CC2(CCNCC2)c2ccccc21

Procedure:
For the synthesis of the title compound, m.p. 222° C. and MS: m/e=437.4 (M+H+), 1-methyl-spiro[3H-indole-3,4'-piperidin]-2(1H)-one is reduced with borane according to example 16 to yield 1-methyl-1,2-dihydro-spiro[indole-3,4'-piperidine], which was further reacted with 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-propan-3-ol in accordance with the general method of example 8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH-].[K+].[NH2:20]OS(O)(=O)=O>O>[NH2:20][N:8]1[C:9]2[C:4](=[C:3]([N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=2)[NH:5][C:6](=[O:14])[C:7]1=[O:13]
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Cl)c(Cl)cc21
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
The procedure of Shin, S. C. and Lee, Y. Y., Taehan Hwahakhoe Chi 27(5):382-4 (1983) was adapted. A red solution of 6,7-dichloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (100 mg, 0.36 mMol, Cheeseman, supra) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added to a colorless solution of NH2OSO3H (75 mg, 0.66 mMol, Aldrich) in distilled water (0.5 mL) with stirring. A yellow precipitate came out after 10 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C. and was washed with distilled water (2 ml), then dried at 50° C. overnight, affording 85 mg (80%) of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, as a yellow amorphous solid (80% of desired 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). A 85 mg sample of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (free base Na+, 0.293 mMol) was dissolved into distilled water (10 mL) at 50° C., then was acidified with AcOH to pH=5. After removal of the insoluble material by filtration, the mixture was heated at 60°-70° C. until a clear solution was obtained, which was slowly cooled, whereupon a yellow precipitate came out. The precipitate was crystallized from hot EtOH and the yellow microcrystals were collected by filtration, washed with cold ethanol (2 mL), and dried in the air at 60° C. for 4 h, affording 31 mg (29%) of pure 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione. Mp was measured: the color of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 275° C.; the decomposition of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione is obvious at 280° C. and it melted to a black liquid at 290°-1° C. IR (KBr, cm-1): 3442; 3315; 3231; 1747; 1723; 1680; 1632; 1547. NMR (1H, DMSO-d6): δ5.848 (s, 2H); 7.951 (s, 1H); 12.595 (s, 1H). HRMS: calcd for C8H4N4O4Cl2 (M+) m/z:289.9623; found 289.9616.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:3][CH:2]=1.[C:14]([O:21]CC)(=O)[C:15]([O:17]CC)=O.[O-]CC.[Na+]>C(O)C>[O:21]=[C:14]1[C:15](=[O:17])[CH:10]([C:11]#[N:12])[CH2:9][CH2:8][N:7]1[C:4]1[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(NCCCC#N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(N2CCC(C#N)C(=O)C2=O)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
4-(p-Tolylamino)butanenitrile (13.23 g, 75.929 mmol) was dissolved in ethanol (189.8 mL). After adding diethyl oxalate (10.3 mL, 75.929 mmol) and then adding sodium ethoxide (34.0 mL, 91.115 mmol) to the resultant reaction mixture, reaction was carried out under reflux for 2 days. The reaction solution was cooled to room temperature and the concentrated solution was filtered. A target compound (8.94 g, 39.167 mmol, 51.6%) was yielded as yellow solid.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[CH2:9]([O:11][C:12](=[O:44])[C:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=1)[C:14]([O:16]CC)=[O:15])[CH3:10]>C(OCC)(=O)C.S(=O)(=O)(O)O>[CH2:9]([O:11][C:12](=[O:44])[C:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH:21]=1)[C:14]([OH:16])=[O:15])[CH3:10]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)O)C(=O)OCC
Reaction time: 8 h

Procedure:
Sodium hydroxide, 1M, (21.5 mL, 21.5 mmol) was added in portions over 30 minutes to a dioxane (22 mL) solution of 2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonylpyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester (10.95 g, 21.5 mmol). After stirring overnight, the reaction had not gone to completion. An additional 0.2 equivalents of 1M sodium hydroxide (4.2 mL, 4.2 mmol) was added and stirring continued for 3 hours. The reaction was diluted with ethyl acetate (50 mL) and 1M sulfuric acid (23 mL) was added dropwise at 0° C. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate and concentrated in vacuo to give a the title compound. The crude product was used directly in the next step without separation of the unreacted diester. MS (CI) m/z 382.2 (M−99).