Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.C([Li])CCC.CON(C)[C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:19]([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])[CH:5]=[C:4]([Cl:10])[CH:3]=1
Reactant: CON(C)C(=O)c1cnc2ccccc2c1
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(C#Cc1cc(Cl)cc(Cl)c1)c1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of the 1,3-dichloro-5-ethynylbenzene (200 mg, 1.16 mmol) in anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (800 μL, 1.28 mmol). After 5 minutes a solution of the intermediate from step A (380 mg, 1.75 mmol) in THF (3 mL) was added. The reaction was gradually warmed to room temperature over 30 minutes and quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 15% ethyl acetate-hexanes to afford the product as a light yellow solid. 1H NMR (CDCl3, 500 MHz): 9.63 (s, J=2.1 Hz, 1H), 8.96 (d, J=1.6 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.94 (t, J=8.0 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.64 (d, J=1.8 Hz, 2H), 7.55 (t, J=2.0 Hz, 1H). LC-MS: 3.99 min; (M+H)=326.0.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:11]1[NH:15][CH:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:13]2([CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[S:12]1)[C:4]([O:6]C(C)(C)C)=[O:5]>[N+](C)([O-])=O>[ClH:1].[ClH:1].[NH2:2][CH:3]([CH:11]1[NH:15][CH:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:13]2([CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)[S:12]1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)C(N)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: NC(C(=O)O)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A stream of gaseous hydrogen chloride is passed through a suspension of 11 g (0.0206 mole) of tert-butyl alpha-amino-4-benzyloxycarbonyl-8-phenyl-1-thia-3,8-diazaspiro[4.5]decane-2-acetate (obtained in 4.3) in 200 ml of nitromethane. After 1 hour, a clear solution is obtained which is filtered through "Hyflocel" and the filtrate is evaporated to dryness. The residue is taken up in diethyl ether, filtered and washed with diethyl ether. There are obtained 9.4 g of alpha-amino-4-benzyloxycarbonyl-8-phenyl-1-thia-3,8-diazaspiro[4.5]decane-2-acetic acid dihydrochloride. Yield: 95.5%; M.P. 164°-167° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26](C3CCCCO3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].CO>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Yield: 48.7 %

Procedure:
2-Methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol) was treated with Trifluoroacetic Acid (0.30 mL, 3.9 mmol) in Methylene chloride (1.5 mL, 23 mmol) at r.t. for 16 hours. The solvent and TFA were removed by purging with N2. The residue was treated with Potassium carbonate (82 mg, 0.59 mmol) in Methanol (2.0 mL, 49 mmol) at r.t. for 3 hours. The solvent was removed and the residue was suspended in 5% MeOH/DCM, filtered. The filtrate was purified by chromatograph in a 8 g AnaLogix column using MeOH/DCM (0/100 to 10/90) to afford a solid product (0.012 g, 48.7% yield). LCMS: (FA) ES+ 387, ES− 385. 1H NMR (400 MHz, d6-DMSO) δ 10.39 (σ, 1H), 10.03 (σ, 1H), 8.71 (σ, 1H), 7.99-8.01 (m, 2H), 7.82 (s, 1H), 7.43-7.50 (m, 4H), 2.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:28])[N:12](CC4C=CC(OC)=CC=4OC)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.O.C([O-])(O)=O.[Na+].CC(C)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:28])[NH:12][CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)=O
Product: O=c1[nH]ccc2nc(-c3ccc(Cl)cc3)sc12
Temperature: 70 °C
Yield: 116.9 %

