Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH2:3]([C:5]1[O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:10](O)=[O:11])[N:9]=1)[CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C1(C)C=CC=CC=1>[CH2:3]([C:5]1[O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:10]([Cl:27])=[O:11])[N:9]=1)[CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1nc(C(=O)Cl)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-ethyl-5-phenyl-oxazole-4-carboxylic acid (54 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-ethyl-5-phenyl-oxazole-4-carbonyl chloride.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C[O:6][C:7](=O)[CH:8]([Cl:10])[CH3:9]>>[Cl:10][CH:8]([CH3:9])[C:7]([NH:4][CH2:3][CH2:1][OH:2])=[O:6]
Reactant: NCCO
Reactant: COC(=O)C(C)Cl
Product: CC(Cl)C(=O)NCCO
Reaction time: 60 h
Yield: 91.5 %

Procedure:
Ethanolamine (13.45 g, 0.22 mol) is added to 21.5 ml (0.2 mol) of 2-chloropropionic acid methylester. The mixture solidifies after standing at room temperature for 60 h. The solid is triturated with ethylacetate, the crystals are filtered off and dried to afford 27.75 g of the title compound as white crystals, mp. 64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11]
Reactant: CC(=O)c1cnc(OCC(C)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(C)(F)F)c(Cl)c1
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (3.5 g, yellows oil) from 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanone (4.0 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (2.91 g, 24.0 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C([N:14]1[CH2:18][CH:17]2[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][S:22](=[O:24])(=[O:23])[CH:16]2[CH2:15]1)C1C=CC=CC=1>ClCCCl>[C:31]1([C:19]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]3[CH:16]([CH2:15][N:14]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:18]3)[S:22](=[O:23])(=[O:24])[CH2:21][CH2:20]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=COC(=O)Cl
Reactant: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(C1)S(=O)(=O)CCC2(c1ccccc1)c1ccccc1

Procedure:
0.16 cm3 of vinyl chloroformate is added to a solution of 0.7 g of (4aRS,7aRS)-6-benzyl-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide in 10 cm3 of 1,2-dichloroethane. The mixture is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. The crystalline solid is washed with ethyl ether, drained and then dried. 0.58 g of (4aRS,7aRS)-4,4-diphenyl-6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:8]([CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])=[O:9])(=O)C.Cl>[OH-].[Na+]>[OH:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:8]([CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: CC(=O)Oc1cc(C(=O)C(C)CC(=O)O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)C(=O)c1ccc([N+](=O)[O-])c(O)c1

Procedure:
3-(3-Acetoxy-4-nitrobenzoyl)butyric acid was dissolved in dilute sodium hydroxide solution, and the solution was warmed on a steam bath, cooled and acidified with hydrochloric acid to give 3-(3-hydroxy-4-nitrobenzoyl)butyric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([NH2:9])[N:3]=1.[Cu][C:11]#[N:12]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:11]#[N:12])[CH:5]=[C:4]([NH2:9])[N:3]=1
Reactant: N#C[Cu]
Reactant: Nc1cc(Br)cc(N)n1
Solvent: CN(C)C=O
Product: N#Cc1cc(N)nc(N)c1
Temperature: 230 °C
Yield: 74 %

Procedure:
A mixture of 1.00 g 2.6-diamino-4-bromopyridine and 0.992 g copper(I)cyanide in 10 ml dimethylformamide was heated under microwave irradiation to 230° C. for 1000 sec. The resulting mixture was partitioned between 10% aqueous ammonium chloride and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were washed with water and brine, dried over magnesium sulfate dihydrate and evaporated. The solid residue was dissolved in hot ethyl acetate and passed through a filter. To the clear mother liquor was added heptane until crystallization started. The mixture was cooled to room temperature and the crystals were collected by filtration to yield 0.528 g of the title compound as yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN(C)C(=O)c1ccc(N)cc1F
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
To a 100 mL round bottom flask, 4-amino-2-fluoro-N,N-dimethyl-benzamide (2.5 g, 0.0137 mol), 4-bromophenylisocyanate (3.3 g, 0.0164), TEA (3.9 mL, 0.0274 mol) and DCM (50 mL) was added. The reaction mixture was stirred at room temperature for 12 h. After 12 h, the precipitate was formed and was collected by filtration. The solid was washed with diethyl ether and dried to get the title compound [3.0 g, 58%]. Calculated mass: 379.0; Observed mass: 380.0 (RT: 1.46 min). This compound was directly taken to the next step.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>>[NH:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Brc1cccc2cnccc12
Product: c1cc(N[C@H]2CCNC2)c2ccncc2c1

