Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:20][C:21](=O)[C:22]([F:25])([F:24])[F:23]>CO.ClCCl>[C:13]1([C:10]2([CH2:9][O:8][C:7]3[C:2]4[N:3]([CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[N:1]=4)[CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Nc1ncccc1OCC1(c2ccccc2)CC1
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1cn2cccc(OCC3(c4ccccc4)CC3)c2n1
Yield: 99 %

Procedure:
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (0.731 g, 3.04 mmol, step 3), 3-bromo-1,1,1-trifluoroacetone (1.3 mL, 13 mmol) and molecular sieves (4.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (15 mL) was refluxed for 22.5 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to yield a brown oil which was dissolved in dichloromethane (100 mL) and washed with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude desired product. Purification by dry column (600 mL funnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine) yielded 1.00 g (99% yield) of 8-[(1-phenylcyclopropyl)methoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridine (Rf=0.33 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of the free amine (0.950 g, 2.86 mmol) in dichloromethane (4 mL) and anhydrous diethyl ether (16 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. After 20 min, the solvent was removed in vacuo, and the residue was triturated in anhydrous diethyl ether to give the title compound as a pale yellow solid (0.414 g, 39% yield). 1H-NMR (300 MHz, CDCl3) δ 8.58 (d, 1H, Ar), 8.55 (s, 1H, Ar), 7.50 (m, 1H, Ar), 7.06 (m, 2H, Ar), 6.91 (m, 2H, Ar), 6.78 (m, 1H, Ar), 6.72 (d, 1H, Ar), 4.11 (s, 2H, CH2O), 0.69 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 146.50 (+), 141.44 (+), 137.01 (+), 129.76/129.21 (+), 127.90 (−), 125.98 (−), 121.69/118.12 (+), 120.97 (−), 116.31 (−), 114.85 (−), 107.82 (−), 76.35 (+), 23.03 (+), 13.75 (+); LRMS-FAB m/z: MH+ 333 (100%); Anal. calcd for C18H15N2OF3.HCl: C, 58.63; H, 4.37; N, 7.60%. found: C, 56.80; H, 4.07; N, 7.03%.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29](=O)[CH2:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[CH3:25].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:24]([O:26][C:27]([C:28]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:39])[CH3:25]
Reactant: CCOC(=O)CC(=O)CCCn1ccnc1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCCn2ccnc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (453 mg), 6-(1-imidazolyl)-3-oxohexanoic acid ethyl ester (320 mg) and acetic acid (5 ml), concentrated sulfuric acid (0.03 ml) was added, followed by stirring at 100° C. for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured over water, alkalinized with 2N sodium hydroxide and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[3-(1-imidazolyl)propyl]quinoline-3-carboxylic acid ethyl ester (310.0 mg, 43%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 164° to 165° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:8]=[C:9]([CH3:15])[C:10](=[CH:12][C:13]=1[CH3:14])[NH2:11].[Br:21]Br>ClCCl>[Br:21][C:12]1[C:13]([CH3:14])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)[CH:8]=[C:9]([CH3:15])[C:10]=1[NH2:11]
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)c(C)cc1N
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)c(C)c(Br)c1N

Procedure:
To a stirred solution of the product from stage b) above (1.12 g) in dichloromethane (20 ml) was added dropwise bromine (0.64 g) in dichloromethane (5 ml) at 0° C. The mixture was washed with sodium bicarbonate solution, dried (MgSO4), filtered and evaporated to give a crude oil which was purified by silica gel chromatography eluting with ethyl acetate/light petroleum (b.p. 60-80° C.) (1:4) to give the title product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C@@H:18]([CH2:22][CH3:23])[CH:19](N)[OH:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([N:26](CC)CC)C.P([O-])(O)(O)=O.[Na+]>C(Cl)Cl>[C:11]([C@:18]([NH2:26])([CH2:22][CH3:23])[CH:19]=[O:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CCN(CC)CC
Reactant: CC[C@H](C(=O)OC(C)(C)C)C(N)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
A solution of oxalyl chloride (40.39 g, 265 mmol) in MeCl2 (700 mL) was stirred and cooled to −60° C. Dimethylsulfoxide (51.7 g, 663 mmol) in MeCl2 (100 mL) was added dropwise. After 10 min., a solution of 2(S)-Boc-amino-1-butanol (50 g, 265 mmol) in MeCl2 (100 mL) was added dropwise at −70° C. The reaction mixture was allowed to warm to −40° C. for 10 min. and then cooled to −70° C. again. A solution of triethylamine (74.9 g, 742 mmol) in MeCl2 (100 mL) was added. The reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 mL) was added, and then the organic layer was washed with brine and dried over MgSO4. The solvent was removed to yield 45 g of 2(S)-Boc-aminobutyraldehyde.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7](C[C@@H](N)C(O)=O)[C:5]=2[CH:6]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.C[N:29](C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[C:8]1[NH2:29]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1cc2ccccc2[nH]1