Procedure:
Mix 2-(4-chloro-phenyl)-5-(2,4-dimethoxy-benzyl)-5H-thiazolo[5,4-c]pyridin-4-one (24.6 g, 59.6 mmol) in trifluoroacetic acid (143 mL) and heat at 70° C. for 2 h. Cool the mixture to room temperature and add water (325 mL) and saturated NaHCO3 (710 mL) with stirring. Add acetone (180 mL) and stir the resulting slurry for one hour at room temperature. Filter and wash the solids with water (110 mL) and then acetone (110 mL). Dry the solids in a vacuum oven at 60° C. overnight. Triturate the solids three times with CH3CN (700 mL) at 60° C. and filter. Dry the solids in a vacuum oven at 60° C. overnight to obtain 18.3 g (117%) of the title compound that still contains salt impurities. 1H NMR (400 MHz, DMSO-d6) δ11.86 (s, 1H), 8.12 (d, 2H, J=8.2), 7.65 (d, 2H, J=8.7), 7.49 (t, 1H, J=6.0), 6.91 (1H, J=6.6).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[NH:6][C:5]=1[C:3]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1ccccc1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A mixture of 9.58 gm (0.03 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2thiazine-3-carboxylic acid methyl ester-1,1-dioxide, 3.72 gm (0.04 mol) of aniline and 150 ml of anhydrous xylene was refluxed for 10 hours in a Soxhlet apparatus equipped with a 4-A-molecular sieve. After cooling, the reaction mixture was allowed to stand overnight, whereupon the precipitaed crystals were suction-filtered off and recrystallized from ethylene chloride. 6.10 gm (55% of theory) of 4-hydroxy-N-phenyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 260°-262° C, were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C.O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(c1cccnc1)C2=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccc(O)cc2CCC1c1cccnc1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a suspension of 6-methoxy-2-(3-pyridyl)-1-tetralone (288 mg; 1.1 mmol) in CH2Cl2 (10 ml) was added, at 0° C. under argon, boron tribromide (215 μl; 2.2 mmol). It was left for 10 minutes and then, water, ethyl acetate and 2N NaHCO3 were added to bring the mixture to pH 9.5. The mixture was then acidified to pH 7-8 with 2N HCl and then extracted three times with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of NaCl , dried over MgSO4 filtered and evaporated. The residue was subjected to chromatography using a silica column, eluting with petroleum ether/ethyl acetate (1/9), to give 6-hydroxy-2-(3-pyridyl)-1-tetralone (208 mg; 79%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[O:9])=[C:6]([NH:26]C(=O)C(F)(F)F)[CH:5]=1)([O-:3])=[O:2].[Cl-].[Na+]>N1CCCCC1>[NH2:26][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:25]=[CH:24][C:7]=1[C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16]1)=[O:9]
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNCC1
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
0.275 g (0.00061 mol) of 1-benzyl-piperidin-4-yl 4-nitro-2-trifluoroacetamido-benzoate was suspended in 12 ml of 1N aqueous piperidine in an ultrasound bath for 1/2 hr. and subsequently stirred at room temperature for 20 hrs. The suspension was treated with semi-saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were dried over sodium sulfate, concentrated and chromatographed on silica gel with ethyl acetate/hexane (1:2). 0.20 g (92%) of 1-benzyl-piperidin-4-yl 2-amino-4-nitro-benzoate was obtained as a yellow oil. MS: me/e=356 (C19H22N3O4 +).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:21]=[CH:20]C(C#N)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([OH:26])(=[O:25])[CH3:24]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:21]=[CH:20][C:24]([C:23]([OH:26])=[O:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 38 %

Procedure:
4-(4-Benzylpiperazin-1-yl)benzonitrile (4.0 g, 15 mmol) was dissolved in glacial acetic acid (40 mL), 6 M hydrochloric acid (50 mL) was added and the reaction mixture was stirred at 100° C. for 17 h. The solvent was evaporated, the residue was suspended in water (10 mL) and the pH was adjusted to 3 by addition of 2 M sodium hydroxide (35 ml). The slurry was stirred at 50° C. for 2 h, cooled and the precipitate was filtered and dried in vacuo to give 4.1 g of a crude product. The solid was partitioned between methylene chloride (40 mL) and water (220 mL) with 2 M sodium hydroxide (8 mL). The aqueous phase was washed with methylene chloride (40 mL) and the pH was adjusted to 5 with 2 M hydrochloric acid. The aqueous phase was cooled, the precipitate was filtered and dried in vacuo to give 1.6 g (38% yield) of the title compound: mp 226° C. (dec); EIMS (70 eV) m/z (relative intensity) 296 (44, M+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:29][C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([O:35]C)=[O:34])[C:3]1=[O:40].[Li+].[OH-]>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:29][C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([OH:35])=[O:34])[C:3]1=[O:40]
Reactant: COC(=O)c1cccc(Cn2c(=O)n(C)c(=O)c3c(-c4ccncc4)n(Cc4cccc5ccccc45)nc32)c1
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc2n(Cc2cccc(C(=O)O)c2)c1=O

