Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OC)(OC)OC.CSC.B.B([O-])([O-])[O-].CSC>O1CCCC1.CO>[CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](O)C(=O)O
Agent: B
Agent: COB(OC)OC
Agent: [O-]B([O-])[O-]
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-(benzyloxy)-2-hydroxybutanoic acid (the product of step i) (0.79 g) and trimethyl borate (0.67 mL) in anhydrous tetrahydrofuran (4 mL) at 0° C. was added dropwise borane-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran). The reaction mixture was stirred at room temperature overnight, then further borate-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran) was added at 0° C. and the reaction mixture stirred at room temperature for a further 2d. The mixture was cooled to 0° C. and methanol (10 mL) slowly added. When effervescence had ceased, the volatiles were evaporated, further methanol added and the mixture concentrated again to give the subtitle compound as a yellow oil which was used without further purification. Yield: 0.68 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>CCOC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2-hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (0.8 g; 3.6 mmol) in EtOAc (15 ml) at 0° C. is added NEt3 (610 μl) and methanesulfonyl chloride (340 μl). After addition the mixture is warmed to RT and stirred for 3 days. After completion the reaction mixture is acidified with diluted hydrochloric acid and extracted twice with EtOAc. The organic phase is washed with brine, dried over MgSO4 and evaporated to give methanesulfonic acid 2-tert-butoxycarbonylamino-benzyl ester (0.73 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10]>COCCOC>[CH3:7][N:8]([CH3:13])[S:9]([O:5][CH2:4][CH2:3][O:6][S:9](=[O:11])(=[O:10])[N:8]([CH3:13])[CH3:7])(=[O:11])=[O:10]
Reactant: OCCO
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)S(=O)(=O)OCCOS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 57% oil dispersion of sodium hydride (8.45 g.; 0.20 mol.) is added to a solution of ethylene glycol (3.1 g.; 0.05 mol.) in 1,2-dimethoxyethane (100 ml.). The resulting suspension is stirred at room temperature for 2 hours and then cooled to +4° C. N,N-dimethylsulfamoyl chloride, 25.8 g. (0.18 mol.), is dissolved in 1,2-dimethoxyethane (400 ml.) and added dropwise to the solution with stirring. The reaction mixture is stirred at +4° C for an additional 24 hours. A precipitate forms which is filtered off and the filtrate is concentrated. The residue is partitioned between heptane and methanol, and the methanol solution is concentrated to a syrup which crystallizes from ethyl acetate to yield 1,2-bis-O-(N,N-dimethylsulfamyl)-1,2-ethanediol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.CN(C)[CH:24]=[O:25]>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([CH:24]=[O:25])=[CH:12]1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(ccn2CCCCBr)n1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(n1)c(C=O)cn2CCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 730 μl (7.95 mmol) of phosphorus oxychloride are added dropwise to 12.5 ml of N,N-dimethylformamide maintained at 0° C.: after 30 minutes' stirring, 1.50 g (5.3 mmol) of the compound obtained in Step A dissolved in 25 ml of N,N-dimethylformamide are added by transfer. The reaction mixture is stirred for 30 minutes at 0° C. and then for 3 hours at room temperature. The reaction mixture is evaporated to dryness and then taken up in water, the aqueous phase is rendered alkaline with a 6N sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and then evaporated. After washing with a petroleum ether/diethyl ether mixture, the title compound is obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1>O1CCOCC1>[Cl:16][C:17]1[N:18]=[N:19][C:20]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 143.3 %

Procedure:
tert-Butyl ethyl malonate (41.3 ml, 211 mmol) was added drop-wise to a suspension of sodium hydride (19.33 g, 483 mmol) in dioxane (1000 mL) at 0° C. The reaction was stirred at 0° C. for 1 hr and then allowed to warm to ambient temperature. 3,6-dichloropyridazine (30 g, 201 mmol) was then added portion wise at 25° C. The reaction was stirred at reflux for 2 hrs and then solvent was removed via rotary evaporation. The resulting residue was dissolved in EtOAc (400 mL), and the organic phase was washed with saturated NaHCO3 (400 mL), dried over MgSO4, filtered, and concentrated to dryness via rotary evaporation. This reaction was repeated. The combined crude residues from both batches was purified via MPLC (Hex:EtOAc, 8:2) to provide the title compound, 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate (86.5 g, 288 mmol, 71.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.23 (m, 3 H) 1.36-1.52 (m, 9 H) 4.20 (m, J=10.71, 7.22, 7.22, 3.85, 3.85 Hz, 2 H) 5.29 (s, 1 H) 7.85 (d, J=8.84 Hz, 1 H) 7.99 (d, J=8.84 Hz, 1 H). ESI-MS:m/z 301.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1.[CH2:21]=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(O)CCC>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[C:11]([CH2:21][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1
Reactant: CCNCC
Reactant: C=O
Reactant: OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Solvent: CCCCO
Product: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 105 °C
Yield: 93.9 %

Procedure:
In 25 ml of n-butanol were dissolved 29.0 g (0.1 mols) of the purified product of 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 7, 5.2 g of 80% paraformaldehyde and 11.0 g (0.15 mols) of diethylamine. The solution was refluxed with heating at 105° C. for 24 hours. After completion of the reaction, the solvent and remaining raw materials were collected under reduced pressure, giving 37.0 g of objective 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol as a brown oil (yield 93.9%, purity 95.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1C1CCN(Cc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
A mixture of 4-(2-methoxyphenyl)piperidine (0.2 g, 1.06 mmol), 2-chloromethyl-benzimidazole (186, 1.1 mmol) and Cs2CO3 (0.36 g, 0.36 mmol) in DMF (8 mL) were stirred at room temperature for 18 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (2×30 mL) and dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% methanol in dichloromethane to give the title compound (82 mg, 25%). 1H NMR (CDCl3, 300 MHz) δ 1.69 (m, 4H), 2.19 (m, 2H), 2.87(m, 1H), 2.96 (m, 2H), 3.75 (s, 2H), 3.77 (s, 3H), 6.92 (m, 2H), 7.45 (m, 1H), 7.55 (m, 1H), 12.26 (s, 1H). MS (DCI-NH3) m/z 322 (M+H)+.
Reaction SMILES: [N:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:2]=1[CH2:3][C:4](OCC)=O.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])C.[O-:23]CC.[Na+].Cl>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:17]([CH2:4][C:3]([C:2]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1)=[O:23])=[O:19])[CH3:22]
Reactant: CC[O-]
Reactant: CCOC(=O)Cc1ccc2ccccc2n1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc2ccccc2n1
Yield: 46.2 %

Procedure:
A mixture of ethyl quinaldinate (58.0 g, 0.288 mol), ethyl acetate (42.6 mL, 0.432 mol), and sodium ethoxide (29.4 g, 0.432 mol) in toluene (1 L) was heated at reflux temperature for 2 h. The mixture was neutralized by addition of diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified with silica gel column chromatography with 15:1 to 3:1 hexane/ethyl acetate to give 32.34 g of 2-ethoxycarbonylmethylcarbonylquinoline (46%): 1H NMR (270 MHz, CDCl3) δ8.28 (d, 1H, J=8.3 Hz), 8.17 (dd, 1H, J=8.2, 1 Hz), 8.14 (d, 1H, J=8.3 Hz), 7.84 (dd, 1H, J=8.2, 1 Hz), 7.79 (td, 1H, J=8.2, 1 Hz), 7.66 (td, 1H, J=8.2, 1 Hz), 4.36 (s, 2H), 4.22 (q, 2H, J=7.3 Hz), 1.24 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1C(C2NC=CN=2)=[CH:29][N:28]=[C:27]([NH:36][CH2:37][CH2:38][NH:39]C2C=CC([N+]([O-])=O)=CN=2)[N:26]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:29][N:28]=[C:27]([NH:36][CH2:37][CH2:38][NH:39][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=2)[N:26]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1nccn1C
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: Cn1ccnc1-c1cnc(NCCNc2ccc(C#N)cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-(1-methylimidazol-2-yl)pyrimidin-2-yl]amino}-ethyl)amino]pyridine-3-carbonitrile was prepared from 1,2-dimethylimidazole and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:5][C:6]=1[F:9]
Reactant: Cc1c(F)cc(S(N)(=O)=O)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: NS(=O)(=O)c1cc(F)c(CBr)c(F)c1
Yield: 30.5 %

Procedure:
A mixture of 3,5-difluoro-4-methylbenzenesulfonamide (1.237 g, 6 mmol), N-bromosuccinimide (1.4 g, 1.3 eq) and benzoyl peroxide (87 mg, 0.1 eq) in carbon tetrachloride (24 mL) was heated to reflux for 6 h under a halogen light. After the reaction was determined to be complete by GC-MS, the mixture was concentrated and purified by column chromatography (silica, EtOAc-hexane, 1:4 to 4:1) to give the title compound (524 mg). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, 2H), 4.83 (s, 3H); GC-MS (ES) m/z 285 (M), 287 (M+2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[K].[CH:13](=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>O>[N+:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[O:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[CH:13]=[O:21])([O-:11])=[O:10]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