Procedure:
Human indoleamine 2,3-dioxygenasae (IDO) with an N-terminal His tag was expressed in E. coli and purified to homogeneity. IDO catalyzes the oxidative cleavage of the pyrrole ring of the indole nucleus of tryptophan to yield N′-formylkynurenine. The assays were performed at room temperature as described in the literature using 95 nM IDO and 2 mM D-Trp in the presence of 20 mM ascorbate, 5 μM methylene blue and 0.2 mg/mL catalase in 50 mM potassium phosphate buffer (pH 6.5). The initial reaction rates were recorded by continuously following the absorbance increase at 321 nm due to the formation of N′-formlylkynurenine (See: Sono, M., et al., 1980, J. Biol. Chem. 255, 1339-1345).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].[K+].C([OH:38])(C)(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH2:24])=[O:38])=[N:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(C#N)nc2)n1)c1ccc(F)cc1
Reactant: CC(C)(C)O
Agent: [F-]
Agent: [K+]
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(C(N)=O)nc2)n1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To 38 mg of (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidin-4-yl}picolinonitrile, was added t-butanol, and 60 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was stirred at 90° C. for 4 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 25 mg of the objective compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([OH:27])=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5].C(Cl)(=O)C([Cl:36])=O.CN(C=O)C>C1COCC1>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([Cl:36])=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5]
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (0.1 g) in THF (5 mL) at 0° C. under N2 was added oxalyl chloride (0.055 mL) followed by a drop of DMF. The solution was stirred at 0° C. for 2 h followed by stirring at room temperature for 2 h. THF was evaporated and fresh THF (5 mL) was added and the solution was evaporated again. This process was repeated one more time and the residue was dried under vacuum to yield N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanyl chloride.
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NN1C(=O)C(CC(=O)C(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 3-E) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and warmed to 60° C. To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 mL, 0.74 mmol) (Aldrich) and stirring continued for 17 hours. After cooling to 23° C., the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was isolated as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:13]#[N:14].[K+].Cl.C#N>CN(C=O)C.O>[Cl:12][C:4]1[C:3]([CH2:2][C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(CBr)c1Cl
Reactant: [C-]#N
Agent: C#N
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(bromomethyl)-2-chlorobenzoic acid [Aromatic Intermediate 11, step a] (13.2 g) in DMF (150 mL) was treated with a solution of potassium cyanide (7.23 g) in water (50 mL) and the resulting solution was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and carefully acidified with concentrated hydrochloric acid (25 mL), venting any liberated HCN through bleach solution via a stream of nitrogen. After being stirred for 2 hours, the aqueous phase was extracted with ethyl acetate (3×250 mL). The combined organic phases were washed with water (3×250 mL) and brine (250 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 10.3 g.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])[CH:6]=[C:7]([F:9])[CH:8]=1.S(=O)(=O)(O)O.CC(O)=O.C1C(=O)N([I:36])C(=O)C1>C(Cl)Cl>[F:19][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([I:36])=[CH:12][C:11]=2[F:18])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(F)c(-c2cc(F)cc(C(F)F)c2)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2cc(F)cc(C(F)F)c2)c(F)cc1I
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a 250-mL RBF was added 3′-(difluoromethyl)-2,5′-difluoro-5-methoxy-1,1′-biphenyl (642 mg, 2.376 mmol) and sulfuric acid (69.7 μl, 1.307 mmol). DCM (3960 μl) and AcOH (3960 μl) were added to give a colorless clear solution. To this solution was added n-iodosuccinimide (238 μl, 2.376 mmol) as a solid in a single portion to give a maroon-colored solution. After 3 h at rt, the mixture was diluted with DCM (30 mL), washed with water (10 mL), washed with saturated aq. sodium thiosulfate (10 mL, DCM was upper layer for separation), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g silica gel column, 0-5% EtOAc/Heptane) to provide 3′-(difluoromethyl)-2,5′-difluoro-4-iodo-5-methoxy-1,1′-biphenyl (771 mg, 1.946 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.87 (m, 1H), 7.67-7.73 (m, 1H), 7.63-7.67 (m, 1H), 7.48-7.57 (m, 1H), 7.08-7.18 (m, 2H), 3.91 (d, J=2.54 Hz, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH3:13])=[O:12].[N-:14]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH3:13])(=[NH:14])=[O:12]
Reactant: Cc1cc([N+](=O)[O-])ccc1S(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1S(C)(=N)=O
Temperature: 25 °C