Procedure:
Reaction of (5)-tert-butyl 3-aminopyrrolidine-1-carboxylate and 5-bromoisoquinoline using the method of Example 16 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[C:13]([C:17]1[O:21][N:20]=[C:19]([NH:22][C:23]([C@@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26]2)=[O:24])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CCOC(C)=O>[C:13]([C:17]1[O:21][N:20]=[C:19]([NH:22][C:23]([C@@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[CH:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)=[O:24])[CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2C2CCOCC2)no1
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (71 mg, 1.13 mmol) and tetrahydro-pyran-4-one (75 mg, 0.75 mmol) are added to a solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.2 g, 0.75 mmol) in DCM (8.0 mL). After stirring for four hours, the reaction mixture is diluted with EtOAc and washed twice with water. The organic phase is dried over anhydrous Na2SO4 and after removal of the solvent under reduced pressure, the crude is purified by prep TLC to afford the title compound; m/z 350 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1O)([CH3:4])([CH3:3])[CH3:2].C1([OH:22])C=CC=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:9][C:10]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Oc1ccccc1
Product: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1

Procedure:
106 grams of crude 2,6-di-tert-butylphenol containing 75.4% 2,6-di-tert-butylphenol and 0.43% 2-sec-6-tert-di-butylphenol was transalkylated with phenol using 5 grams of Dowex® 2030 ion exchange resin (DR-2030; a styrenic plastic bead functionalized with sulfonic acid groups) at 75° C. for 5 hours to produce 75.4% 2,4-di-tert-butylphenol containing 0.3% 2-sec-4-tert-di-butylphenol and no measurable amounts of 2-sec-6-tert-di-butylphenol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](O)[CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:3]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:5][CH:6]=1)[CH2:9][CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCCC(O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Solvent: ClCCl
Product: CCCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
0.276 g (0.892 mmol) of the above prepared [rac]-1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butan-1-ol was dissolved in 4.3 ml of CH2Cl2 and treated dropwise at 0° C. with 0.13 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents yielded 0.289 g of pure title compound as light yellow oil.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4]1.O.[C:11]([C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([Cl:20])[CH:14]=1)#[N:12]>CN1CCCC1=O>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]#[N:12])[CH:18]=[C:17]([O:9][CH2:8][C:5]2[CH:6]=[CH:7][S:3][CH:4]=2)[N:16]=1
Reactant: OCc1ccsc1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)nc(OCc2ccsc2)c1
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.24 g (ca.60% in mineral oil), 0.006×1.0 mol) was suspended in 20 ml of N-methyl-2-pyrrolidinone, and 3-thiophenemethanol (0.69 g, 0.006×1.0 mol) was added thereto and the resultant solution was stirred for about 30 minutes at room temperature. The resultant mixture was cooled to 4° C. with iced water, then 4-cyano-2,6-dichloropyridine (1.04 g, 0.006 mol) was added thereto and stirred for about 1.5 hour while cooling with iced water.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-])=O)=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[H][H]>[OH-].[NH4+].[Pd]>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:14]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(N)c1OC
Yield: 78.1 %