Briefly, 200 parts of 2,5-dichloro-nitrobenzene were heated to 160° C. and stirred, and 160 parts of the potassium salt of salicylaldehyde was added over a period of 30 minutes. After the addition was complete, an exothermic reaction took place, and the temperature rose to about 195° C. Heating was discontinued until the reaction subsided, and the mixture was heated for 1 hour at 150° C. The mixture was cooled, ice and water were added, and it was extracted with ether (Et2O). The ether layer was filtered to remove insoluble material, and the resultant solution was dried over sodium sulfate (Na2SO4). The ether solvent was evaporated, and the residual oil was recrystallized from a mixture of hexane and benzene to give 2-(2-nitro-4-chlorophenoxy)benzaldehyde melting at about 100°-101° C.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][CH2:26][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1cccc(CCN2CCCC[C@@H](Cl)C2)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1cccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (27 mg, 0.68 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (5 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (122 mg, 0.68 mmol) was added to the suspension, and they were stirred at room temperature for 20 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(3-methoxyphenethyl)homopiperidine (182 mg, 0.68 mmol) in dimethyl sulfoxide (3 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 150 minutes. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (4:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3-methoxyphenethyl)piperidine-2-ylmethyl] dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (78 mg, 30%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[CH:53]=2)=[CH:46][C:45]=1[C:61]1[N:65]([CH3:66])[N:64]=[CH:63][CH:62]=1.CCOCC>ClCCl.Cl>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[CH:53]=2)=[CH:46][C:45]=1[C:61]1[N:65]([CH3:66])[N:64]=[CH:63][CH:62]=1)=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)CN(C)C)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
2-(dimethylamino)acetic acid (16.0 mg, 1.25 eq), triethylamine (34.6 mL, 2.0 eq) and HATU (59.0 mg, 1.25 eq) were dissolved in 3 mL of dichloromethane and stirred at room temperature for 10 minutes. At this time N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (50.0 mg, 124 μmol) dissolved in 2.0 mL of dichloromethane was added and the reaction was stirred at room temperature for 3 hr. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized. It was then stirred overnight in 2.0M hydrochloric acid in ether (310.3 μl, 5 eq). The solvents were evaporated under a stream of nitrogen and lyophilized to afford the title compound as a white solid in 43.0% yield. LCMS m/z (%)=452 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 2.83 (s, 3H), 2.90 (s, 3H), 3.61-3.67 (m, 2H), 3.82 (s, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 4.07 (t, J=4.55 Hz, 2H), 6.42 (d, J=2.53 Hz, 1H), 6.99 (d, J=8.59 Hz, 1H), 7.10 (dt, J=4.55, 2.53 Hz, 1H), 7.40 (d, J=5.05 Hz, 2H), 7.44 (s, 1H), 7.57 (dd, J=9.09, 2.53 Hz, 1H), 7.70 (d, J=2.53 Hz, 1H), 7.82 (d, J=2.53 Hz, 1H)
Reaction SMILES: [C-:1]#[N:2].[Na+].F[C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:21])[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][C:13]([O:19][CH3:20])=[CH:12][CH:11]=3>CN(C)C=O>[CH3:20][O:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:21])[C:8]1[CH:7]=[CH:6][C:5]([C:1]#[N:2])=[CH:18][C:17]=1[O:16]2
Reactant: COc1ccc2c(=O)c3ccc(F)cc3oc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)c3ccc(C#N)cc3oc2c1
Temperature: 100 °C

Procedure:
A mixture of finely ground sodium cyanide (1.3 g, 26.5 mmol) and 3-fluoro-6-methoxy-xanthen-9-one (2.3 g, 9.42 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. for 4 hours. Sodium cyanide (0.7 g, 14.3 mmol) was added and heating continued an additional hour. The mixture was allowed to cool to room temperature, then poured into ice water (˜150 mL). The product was collected by filtration, washed with water and air dried to give Compound 5i, 1.42 g (60%). MS: m/z 251.9 (MH+). 1H NMR(CDCl3): δ 3.96 (s, 3 H), 6.91 (d, 1 H, J=2.3 Hz), 7.00 (dof d, 1 H, J=2.3 & 8.9 Hz), 7.61 (d of d, 1 H, J=1 & 8.1 Hz), 7.79 (d, 1 H, J=1 Hz), 8.24 (d, 1 H, J=8.9 Hz) and 8.42 (d, 1 H, J=8.1 Hz).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:12][C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:8](=[O:18])[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]=2[N:5]=1.[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24].O>C(COC)OC.C(OCC)(=O)C>[NH2:3][C:4]1[N:12]([S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27])[C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]3[CH2:16][CH2:17]3)[C:8](=[O:18])[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]=2[N:5]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)S(=O)(=O)n1c(N)nc2c1c(=O)n(CC1CC1)c(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Sodium hydride (0.35 g of a 60% suspension in oil, 8.7 mmol) was added to a suspension of 8-amino-1,3-di(cyclopropylmethyl)xanthine (2 g, 7.3 mmol ) in dimethoxyethane (40 ml) and the resulting mixture stirred at ambient temperature for 2 hr. Isopropylsulphonyl chloride (1.24 g, 8.7 mmol) was added and the mixture was heated at reflux for 18 hours. The reaction mixture was allowed to cool and then water (1 ml) was added dropwise. The mixture was added to ethyl acetate (200 ml), washed with water (50 ml) and dried (MgSO4). The solvent was removed at reduced pressure to afford the crude residue which was chromatographed on silica (acetone/hexane 1:3) to afford 8-amino-1,3-di(cylcopropylmethyl )-7-(isopropylsulphonyl)xanthine (1.25 g, 45%) as a yellow foam. Recrystallisation from ethyl acetate/hexane afforded a white flocculent solid, m.p. 119°-120° C.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:4]([OH:12])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.CO[C:23]([CH3:25])=[CH2:24]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:4]([C:5]2[CH:6]=[CH:7][C:8]([I:11])=[CH:9][CH:10]=2)[O:12][C:23]([CH3:25])([CH3:24])[N:13]1[C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20]
Reactant: C=C(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CF)[C@H](O)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A 1 L round bottom flask containing tert-butyl ((1R,2S)-3-fluoro-1-hydroxy-1-(4-iodophenyl)propan-2-yl)carbamate (24.4 g, 61.8 mmol) is charged with CH2Cl2 (250 mL) followed by 2-methoxypropene (9.0 mL, 92.8 mmol). The solution is cooled via ice bath and para toluene sulfonic acid (59 mg, 0.31 mmol) added. The reaction is stirred for 2 hours at room temperature then quenched with saturated sodium bicarbonate solution (200 mL). The organics were separated, dried over MgSO4 and concentrated to give the title compound (26.5 g): 1H NMR (400 MHz, CDCl3) 7.73 (d, 2H), 7.20 (d, 2H), 5.08 (d, 1H), 5.03-4.69 (m, 1H), 4.54-4.31 (m, 1H), 3.91-3.68 (m, 1H), 1.70 (s, 3H), 1.58 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[BrH:17]>O.CCOC(C)=O>[Br:17][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([CH3:9])=[CH:8][C:2]=1[F:1]
Reactant: Br
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
2-Fluoro-4-methyl-5-nitro-aniline (1.85 g, 10.90 mmol) was suspended in concentrated hydrobromic acid (22 mL) and cooled to 0° C. Solution of sodium nitrite (0.83 g, 12.00 mmol) in water (3.6 mL) was added dropwise while maintaining the temperature at 0˜5° C. After stirring for 15 min, the mixture was filtered through a cotton pad and slowly poured into a solution of cuprous oxide (2.60 g, 17.5 mmol) and concentrated hydrobromic acid (20 mL) at 0° C. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with 10% aq NaOH and 5% aq Na2S2O5 successively, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane; 2:98) to afford 1-Bromo-2-fluoro-4-methyl-5-nitro-benzene as a colorless oil (2.30 g, 91%). 1H NMR (CDCl3, 400 MHz,): 2.59 (s, 3H), 7.11 (d, J=8.4 Hz, 1H), 8.24 (d, J=6.3 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC1C=CC=CC=1)[C:3]([OH:5])=[O:4].C(Cl)C1C=CC=CC=1>O1CCCC1>[C:14]1([CH2:6][C:2](=[O:1])[C:3]([OH:5])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)C(Cc1ccccc1)c1ccccc1
Solvent: ClCc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)C(=O)Cc1ccccc1
Yield: 68 %

Procedure:
By the same operation as in Example 61 except that 6 ml of tetrahydrofuran was used as the solvent, 2-oxo-3,4-diphenylbutanoic acid formed in a yield of 68 % by the reaction of 0.49 g (3 mmoles) of phenylpyruvic acid with 0.5 ml of benzyl chloride, as determined by NMR spectral analysis.