Procedure:
This compound was synthesized by the hydrolysis of methyl 3-{[5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-3-pyridin-4-yl-2,4,5,6-tetrahydro-7H-pyrazolo[3,4-d]pyrimidin-7-yl]methyl}benzoate with 0.5N LiOH at room temperature for eight hours. Mass: 517.79 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O.ON1C2C=CC=CC=2N=N1.ClCCl.Cl.[CH3:28][NH:29][O:30][CH3:31]>O.C(N(CC)CC)C>[CH3:31][O:30][N:29]([CH3:28])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CNOC
Reactant: CCCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A mixture of 4-n-propylbenzoic acid (10.0 g), 1-hydroxybenzotriazole hydrate (8.20 g), 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.5 g) and dichloromethane (1000 ml) was treated dropwise with triethylamine (42.6 ml) and N,O-dimethylhydroxylamine hydrochloride (6.6 g). The mixture was stirred overnight at room temperature and then treated with water (700 ml). The organic layer was separated, washed with 2N aqueous hydrochloric acid (4×500 ml) and then saturated aqueous sodium bicarbonate solution (4×500 ml). The organic phase was dried (MgSO4) and concentrated to give the title compound as a clear oil (10.8 g).
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[CH3:18]CN(C(SCC)=O)C1CCCCC1>CS(C)=O.O>[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][C:14]2([O:17][CH2:18]2)[CH2:13][CH2:12]1
Reactant: CCSC(=O)N(CC)C1CCCCC1
Reactant: COC1CCC(=O)CC1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: COC1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 1.20 g, 30.0 mmol) in dimethylsulfoxide (19 mL) was added trimethylsulfoxonium iodide (6.89 g, 31.3 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min. To this mixture was added a solution of 4-methoxycyclohexanone (3.53 g, 10.0 mmol, prepared according to Shvily, Ronit et al., J. Chem. Soc. Perkin Trans. 2, 1997, 6, 1221) in dimethylsulfoxide (95 mL) dropwise at room temperature, and the mixture was stirred at room temperature for 20 h. Then the mixture was diluted with water (1.0 L), and extracted with diethyl ether (200 mL×6). The combined organic layers were dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting n-hexane/ethyl acetate (v/v=15/1˜10/1) to give 338 mg (9%, cis) and 204 mg (5%, trans) of the title compound as colorless oil respectively.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]([C:28]([OH:30])=O)=[CH:7][C:8]1[CH:9]=[C:10]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14].CN(C)C=O>C1(C)C=CC=CC=1>[Br:5][C:6]([C:28]([Cl:3])=[O:30])=[CH:7][C:8]1[CH:9]=[C:10]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)O)c2)c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)Cl)c2)c1=O

Procedure:
1.6 g of thionyl chloride were added to a solution of 4.5 g of 3-[3-(2-bromo-2-carboxyethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.1 ml of dimethylformamide in 100 ml of toluene. The reaction mixture was heated slowly to the reflux temperature, stirred under reflux for 5 hours and evaporated down, and the residue was dried under greatly reduced pressure.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.Cl[CH2:24][O:25][CH3:26]>ClCCl>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:24][O:25][CH3:26])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)c1ccc(O)c(C)c1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)c1ccc(OCOC)c(C)c1O
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture composed of 1-(2,4-dihydroxy-3-methylphenyl)propan-1-one (5.00 g, 27.8 mmol) and dichloromethane (80 mL), diisopropylethylamine (5.26 mL, 30.5 mmol) was added under cooling with ice, and then a solution of chloro(methoxy)methane (2.30 mL, 30.5 mmol) in dichloromethane (20 mL) was added dropwise to the mixture over 20 minutes. After the completion of dropwise addition, the mixture was brought back to room temperature and stirred overnight. Dichloromethane was added to the reaction solution. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=90/10→70/30) to obtain 5.73 g of the title compound (yield: 92%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23][CH3:24])=[N:19][CH:20]=2)[N:15]([CH2:25][CH3:26])[C:14]1=[O:27].C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23]([CH3:24])=[O:36])=[N:19][CH:20]=2)[N:15]([CH2:25][CH3:26])[C:14]1=[O:27]
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(SC)nc21
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reaction time: 8 h

