Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([CH3:8])[CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>COCCOC>[CH2:28]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([C:2]2[CH:3]=[C:4]([CH3:17])[C:5]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]([CH3:8])[CH:7]=2)([OH:44])[C:36]1=[O:45])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Li]C(C)(C)C
Solvent: COCCOC
Solvent: CCCCC
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
Dissolve 5-bromo-1,3-dimethyl-2-(phenylmethoxy)-benzene (2.56 g, 8.8 mmol) in ethylene glycol dimethyl ether (40 mL) under nitrogen. Cool to −70° C. with a dry ice/acetone bath and add slowly a 1.7M solution of t-butyllithium in pentane (10.4 mL, 17.6 mmol). After 15 min add 1-benzyl-1H-indole-2,3-dione (1.90 g, 8 mmol) in ethylene glycol dimethyl ether (32 mL). Remove the bath and allow to warm to room temperature with stirring for 18 h. Quench with saturated NH4Cl solution and extract with ethyl acetate (2×). Wash combined organics with brine and then dry (Na2SO4), filter and concentrate in vacuo to give 3.42 g of a dark purple oil. Purify initially by flash chromatography (25% EtOAC/hexanes) to give 1.20 g of material which by TLC is mostly starting material and product. Purify further by chromatography (step gradient of CH2Cl2, 5% acetonitrile/CH2Cl2, 10% acetonitrile/CH2Cl2) to give 803 mg (22%) of the title compound as a yellow foam. MS (ES): m/z=432 (M+1−H2O); 1H NMR(DMSO-d6); δ7.50-7.18 (m, 12H), 7.00 (m, 2H), 6.95 (s, 2H), 6.77 (s, 1H), 4.93 (q, J=2 Hz, J=18 Hz, 2H), 4.77 (s, 2H), 2.20 (s, 6H).
Reaction SMILES: ClC1C=CC=CC=1N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12].[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(#N)CC#N.O.[NH2:29][NH2:30]>>[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][N:9]=[C:10]1[C:11]([NH2:12])=[N:30][N:29]=[C:13]1[NH2:14]
Reactant: N#CC(C#N)=NNc1ccccc1Cl
Reactant: NN
Reactant: Nc1ccccc1Cl
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccccc1Cl

Procedure:
4-[(2-chlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 102 mg (0.5 mmol) of 2-[(2-chlorophenyl)hydrazono]malononitrile, which was derived from 2-chloroaniline (105 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 34 mg (29%) of the compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>ClCCl.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[C:17]([OH:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4](=[O:9])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 72 g) in dichloromethane (1 l) was added pyridine (81 ml). Then, palmitoyl chloride (150.7 g) was added thereto at 0° C. The mixture was stirred at 0° C. for 1 hour and for additional 2 hours at ambient temperature. The reaction mixture was diluted with chloroform (1 l), poured into ice water (1 l), acidified with dilute hydrochloric acid solution, and washed with water (500 ml×3). After drying over magnesium sulfate, the solvent was evaporated under reduced pressure to give 2,2-dimethyl-5-(1-hydroxyhexadecylidene)-1,3-dioxane-4,6-dione (200 g) as an oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:28][CH3:29])[C:20]2[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:28][CH3:29])[C:20]2[C:25]([CH:26]=[CH:1][CH3:2])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=Cc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 14 and making non-critical variations but starting with n-butyl lithium (1.6M, 1.16 ml, 1.86 mmol), ethyltriphenylphosphonium bromide (0.69 g, 1.86 mmol), and 1-benzyl-4-[N-ethyl-N-(3-(formyl)-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 12, 0.40 g, 1.24 mmol), the title compound is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([C:11]=1Br)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cu][C:18]#[N:19].[N:20]1C=CC=C[CH:21]=1.CN1CCCC1=O>O.[NH4+].[OH-].CCOC(C)=O>[C:21]([C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([C:11]=1[C:18]#[N:19])=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:20]
Reactant: COC(=O)c1cc(Br)c(Br)c2ccccc12
Reactant: c1ccncc1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)c(C#N)c2ccccc12
Temperature: 150 °C
Yield: 26.6 %

