Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[N:19]([O:20][CH3:21])[CH3:18])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
A solution of 30 g (130.9 mmol) of Boc-isonipecotic acid in 1.5 1 CH2Cl2 was treated with 20.42 g (209.3 mmol) of N,O-dimethylhydroxylamine hydrochloride, 23.1 ml (209.3 mmol) of N-methylmorpholine and at 0° C. with 32.6 g (170.1 mmol) of EDCI and 3.53 g (26.2 mmol) of HOBT. The reaction was stirred overnight at room temperature and partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to give 37.54 g (quantitative) of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 273(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:5]=1.[H][H]>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:5]=[C:6]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(O)cc2)cc(C(=O)OC)c1
Yield: 51.2 %

Procedure:
A mixture of 0.40 g of 3-(octadecyloxy)-5-[3-[4-(phenylmethoxy) phenoxy]propoxy]benzoic acid methyl ester and 0.1 g of 10% palladium on carbon in 25 ml of THF was stirred in a hydrogen atmosphere for 4 hours. The usual workup followed by purification by chromatography on 12 g of silica gel (230-400 mesh) using 20% ethyl acetate-hexane to give 0.177 g (51% yield, mp 85°-88°) of 3-[3-(4-hydroxyphenoxy)propoxy]-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1.[CH2:25](OC1OC(C(O)=O)=CC=1)CCCCCCCCC/C=C\CC>>[CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11]([CH3:25])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1
Reactant: CC/C=C\CCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CC(=O)c1ccc(OCCC(C)CCCC(C)CCCC(C)C)o1

Procedure:
In the procedure of Example 4(B), 5-(3,7,11-trimethyldodecyloxy)-2-furancarboxylic acid was substituted for cis-5-(11-tetradecenyloxy)furancarboxylic acid, to yield as a pale yellow oil, methyl 5-(3,7,11-trimethyldodecyloxy)-2-furyl ketone, B.P. 165° C. (0.25 mm Hg.).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>CN(C=O)C>[CH:1]1([NH:6][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NC2CCCC2)nc1
Temperature: 200 °C

Procedure:
To a 20 mL vial containing cyclopentylamine (300 mg, 3.53 mmol) was added DMF (5 mL), 2-chloro-5-nitro-pyridine (559 mg, 3.53 mmol), and the TEA (0.98 mL). The vessel was purged with argon, sealed, and heat by microwave at 200° C. for 5 min (Personal Chemistry, Emrys Optimizer). The reaction mixture was concentrated, diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, and evaporated to give cyclopentyl-(5-nitro-pyridin-2-yl)-amine. LCMS calcd. C10H13N3O2 (m/e) 207, observed 208 (M+H). This intermediate nitropyridyl compound was transferred to a PARR vessel with MeOH (5 mL), Pd/C (10%) was added and the vessel was pressurized with H2 at 55 psi and shaken for 2.5 hr. The mixture was then filtered through a bed of celite and concentrated to dryness twice from CH2Cl2. The purple black material was used immediately for amide coupling (LCMS calcd. for C10H15N3 (m/e) 177, observed 178 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:17][C:16](=S)[NH:15][C:14](=[O:19])[CH:13]=1.N.[CH3:21][CH2:22]O>[Ni]>[O:2]1[CH2:1][CH2:22][CH2:21][CH:3]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][NH:15][C:14](=[O:19])[CH:13]=1
Reactant: COCCOc1ccccc1-c1cc(=O)[nH]c(=S)[nH]1
Reactant: CCO
Agent: [Ni]
Agent: N
Product: O=c1cc(-c2ccccc2OCC2CCCO2)nc[nH]1