Procedure:
1.5 g (7.5 mmol) of (RS)-2-methyl-1-(methylsulfinyl)-4-nitrobenzene and 1.1 g (17.1 mmol) of sodium azide in 10.0 ml of CHCl3 are carefully mixed at 0° C. with 2.2 ml of concentrated sulfuric acid. The batch is heated first to room temperature and then to 45° C. while being stirred vigorously. It is stirred for 116 hours at this temperature. After cooling, it is mixed with water and extracted from DCM (2×). The aqueous phase is made basic with 2N NaOH solution and extracted from DCM. The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. The crude product that is obtained is recrystallized from ethyl acetate. 1.3 g (6.1 mmol, corresponding to 81% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]=[O:18]>>[CH2:13]([C:12]1[CH:11]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]=[CH:14][C:17]=1[OH:18])[C:14]1[CH:15]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:11]=[CH:12][C:13]=1[OH:16]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C=O
Product: CCCCCCCCCc1ccc(O)c(Cc2cc(CCCCCCCCC)ccc2O)c1

Procedure:
2,2' methylenebis (4-nonylphenol) was prepared in a similar manner by replacement of the 1,1,3,3,-Tetramethylbutylphenol by 4-nonylphenol in the same mole ratio to formaldehyde.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].C([O-])(=O)/C=C\C([O-])=O.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>>[CH:20]12[C@@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:21]1[S:17][CH:18]=[CH:19]2
Reactant: c1ccsc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: CCOC(=O)[C@@H]1C2C=CSC21
Temperature: 46 °C
Reaction time: 0.17 h