Procedure:
A solution of 3,4-dimethoxy-2-nitro benzoic acid (1011 g., 4.45 moles) in 14 liters of 1.3 N ammonium hydroxide was reduced at 60 psi in presence of 60 grams of palladium on barium carbonate. Hydrogen uptake ceased after four hours. The reaction mixture was filtered through diatomaceous earth and acidified with glacial acetic acid (1.2 liters) to yield 685 grams (78%) of the anthranilic acid, M.P. 183°-184° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:15]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:16]=3[C:17]#[N:18])[C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)NCCO2
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
A 250 ml round bottom flask charged with 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.00 g, 32.6 mmol) was dried under high vacuum and placed under nitrogen prior to the addition of THF (131 ml). The solution was cooled in an ice water bath for 10 mins prior to the addition of sodium hydride (60% in mineral oil) (1.436 g, 35.9 mmol), added carefully in two portions 5 mins apart. The resulting suspension was stirred for 15 min at 0° C. then 90 min at room temp yielding a brownish suspension. To the suspension was added 2-fluoro-5-(trifluoromethyl)benzonitrile (6.79 g, 35.9 mmol) at room temperature. The mixture was stirred at 60° C. overnight affording about 75% conversion according to LC-MS. The dark solution was cooled in an ice water bath and carefully added to a stirred flask of water/ice/NH4Cl which was extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude residue was purified with a 120 g ISCO gold column (load column loaded with crude brown oil directly with DCM rinsing) ramping EtOAc in heptane (0-25%, then isocratic at 25%) providing product cleanly (3.65 g, yellow solid) as well as a large portion which coeluted with starting amine and other minor impurities. The mixture was dried under reduced pressure and passed through a 25 g SCX-2 column, then a second 25 g SCX-2 column since after the first wash some dark materials eluted through. DCM was used as the eluent providing 2-(6-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)benzonitrile as a tan solid (3.0 g) (6.65 g total, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.84-3.91 (m, 2 H) 4.26-4.31 (m, 2 H) 6.53 (dd, J=9.93, 2.89 Hz, 1 H) 6.64 (ddd, J=9.00, 7.82, 2.93 Hz, 1 H) 6.90 (dd, J=8.95, 5.33 Hz, 1 H) 7.55 (d, J=8.71 Hz, 1 H) 7.76 (ddd, J=8.71, 2.25, 0.59 Hz, 1H) 7.95 (dd, J=1.57, 0.68 Hz, 1 H). m/z (ESI) 323.1 (M+H)+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C@@H:8]([C@H:11]([OH:13])[CH3:12])[C:9]#[CH:10].C(=O)([O-])[O-].[K+].[K+]>Cl.C(OCC)C>[CH3:7][C@@H:8]([C@H:11]([O:13][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH3:12])[C:9]#[CH:10]
Reactant: C#C[C@@H](C)[C@@H](C)O
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@@H](C)[C@@H](C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To dihydropyran (1.3 g) cooled in an ice bath was added (3R*,4R*)-3-methyl-1-pentyn-4-ol (1.3 g) followed by concentrated hydrochloric acid (1 drop) and the mixture was stirred for 16 h at room temperature. Potassium carbonate (100 mg) was added and the mixture stirred for 15 minutes. Diethyl ether (10 ml) was added and the mixture was filtered before evaporation to an oil. The residue was distilled to give the title compound (1.2 g) (b.p. 130°-5° C. at 10 mm Hg).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:14][C@@:13]1([C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=1)[C:15]([O:17]C)=[O:16])=O)(C)(C)C>Cl>[NH2:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:14][C@@:13]1([C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=1)[C:15]([OH:17])=[O:16]
Reactant: COC(=O)[C@]1(c2cn(-c3ccccc3)cn2)C[C@@H]1CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: NCCC[C@H]1C[C@]1(C(=O)O)c1cn(-c2ccccc2)cn1
Yield: 86.6 %

Procedure:
The compound (271 mg) obtained in Step 1 of this Example was heated to reflux for 2 hours in 5 N hydrochloric acid (10 mL). The reaction solution was concentrated, and the residue was then charged to Dowex 50WX8 (1.5 g) adjusted in advance with dilute hydrochloric acid and deionized water. The resin was washed with deionized water, followed by elution with 5% ammonia water. The eluate was concentrated to obtain the title compound (134 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])[CH3:11])(C(C)(C)C)(C)C.Cl>CO.C(OCC)(=O)C>[OH:8][CH2:9][C@@H:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2[C@@H](C)CO)cc1