Procedure:
A mixture containing methyl 3,4-dibromo-1-naphthoate (126 mg, 0.366 mmol), copper (I) cyanide (618 mg, 6.89 mmol), pyridine (0.1 mL), and dry N-methylpyrrolidinone (2.0 mL) was heated at approximately 150° C. for 1 h. cooled to room temperature, diluted with water, NH4OH and EtOAc. The mixture was stirred briefly and filtered. The organic phase was separated and the aqueous phase extracted with additional EtOAc. The combined organic extracts were washed (dilute aqueous NH4OH and saturated NaHCO3). dried (Na2SO4), filtered, and EtOAc was removed in vacuo. The products were separated by chromatography (5-15% EtOAc in hexane and hexane:DCM (2:1)) to afford methyl 3,4-dicyano-1-naphthoate (22 mg; 25%) [1H NMR (CDCl3) δ 9.01 (m, 1H), 8.41 (m, 1H), 8.36 (s, 1H), 7.9 (m, 2H), 4.08 (s, 3H); MS (EI) m/z 236 (M)], methyl 3-bromo-4-cyano-1-naphthoate (21.9 mg; 20.6%) [1H NMR (CDCl3) δ 8.86 (m, 1H), 8.31 (s, 1H), 8.28 (m, 1H). 7.75 (m, 2H), 4.05 (s, 3H); MS (EI) m/z 289 (M).], and methyl 4-bromo-3-cyano-1-naphthoate (28.3 mg; 26.6%) [1H NMR (CDCl3) δ 9.02 (m, 1H), 8.43 (m, 1H), 8.28 (s, 1H), 7.8 (m, 2H) 4.04 (s, 3H); MS (EI) m/z 289 (M)]. The esters were separately saponified by stirring with 1.1-1.2 equivalents of LiOH in THF:water:methanol (20:10:1) at room temperature. The solutions were concentrated in vacuo, diluted with additional water, acidified with 1N HCl, extracted with EtOAc, dried (Na2SO4), filtered, and the EtOAc was removed in vacuo to afford the individual carboxylic acids. Prior to use, the 3,4-dicyano-1-naphthoic acid was further purified by chromatography (10-20% methanol in DCM) to afford the title compound (15.3 mg, 87%) as an off-white solid. MS (EI) m/z 222 (M).
Reaction SMILES: [CH3:1][C:2]1O[C:10](=[O:12])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)(=O)C>[CH3:1][C:2]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1ccccc1N
Reactant: Cc1nc2cnccc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(C)nc2cnccc2c1=O

Procedure:
2-Methyl-3-oxa-1,7-diaza-naphthalen-4-one (1.95 g, 12.0 mmol) was dissolved in acetic acid (30 mL) and o-toluidine (1.92 mL. 18 mmol) was added. The reaction was refluxed 7 hours, cooled and concentrated. The residue was taken up in ethyl acetate and extracted with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (2×4 inches, packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (500 mL); 25% ethyl acetate/hexane (800 mL); 25% ethyl acetate/hexane (200 mL) and 40% ethyl acetate/hexane (200 mL), unweighed recovered 2-methyl-3-oxa-1,7-diaza-naphthalen-4-one; 40% ethyl acetate/hexane (300 mL), unweighed mixed fraction; 40% ethyl acetate/hexane (3000 mL), 2-methyl-3-o-tolyl-3H-pyrido[3,4-d]pyrimidin-4-one (2.47 g, 81%) of as an off white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]12([N:47]=[C:48]=S)[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2.C(N(CC)CC)C.CN(C)C=[O:60]>>[C:37]12([NH:47][C:48]([NH:3][C:4]3[CH:36]=[CH:35][C:7]([O:8][C:9]4[CH:10]=[CH:11][C:12]5[N:16]=[C:15]([CH2:17][O:18][C:19]6[CH:32]=[CH:31][C:22]([CH2:23][CH:24]7[S:28][C:27](=[O:29])[NH:26][C:25]7=[O:30])=[CH:21][CH:20]=6)[N:14]([CH3:33])[C:13]=5[CH:34]=4)=[CH:6][CH:5]=3)=[O:60])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2
Reactant: CN(C)C=O
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)NC45CC6CC(CC(C6)C4)C5)cc3)cc21
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 1-adamantyl isothiocyanate (284 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 4.5 hours, at 50° C. for 2.5 hours and then at 80° C. for 4.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:1→2:1→3:1 as the eluant and the product was recrystallized from ethyl acetate to afford the title compound (192 mg, mp 164.0-166.6° C.).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: COc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 72.7 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 308 mg of 4-methoxyindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 269 mg of 2-[2-(4-methoxy-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a pinkish powder, the characteristics of which are the following:
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:6])[CH3:5].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])#[N:25].Cl>ClCCl.C(OCC)(=O)C.N1C=CC=CC=1>[C:4]([C:7]([C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:24]#[N:25])[CH:27]=1)([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])(=[O:6])[CH3:5]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)CCCCC(C(C)=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCCCC(C(C)=O)(C(=O)OC(C)(C)C)C(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.9 %