Procedure:
A solution of 4.23 g (10.67 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one in 90 mL of chloroform was treated with 3.35 g (12.80 mmol) of 3-phenyl-2-(phenylsulfonyl)-oxaziridine and stirred at room temp. under N2 atmosphere overnight. Crude product was purified by medium-pressure chromatography eluting with straight ethyl acetate and a gradient of 1% to 3% MeOH in chloroform to give 4.45 g (quantitative) title compound. MS (APCI) (m+1)/z 413.1.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:5]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH2:13]1)=[N:6]2.[BrH:31].[OH2:32]>>[BrH:31].[BrH:31].[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:4]2[C:3]3[C:7](=[N:8][CH:9]=[N:10][C:2]=3[OH:32])[N:6]=[C:5]2[NH:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:25][CH:26]=1
Reactant: O
Reactant: CCOC(=O)N1CCC(Nc2nc3ncnc(Cl)c3n2Cc2ccc(F)cc2)CC1
Agent: Br
Product: Oc1ncnc2nc(NC3CCNCC3)n(Cc3ccc(F)cc3)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 7.5 parts of ethyl 4-[[6-chloro-7-[(4-fluorophenyl)methyl]-7H-purin-8yl]amino]-1-piperidinecarboxylate and 150 parts of a hydrobromic acid solution 48% in water was stirred overnight at 80° C. The reaction mixture was evaporated. The residue was stirred in 2-propanone. The product was filtered off and dried, yielding 8.5 parts (100%) of 7-[(4-fluorophenyl)methyl]-8-(4-piperidinylamino)-7H-purin-6-ol dihydrobromide as a residue (compound 41).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:27][C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:18]2=[O:33])[CH2:13][CH:14]([OH:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:27][C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:18]2=[O:33])[CH2:13][C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@@H](CC(C)O)N2C(=O)c3cccc(Cc4ccc[nH]4)c3C2=O)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1cc([C@@H](CC(C)=O)N2C(=O)c3cccc(Cc4ccc[nH]4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
A mixture of 2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione (1.26 g, 2.81 mmol), pyridinium chlorochromate (1.21 g, 5.62 mmol), and celite (0.6 g) in methylene chloride (35 mL) was stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL). The organic layer of the filtrate was dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, Hexane:ethyl acetate 6:4) to give 2-[(1 R)-1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione (0.83 g, 66%) as a white solid: mp 143-145° C.; 1H NMR (CDCl3) δ7.66 (d, J=7.3 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.10-7.06 (m, 2H), 6.93 (d, J=7.7 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.73-6.71 (m, 2H), 6.22-6.21 (m, 2H), 5.78-5.72 (dd, J=5.4, 9.8 Hz, 1H), 3.32-3.23 (dd, J=5.4, 18.0 Hz, 1H), 2.18 (s, 3H), 1.46 (t, J=6.9 Hz, 3H); 13C NMR (CDCl3) δ205.31, 168.53, 167.83, 149.11, 148.33, 138.31, 134.43, 132.37, 132.04, 131.55, 127.05, 122.34, 121.46, 120.14, 112.59, 111.29, 109.08, 64.39, 55.91, 50.01, 48.53, 44.88, 30.17, 14.72; Anal. Calcd. for C26H26N2O5; C, 69.94; H, 5.87; N, 6.27. Found: C, 70.01; H, 6.01; N,6.08.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH3:12]>O1CCOCC1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH2:12])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N
Reactant: Clc1ccc2nnc(Cl)n2n1
Solvent: C1COCCO1
Product: Nc1ccc2nnc(Cl)n2n1

Procedure:
A mixture of 190 mg of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine and 1 cm3 of aqueous ammonia at 35% in 1 cm3 of dioxane, in a sealed tube, is heated at between 70° C. and 90° C. for 3 h. The precipitate formed is filtered off, to give 156.4 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: C(O)C.O[CH:5]([C:17]1[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[NH:20][CH:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[C].[Pd].C(Cl)(Cl)Cl>[CH2:5]([C:17]1[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[NH:20][CH:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(O)c1c[nH]c(C(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Reaction time: 5.5 h
Yield: 83.8 %

Procedure:
To an ethanol solution (2.0 liters) of 258.0 g (0.73 mol) of methyl 4-(1-hydroxydodecyl)pyrrole-2-carboxylate prepared in Synthetic Example 11 was added 16 g of 10% palladium-carbon. A catalytic reduction with hydrogen was carried out at 50° C. under hydrogen atmosphere. After the reaction was completed within 5.5 hours, 1.5 liters of chloroform was added to the reaction mixture. The catalyst was filtered off, and the solvent was removed under a reduced pressure to give crystals. Recrystallization from 950 ml of ethanol afforded 179.6 g (83% yield) of methyl 4-dodecylpyrrole-2-carboxylate as white crystals, m.p. 68°-69° C.