Procedure:
A 3-neck, 5 liter flask is fitted with a stirrer, a thermocouple, and a teflon addition tube, and a N2 inlet is charged 2000 ml of thiophene (d=1.05 g/mL, 25.0 mol at beginning and increasing to 45 mol with addition of ethyl diazoacetate solution in thiophene, 17.1 equiv based upon total addition of ethyl diazoacetate and not corrected for potency of EDA, 19.0 equiv based upon potency corrected ethyl diazoacetate). To this is added, under N2, 0.968 g of Rh2(octanoate)4 (1.24 mmoles, 0.0472 mol % based upon g of ethyl diazoacetate not corrected for potency, 0.052 mole % based upon moles of pure ethyl diazoacetate, Johnson Mathey: Lot No. 059255001). The suspension is heated to 46° C. and stirred at 46° C. for 10 minutes to affect dissolution to a green solution. To the solution is added, by a positive displacement pump, a solution of 300 g of ethyl diazoacetate (90% pure, 2.63 moles, 2.37 moles pura, 1.00 equiv, Aldrich: Lot No. 17603PI) dissolved in 1600 mL of thiophene. The rate of addition is such that the total addition time is 8 hours; the slow rate of addition suppresses formation of the maleate and fumarate ethyl esters. When no ethyl diazoacetate remains (approximately thirty minutes), the dark amber reaction (3,985 g) is cooled to 23° C. The reaction mixture is split into portions and the larger portion (3,240 g of 3,985 g total=81.3%) is directly concentrated to an oil. The crude product is passed through the wiped film distillation apparatus at 1.5 torr and 23° C. to degas the product and to remove residual amount of thiophene. The product is then distilled at 120° C. and 1.3 torr. The title compound (faint yellow) is collected in two fractions, 155.0 g and 32.2 g. Analysis by HPLC determines a potency of 78% and 76% for the two lots respectively. Crystallization of the distillate from above is accomplished by dissolution in methanol (2 mL per 1 g of distillate) and cooling to −10° C., at which time the solution is optionally seeded if crystal growth is not observed. Once crystal growth has commenced, the mixture is further cooled to −45° C. and stirred for 2-3 hours, filtered, and washed with cold (−45° C.) methanol (1×1 mL per 1 g of distillate). The material is dried in vacuo at 24° C. to provide the title compound as a white to off-white solid in 80-85% recovery and >98% potency.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:16])[CH2:4][CH2:5][CH:6]([N+:13]([O-:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17]=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:17][C:6]([N+:13]([O-:15])=[O:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH:3]1[CH3:16]
Reactant: CNC(C)CCC(c1ccccc1)[N+](=O)[O-]
Reactant: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1CCC(c2ccccc2)([N+](=O)[O-])CN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a suspension of 138 mg (0.621 mmol) Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-amine in 2.2 ml dioxane under argon at room temperature, was added 49.8 ul (0.683 mmol) formaldehyde (37% in water). The mixture was stirred at room temperature for 30 minutes and then at 65° C. for 4.5 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. Sodium sulfate was added. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 20%) to provide 76 mg (52%) of the title compound as a colorless oil. MS (m/e): 235.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].Cl[CH2:15][C:16]([NH2:18])=[O:17].O1CCOCCOCCOCCOCCOC=C1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH2:15][C:16]([NH2:18])=[O:17])=[O:5]
Reactant: NC(=O)CCl
Reactant: O=C(O)c1c(F)cccc1F
Agent: C1=COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)COC(=O)c1c(F)cccc1F

Procedure:
This compound was prepared in the manner of Example I, using 10.0 grams (0.063 mole) of 2,6-difluorobenzoic acid, 4.2 grams (0.063 mole) of potassium hydroxide, 5.9 grams (0.063 mole) of 2-chloroacetamide, and 1.7 grams of 1,4,7,10,13,16-hexaoxacyclooctadecene in 250 ml of dry toluene. The crude product was recrystallized once with ethyl acetate, then with ethyl acetate-hexane, using decolorizing carbon. The yield was 5.2 grams of (aminocarbonyl)methyl 2,6-difluorobenzoate; mp 108.5°-110°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:16]2=[O:26])[CH2:13][O:12]1.C(=O)([O-])O.[Na+].[H-].[Na+]>O.C(O)C>[CH3:13][C:11]1([CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][C:16]2=[O:26])[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC1(Cn2nc(-c3ccccc3)oc2=O)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(Cn2nc(-c3ccccc3)oc2=O)Cn2cc([N+](=O)[O-])nc2O1
Yield: 41.1 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (170 mg, 1.15 mmol), 3-(2-methyloxiran-2-ylmethyl)-5-phenyl-3H-[1,3,4]oxadiazol-2-one (310 mg, 0.9 mmol), sodium hydrogencarbonate (120 mg, 1.43 mmol) and ethanol (2 ml) was stirred under reflux for 2.5 hours. The reaction mixture was allowed to return to room temperature, then diluted with water. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in 1,4-dioxane (10 ml). To the solution, sodium hydride (55 mg, 1.38 mmol) was added followed by stirring at room temperature for 1 hour and then stirring under reflux for 1.5 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to afford 3-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-5-phenyl-3H-[1,3,4]-oxadiazol-2-one (127 mg, yield 32%) as a light brown powder.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]3[CH3:25])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:32]>CO.[OH-].[OH-].[Pd+2]>[ClH:32].[CH3:25][C:20]1[N:19]([C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[C:23]([CH3:24])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C)n1-c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C)n1-c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 8-benzyl-3-(2,5-dimethyl-1H-pyrrol-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (60 mg) in methanol (4 mL) was added 20% Pd(OH)2/C (10 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (4 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (50 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered to give the title compound (28 mg, 56%) as a brown powder.