Procedure:
6-[2-(2-methoxy-ethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.6 g, 1.97 mmol) is dissolved in EtOH (12 mL) and aqueous solution of ammonia (25%, 4 mL). After addition of Raney-Nickel (0.5 g) the reaction mixture is stirred under reflux for 1 h, filtered from the solid material, which is washed with a mixture of ammonia and EtOH. The combined solutions were evaporated, dissolved in water (10 mL), neutralized with 10% HCl and extracted with ethyl acetate (3×15 mL). Organic layers were combined, washed with water (7 mL) then dried over anhydrous sodium sulfate and concentrated. The residue was triturated with diethyl ether yielding 0.47 g (87%) 6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-3H-pyrimidin-4-one as cream powder.
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=O)C1C=CC=CC=1.[CH3:18][NH2:19]>O1CCCC1>[CH3:18][NH:19][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][NH:9]1)=[O:17]
Reactant: CN
Reactant: O=C(O)C1CCCCN1OCc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)C1CCCCN1

Procedure:
The general procedure of Referential Example 131 was repeated through use of N-benzyloxypiperidine-2-carboxylic acid (2.0 g) and 1.0 M methylamine in tetrahydrofuran (4 mL), to thereby give the title compound as an oily product (970 mg, quantitative amount).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[CH:17][N:18]=2)[CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([I:1])=[CH:17][N:18]=2)[CH:15]=1
Reactant: Brc1ccc2nccn2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2ncc(I)n2c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
10.7 g N-iodosuccinimide was added in divided portions to 100 mL solution of 9 g 6-bromoimidazo[1,2-a]pyridine in N,N-dimethylformamide, and the mixture was stirred for 2 hours. An aqueous sodium thiosulfate solution was added thereto and stirred for 1 hour, water was added thereto, and the formed crystals were collected by filtration. The product was recrystallized from tetrahydrofuran/ethanol to give 13.5 g of the title compound (colorless crystals).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[F:35][C:36]([F:49])([F:48])[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44](Cl)(=[O:46])=[O:45]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[O:37][C:36]([F:35])([F:48])[F:49])(=[O:46])=[O:45])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)c2ccccc2OC(F)(F)F)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 77.4 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and [2-(trifluoromethoxy)phenyl]sulfonyl chloride (73.6 mg, 282 μmol) were reacted with one another for 16 h. This gave the title compound as a colorless solid (115 mg, 77% of theory).
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([NH2:17])=[O:16])=[S:13])[CH:7]=[CH:8][C:9]=1[Cl:10].O>CCO>[Cl:3][C:4]1[CH:5]=[C:6]([N:11]=[C:12]2[S:13][NH:17][C:15](=[O:16])[N:14]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: NC(=O)N(Cc1cccc(C(F)(F)F)c1)C(=S)Nc1ccc(Cl)c(Cl)c1
Agent: BrBr
Solvent: CCO
Solvent: O
Product: O=c1[nH]sc(=Nc2ccc(Cl)c(Cl)c2)n1Cc1cccc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 103.5 %