Procedure:
To a suspension of magnesium chloride (1.33 g) in dichloromethane (40 mL) was added 1-tert-butyl 7-ethyl 2-acetylheptanedioate (4.0 g) at ambient temperature under N2. To this mixture was added dropwise pyridine (2.26 mL) in an ice-water bath. Then the mixture was stirred at ambient temperature for 40 minutes. To the reaction mixture was added a solution of 3-cyanobenzoyl chloride (3.01 g) in dichloromethane (6 mL) dropwise over 2 minutes. The reaction mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N hydrogen chloride and ethyl acetate in an ice-water bath. The organic layer was washed with 1N hydrogen chloride, water, and brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid. The residue was purified by flash silica gel chromatography (silica gel, 300 mL) eluting with hexane-ethyl acetate=10-1, 8-1, 5-1, and 3-1 to give 1-tert-butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)heptanedioate (4.23 g, 72.9%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1(O)[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][C:26]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(O)(c2ccccc2F)CC1
Reactant: SCc1ccc(Cl)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1CCC(SCc2ccc(Cl)cc2)(c2ccccc2F)CC1
Product: Cl
Reaction time: 48 h

Procedure:
9.9 ml (11.9 g) of 4-chlorobenzyl mercaptan and 11.1 ml of boron trifluoride etherate are added sequentially to 5.00 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine. Example 1a, in 11.1 ml of glacial acetic acid. The reaction is stirred at 55°-60° C. for 48 hours. The excess reagents are removed at 80° C. in vacuo and the residue is taken up with a 1:1 ether-2 N hydrochloride acid mixture. This biphasic mixture is stirred for 2.5 hours and then for an additional ten minutes after 50 ml of ice are added. The ether layer is decanted off. The aqueous layer is sequentially washed with ether and filtered to collect a crude product. The product is washed with a small portion of water and then a large portion of ether to give a white powder. The powder is recrystallized from acetone to give white crystals, mp 164°-166° C. of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)- 1-methylpiperidine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(=O)([O-])[O-].[K+].[K+].O1[CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C)C=O>C(OCC)(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][CH2:40][C:41]3[CH:5]=[C:6]([CH:7]=[CH:43][CH:42]=3)[CH2:9][S:23][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[NH:26][CH:27]=[N:28]4)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: C1CCOC1
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(SCc3cccc(CSc4ncnc5nc[nH]c45)c3)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
A solution of 4,5-bis(4-methoxyphenyl)-2-mercapto-1H-imidazole (3.00 g, 9.60 mmol), 6-mercaptopurine (1.63 g, 9.60 mmol) a,a'-dibromoxylene (2.54 g, 9.60 mmol), and potassium carbonate (3.32 g, 24.0 mmol) and in 5:1 tetrahydrofuran-dimethylformamide (12 mL) was heated to reflux for 20 hours, then cooled. It was poured into ethyl acetate (150 mL), and washed with water (4×150 mL). The aqueous phases were back-extracted in sequence with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (ethyl acetate) to afford the title product as a crystalline solid, m.p. 129°-130° C. (1.64 g, 2.89 mmol, 30%). 1H NMR (CDCl3): 8.63 (1H, s); 8.02 (1H, s); 7.30 (4H, d, J=8.8 Hz); 7.23 (1H, s); 7.16 (1H, d, J=8 Hz); 6.99 (1H, t, J=8 Hz); 6.81 (1H, d, J=8 Hz); 6.71 (4H, d, J=8.8 Hz); 4.44 (2H, s); 4.02 (2H, s); 3.69 (6H, s). Elemental analysis: calculated C 63.58, H 4.62, N 14.83; observed C 63.25, H 4.55, N 14.72.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(=O)[nH]cnc2c1
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Pd/C (100 mg) was added as a single portion to a degassed and flushed (3×Ar) suspension of 7-nitroquinazolin-4-one (1.15 g, 6.02 mmol) in methanol(150 mL). The resulting black mixture was degassed, flushed with hydrogen and allowed to stir for 4 hours. The mixture was filtered through celite, washed well with methanol, and the filtrate concentrated to give a tanned solid. This was purified by column chromatography (silica) using 10% methanol/ethyl acetate as the eluent. Combined fractions gave a beige solid (949 mg, 98% yield).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Li].O>CCOCC>[OH:1][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH2:2]1
Reactant: [Li]c1ccccn1
Reactant: c1ccc2c(c1)CC1OC1C2
Solvent: O
Solvent: CCOCC
Product: OC1Cc2ccccc2C(c2ccccn2)C1
Temperature: -20 °C