Procedure:
A solution of (3S,4R)-4-(1-(R)-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (0.40 g) in methanol (40 ml) was treated with 6N hydrochloric acid (10 ml) with ice-cooling for 20 minutes. The reaction mixture was diluted with ethyl acetate (200 ml), washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by silica gel chromatography to yield (3S,4R)- 4-(1-(R)-hydroxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][CH3:15]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCCI
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 73.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-iodo-butane (121 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-butyl-1H-pyrazole (111 mg, 62%) as a clear oil.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]1=[O:11].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]1=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ncc(Cl)cn1CCO
Product: O=c1ncc(Cl)cn1CCCl
Yield: 52 %

Procedure:
1-(2-Hydroxyethyl)-5-chloropyrimid-2-one (0.001 mol) and phosphorus oxychloride (5 ml) were heated together at 80° C. for 60 min. before the solution was evaporated at reduced pressure. The residue was triturated with chloroform before dissolution in water (4 ml) and neutralisation with sodium bicarbonate. Chloroform extraction and evaporation left a solid which was recrystallised from ethyl acetate, yield 52%, m.p. 167°-168° C. (Found: C, 37.20; H, 3.20; Calc for C6H6Cl2N2O: C, 37.34; H 3.13).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:35][OH:36])=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NO
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Compound A (4.7 g, 9.0 mmol), hydroxylamine hydrochloride (943 mg, 13.6 mmol), pyridine (60 mL, 740 mmol), and water (30 mL, 1.7 mol) were combined and stirred at room temperature overnight. Additional water (30 mL) was added, and the solids were filtered, washed with water, and dried to yield compound B (4.4 g) as a white solid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)c1nc2ccccc2[nH]1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C(C)(C)C)nc4ccccc43)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.3 g) was reacted with tert-butylbenzimidazole via General Procedure I for Buchwald coupling to give 94.3 mg 462 following reverse phase purification. MS (Q1) 547.3 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:17][C:18]4[C:23]([N:24]=3)=[CH:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:17][C:18]4[C:23]([N:24]=3)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=4)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(OC)cc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N2CCN(c3nc4cc(C(=O)O)ccc4nc3-c3ccccc3)CC2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-(4-(4-methoxyphenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (117.1 mg, 0.26 mmol, 1.00 equiv) and sodium hydroxide (51.6 mg, 1.29 mmol, 5.00 equiv) in methanol (15 mL) was placed in a 50-mL round bottom flask and stirred for 5 h at 50° C. in an oil bath. The solution was adjusted to a pH of 3-4 with 1N hydrochloric acid, and then concentrated under vacuum. The resulting solids were washed with methanol yielding 80 mg (70%) of 34444-methoxyphenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[O:11])[CH2:6][CH2:5]2)OC1.[ClH:18].Cl.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH2:25])=[NH:24].Cl>C(O)C>[ClH:18].[NH2:25][C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][C:26]=2[F:30])[NH:20][C:4]2([CH2:5][CH2:6][N:7]([C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[O:11])[CH2:8][CH2:9]2)[N:24]=1
Reactant: N=C(N)c1c(N)cccc1F
Reactant: O=C(N1CCC2(CC1)OCCO2)n1ccnc1
Agent: Cl
Solvent: CCO
Product: NC1=NC2(CCN(C(=O)n3ccnc3)CC2)Nc2cccc(F)c21
Temperature: 55 °C

Procedure:
1-(1H-Imidazol-1-ylcarbonyl)-4-piperidone ethylene ketal (Example EE, 156 mg., 0.66 mmol) was added to 2-amino-6-fluorobenzamidine dihydrochloride (150 mg, 0.66 is mmol) in ethanol (10 ml) together with an excess of HCl (1M in ether). This mixture was heated to 55° C. overnight, concentrated in vacuo and purified by flash column chromatography eluting with dichloromethane, increasing the gradient to dichloromethane/methanol (10:1), to give a solid which triturated from ethanol/ether to give yellow crystals, m.p. 260° C. (dec.).