Procedure:
Bromine (16 mg in 0.5 mL of EtOH) was added dropwise to a solution of 1-[(3,4-dichlorophenyl)carbamothioyl]-1-[[3-(trifluoromethyl)phenyl]methyl]urea (42 mg, 0.1 mmol) in 0.5 mL EtOH at 0° C. HPLC-MS analysis revealed almost complete conversion to product after 30 min of stirring. The reaction was worked up after 1.5 h. Water (3 mL) was added and the resulting aqueous phase was extracted with Et2O (3×15 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 43.5 mg of crude material (approximately 90% purity). The material was purified by preparative HPLC (basic conditions) XTerra Prep MS C18 5 mm 19×50 mm column, flow 25 ml/min, 50 mM pH10 NH4HCO3/ACN, 5-97% ACN in 6 min, fractions collected based on UV-signal (254 nm) to give the product in 21.7 mg (52%). HPLC purity: 98.5%, MS: m/z: 420 (M+H), 1H NMR (500 MHz, Chloroform-d) 8 ppm 7.81 (s, 1 H) 7.70 (d, J=7.81 Hz, 1 H) 7.60 (d, J=7.81 Hz, 1 H) 7.49 (t, J=7.69 Hz, 1 H) 7.40 (d, J=8.55 Hz, 1 H) 7.06 (d, J=2.44 Hz, 1 H) 6.79 (dd, J=8.55, 2.44 Hz, 1 H) 5.04 (s, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:49])[NH:34][CH2:35][CH2:36][CH2:37][C@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][NH2:40])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([NH:40][CH2:39][C@@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:49])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)CC(=O)O
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)C[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.1 g (0.263 mmol) of (3S)-6-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]hexanoic acid (Bioorg. Med. Chem. Lett. (1998) 8:1477-1482) and 0.108 g (0.342 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.066 g (0.342 mmol) of EDC and 0.011 g (0.079 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][CH:7]1[C:11](=O)[CH2:10][CH2:9][O:8]1.[OH-].[Na+]>O>[CH3:6][CH:7]1[O:8][CH2:9][CH2:10][C:11]21[S:5][CH2:4][CH2:3][NH:2]2
Reactant: NCCS
Reactant: CC1OCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1OCCC12NCCS2
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To 15.4 g of 2-aminoethanethiol-HCl (0.13 mole) dissolved into 50 ml of water were added slowly 20 g of 2-methyl-3-tetrahydrofuranone (0.2 mole) (solution pH=2.7). The pH was kept to neutrality by adding 10% aqueous NaOH. After 1 hour, extraction of the water solution with Et2O, drying of the organic phase with MgSO4 and distillation of the crude product (Bp 1.7 mbar, 93°-96° C.) gave 18 g of the desired product (yield=90%). The product was obtained as a mixture of two diastereoisomers (isomers a and b).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[S:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:17]>C1COCC1>[CH3:17][S:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=2[N:9]=1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Suspend 5-nitro-3H-benzooxazole-2-thione (5.15 g, 26.3 mmol) in THF (150 mL). Cool in an ice bath to 5° C. and add sodium hydride (60% dispersion in mineral oil) (1.7 g, 42.5 mmol). Stir for 15 min at 5° C. Add dropwise iodomethane (5.0 mL, 80.1 mmol) dissolved in THF (30 mL) over 1 h. Continue to stir at room temperature for 4 h. Absorb the reaction mixture onto silica gel, and purify using silica gel chromatography, eluting with a gradient of EtOAc in hexane (0-60%) to afford the title compound (4.75 g, 86%). 1H NMR (400 MHz, DMSOd6): δ 8.47 (d, 1H, J=3.1 Hz), 8.24 (dd, 1H, J=9.0, 2.4 Hz), 7.89 (d, 1H, J=8.8 Hz), 2.81 (s, 3H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:19])=[C:15]([CH3:18])[CH:16]=2)[C:11]([CH3:20])=[CH:10][C:9]1([CH3:22])[CH3:21])(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:19])=[C:15]([CH3:18])[CH:16]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:20])[CH2:10][C:9]1([CH3:22])[CH3:21])(=[O:7])[CH3:6]
Reactant: CC(=O)N1c2cc(C)c(N)cc2C(C)=CC1(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)N1c2cc(C)c(N)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 3 h