Procedure:
A solution of 25 g of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene in 250 ml ether is added to a solution of 2-pyridyl lithium (prepared from 2-bromopyridine and butyllithium) cooled to -20° C. After addition, the mixture is allowed to come to room temperature over several hours, then cooled again and treated with water. The separated, dried organics are taken to dryness, and the product purified by chromatography in neutral alumina.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=NN=N1.C(N(CC)[P:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])C.ClC1C=CC=C(C(OO)=[O:45])C=1>ClCCl.C(Cl)(Cl)Cl>[P:24]([O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:45]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(CO)CCO[Si](C)(C)C(C)(C)C
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)COP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: -45 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of the product from Example 10A (0.630 g, 2.7 mmol) and 1H-tetrazole (0.568 g) in dichloromethane (11.0 mL) at room temperature was added di-t-butyl diethylphosphoramidite (1.02 g), and the solution was allowed to stir for 1 hour. The solution was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.33 g). After 1 hour at −45° C., additional m-chloroperbenzoic acid (1.33 g) was added and the mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with chloroform and washed with 10% Na2CO3 and brine, and was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give the title compound (0.441 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:12][CH3:13])[CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21].O>C(Cl)Cl>[C:20]([O:23][CH2:24][C:25]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:12][CH3:13])[CH3:11])[C:3]=1[C:4]#[N:5])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCN(C)c1cccc(N)c1C#N
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(C)c1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(N-ethyl-N-methylamino)-benzonitrile (4 g) in methylene chloride (200 ml) is added pyridine (2.4 ml), and thereto is added dropwise acetoxyacetyl chloride (3.3 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is recrystallized from hexane to give the title compound (4.2 g) having the following physical properties.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]2[CH2:15][CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[C@@H:10]1[C:11]([O:13]2)=[O:12])C1C=CC=CC=1.C(O)(=[O:30])C>O.[Pd]>[OH2:8].[OH:8][C@H:9]1[C@H:14]([OH:13])[CH2:15][CH2:16][NH:17][C@@H:10]1[C:11]([OH:12])=[O:30]
Reactant: CC(=O)O
Reactant: O=C1O[C@@H]2CCN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)[C@H]1NCC[C@@H](O)[C@@H]1O
Yield: 89 %

Procedure:
3-O-Benzyl-N-benzyloxycarbonyl-2,6-imino-2,5,6-trideoxy-D-lyxo-hexono-1,4-lactone (26) (321 mg, 0.875 mmol) was dissolved in a 2:1 mixture of acetic acid and water (10 ml) and stirred under hydrogen with palladium black (70 mg) for 48 hours. The reaction mixture was filtered through celite, the solvent removed and the product purified by flash chromatography (CMAW) and ion exchange chromatography. Freeze drying afforded (2S,3R,4R) 3,4-dihydroxypipecolic acid, monohydrate (140 mg, 89%) as a white crystalline solid, m.p. 253°-260° C. with decomposition, [α]20D -1.3° (c, 0.54 in water); νmax (KBr disc) 3390, 1595 (CO), 1400, 1080, 1060 and 890 cm-1 ; 1H NMR (D2O) δ 1.48-1.61 (1H, m, 5-H); 1.99 (1H, ddt, H-5', J5,5' 14.4 Hz, J5', 6;5',6';5',4 3.7 Hz); 2.88 (1H, ddd, 6-H, J6,6' 13.0 Hz, J5,6 11.9 Hz); 3.26 (1H, dt, H-6', J5,6' 3.7 Hz); 3.30 (1H, d, 2-H, J2,3 9.2 Hz); 3.52-3.61 (2H, m, H-3, H-4); 13C NMR (D2O) δ 28.33 (t, C-2); 41.13 (t, C-1); 61.51 (d, H-5); 70.24, 71.85 (2×d, C-3,4); 172.43 (s, C-1). m/z: 124 (M-2×H2O-H+, 100%), 98 (M-H2O-CO2H+, 95%), 116 (M-CO2H+, 75%), 162 (M+H+, 67%). (Found C, 40.16; H, 7.10; N, 7.56. C6H11NO4.H2O requires C, 40.22; H, 7.31; N, 7.82).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([O:24]CC)=O)=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH2:27][NH2:28]>C(O)C>[Cl:1][C:2]1[C:3]([C:22]([NH:27][NH2:28])=[O:24])=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: NN
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Cl
Solvent: CCO
Product: NNC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Cl
Temperature: 100 °C

Procedure:
A solution of ethyl 4-chloro-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.1 g, 7.2 mmol) in ethyl alcohol (30 ml) was added hydrazine (5 ml, 64% solution in water) in one portion. The reaction mixture was refluxed 100° C. for 6 hours, and then cooled down to room temperature. After volatile solvent was removed in reduced pressure, the residue was purified with silica gel column (5% methanol in methylene chloride) to obtained title compound (3 g, quantitatively) as slightly yellow solid.