Procedure:
AlCl3 (266 mg) was added to a heated (70° C.) solution of 1-acetyl-6-amino-1,2-dihydro-2,2,4,7-tetramethylquinoline (100 mg) in benzene (10 ml). After 3 h, the mixture was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/03/1 (v/v) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[NH2:13])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1CCCC1c1cccc(F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3-fluoro-phenyl)-cyclopentylamine (650 mg, 3.63 mmol) from preparation 14, methylene chloride (15.0 mL) and the solution cooled to 0° C. DBU (0.65 mL, 4.35 mmol) and isopropylsulfonyl chloride (0.49 mL, 4.35 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound.was purified by radial chromatography eluting with methylene chloride to give 573 mg (55%) of the purified title compound as a white solid. The nmr was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccn1Cc1ccccc1
Product: ClCc1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A mixture of 10 gm (45 mmole) of N-benzyl-2-hydroxymethylimidazole and 11 gm (92 mmole) of thionyl chloride was stirred at room temperature for 30 minutes before it was heated to reflux for 30 minutes. The excess thionyl chloride was removed under reduced pressure. The resultant residue (10 gm crude) was crystallized from ethanol/ether to obtain 8.7 gm of N-benzyl-2-chloromethylimidazole, m.p. 180°-182° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:10]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:8])[CH3:2].Cl.[NH2:38]O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:10]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:38]=1)=[O:36])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
4-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-2,4-dioxo-butyric acid ethyl ester (1 eq) was dissolved in ethanol with stirring. Hydroxylamine hydrochloride (1.2 eq) was added and the solution was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, to give a precipitate. This precipitate was obtained by filtration to give 5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Cl:29][Sn]Cl.C(O)C.Cl>O>[ClH:29].[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(N)cc3)nc(=O)c1-2
Yield: 60.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-6-(4-nitrophenyl)pyrazolo[3,4-d]pyrimidin-4-one (1.38 g, 3.9 mmol), SnCl2.2H2O (2.64 g, 11.72 mmol), ethanol (24 ml) and water (10 ml) was added concentrated HCl (14.5 ml). The reaction mixture was refluxed for 2 hours, cooled, and the product was collected by filtration and dried in vacuo to afford 0.85 g (67%) of 1-cyclopentyl-3-ethyl-6-(4-aminophenyl)pyrazolo[3,4-d]pyrimidin-4-one hydrochloride 1/3 hydrate, m.p. 279° C. (dec.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1Cc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 85.4 %

Procedure:
A mixture of 14 g (0.1 mol) of ethyl imidazol-2-carboxylate, 18.9 g (0.11 mol) of o-nitrobenzyl chloride, 13.8 g (0.1 mol) of anhydrous potassium carbonate and 100 ml of dimethylformamide was heated at 100° C. for 2 hours while stirring. Then, the solvent was substantially distilled off in vacuo, the residue was mixed with 100 ml of water and extracted with ethyl acetate. The organic phase was washed twice with water, dried over anhydrous sodium sulfate and concentrated by evaporation. The crystalline residue was suspended in ether, and the suspension was suction-filtered. 23.5 g (85.4% of theory) of ethyl 1-(2-nitrobenzyl)-imidazole-2-carboxylate, m.p. 107°-111° C., were obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[OH-].[Na+].[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>O.C1COCC1>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[NH:2][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[CH2:9]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=S1(=O)CCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(O)CCCNC1C2CC3CC(C2)CC1C3
Yield: 74 %

Procedure:
The 2-aminoadamantane hydrochloride (2×5 g) was treated with NaOH in water. The aqueous mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure. The resulting white solid was dried 30 minutes at room temperature under vacuum. A solution of 1,3-propane sultone (7.4 g, 60 mmol) in THF was added to a solution of the free amine (7.98 g, 52 mmol) in THF (70 mL, total). The mixture was heated under reflux for 4 h, cooled into an ice bath. The solid was collected by filtration, air-dried for 15 min., and further dried in vacuo (11.2 g). Recrystallization was done with methanol/water (60 mL/35 mL). After cooled in a fridge, the solid was collected by filtration, rinsed with methanol, dried in the vacuum oven at 60° C. overnight. A white crystalline sandy solid (small plates, 10.45 g, 74% yield) was obtained. The 1H and 13C NMR were consistent with the structure of Compound BZ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15].[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: COC(=O)CCCc1ccc(F)c(C)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)CCCc1cc(C)c(F)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
The compound obtained in (2) above (10.9 gm) was added to 6 ml of cold concentrated sulfuric acid, and to the mixture was dropwise added 5.8 gm of potassium nitrate in 15 ml of concentrated sulfuric acid, while maintaining the internal temperature below 5° C. After the addition, the mixture was stirred for a further 20 minutes. The reaction product was poured into ice-cold water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (90:7) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 7.1 gm of the title compound.