Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:31]([C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([CH2:27][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:29]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccc(CN5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 56.7 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 3-morpholin-4-ylmethyl-benzaldehyde (26.7 mg, 0.130 mmol) were reacted to produce 35 mg (57%) of the title compound. mp: 184-185° C., 1H NMR (300 MHz, CDCl3): 8.13 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.47 (s, 2H), 6.40 (d, J=8 Hz, 2H), 6.24 (s, 1H), 6.14 (br s, 1H), 6.10 (d, J=8 Hz, 1H), 5.28 (t, J=8 Hz, 1H), 3.74 (br s, 4H), 3.64 (s, 2H), 3.17 (s, 1H), 3.07 (s, 6H), 2.94 (s, 1H), 2.80 (d, J=8 Hz, 1H), 2.54 (s, 3H), 2.35 (d, J=8 Hz, 1H), 2.13 (s, 1H), 1.70 (d, J=8 Hz, 1H). MS: 523, 525 (M+H), HPLC: 1.84 min (G method).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][C:23]([OH:26])([CH3:35])[CH2:22]3)(=[O:20])=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCN(S(=O)(=O)NC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCN(S(=O)(=O)NC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The product from Example 182 (65 mg, 0.12 mmol) in tetrahydrofuran (10 ml) at 0° C. was treated with methyl magnesium bromide (3M solution in tetrahydrofuran, 0.4 ml). The reaction was stirred at 0° C. for 45 minutes then quenched with NH4Cl solution, extracted into ethyl acetate and evaporated. The residue was purified by chromatography on silica (diethyl ether) to afford the desired compound (18 mg). 1H NMR (360 MHz, CDCl3) δ 7.38–7.31 (4H, m), 7.07–7.06 (2H, m) 6.89–6.80 (1H, m), 4.90–4.98 (1H, d, J=4 Hz), 3.58–3.55 (2H, m), 3.49–3.40 (2H, m), 3.24–3.23 (1H, m), 2.56–2.39 (4H, m), 2.12 (1H, s), 2.04–1.94 (4H, m), 1.52–1.46 (2H, m), 1.45 (3H, s). m/z=571, 573 [MNa]+
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:27])[C:19](=[N:25][OH:26])[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+:29].[OH-].[Na+].CC(C)=O>O>[OH:26][N:25]=[C:19]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[C:18]([NH:17][C@@H:16]1[C:15](=[O:28])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][OH:4])[CH2:7][S:8][C@H:9]12)=[O:27].[Na+:29]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NO)c3cccs3)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)C(=NO)c3cccs3)C(=O)N12
Reaction time: 4 h

Procedure:
A solution of sodium 3-acetoxymethyl-7β-[2-hydroxyimino-2-(thien-2-yl)acetamido]ceph-3-em-4-carboxylate (syn-isomer) (2.0 g) in water (160 ml) was warned to 37° and defatted wheat germ (15 g.) was added. The mixture was stirred at 37° for 4 hours, the pH being kept between 6.5 and 6.9 by the addition of 2N sodium hydroxide solution (total 2.3 ml). The mixture was poured into acetone (200 ml) and then filtered through kieselguhr. Acetone was removed under reduced pressure and the aqueous solution was again filtered through kieselguhr, washed with ethyl acetate, then covered with ethyl acetate and taken to ph 2.7 by the careful addition of concentrated hydrochloric acid. The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined extracts were washed with water and the pH was taken to 7.0 by the addition of 2N-sodium hydroxide. The organic layer was further extracted with water and the combined aqueous solution was washed with ethyl acetate and ether, degassed and lyophilised to give the title oxime as a brown solid (1.43 g; 79%), [α]D + 76° (c 0.46, DMSO), λmax. (pH 6 phosphate) 261.5 nm (ε 10,600), λinflex. 284 nm (ε 6,500), νmax. (Nujol) 1760 (β-lactam), 1560 (CO-2), 1650 and 1520 cm-1 (COHN), τ (D2O) values include 2.41, 2.63 and 2.83 (doublet, doublet and triplet respectively, J 4 Hz; thienyl protons)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13])([O-:3])=[O:2].[OH-].[NH4+].[Cl-].[NH4+].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].Cl>O>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cccc([N+](=O)[O-])c1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A suspension of 2,6-dinitrophenol 5.0 g (27 mmol), ammonium hydroxide (3 ml) and ammonium chloride 14.3 g (270 mmol) in 30 ml of water was heated to 70° C. A solution of sodium sulfide nonahydrate (24.19 g, 100 mmol) in water was added and the resulting mixture stirred at 70° C. for 2 h. The reaction was cooled to room temperature, acidified (pH 3.2) with 2N HCl, and the brown precipitate separated by filtration. The filtrate was extracted with chloroform (6×75 ml), the organic extracts combined with the precipitate, and evaporated in-vacuo to yield 2.5 g (60%) of product as a dark brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30]CC)=[O:29])[CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:18])=[CH:15][CH:14]=2)=[C:4]([OH:35])[N:3]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:33][CH:34]=2)=[C:4]([OH:35])[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCCc2c(N)nc(N)nc2O)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(N)c(CCCCc2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.50 g of diethyl N-(4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]benzoyl)-L-glutamate and 40 mL of 1N sodium hydroxide is stirred at room temperature for 72 hours. The mixture is neutralized with hydrochloric acid and the solid which forms is collected by filtration, washed with water and dried to yield N-(4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)-butyl]benzoyl)-L-glutamic acid, m.p. 169°-171° C.; IR (KBr) vmax 3340, 3200, 2920, 2860, 1600, 1380, 1170, and 755 cm-1 ; 1H NMR (dTFA) delta 7.30 (d, J=8.7 Hz, 2H, Ar), 6.90 (d, J=8.7 Hz, 2H, Ar), 4.56-4.61 (m, 1H), 2.26-2.38 (m, 4H, 2' aliphatic), 1.93-2.14 (m, 4H, 2° aliphatic), 1.25-1.34 (m, 2H, 2° aliphatic), 1.05-1.17 (m, 2H, 2° aliphatic).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=2[S:41][CH:42]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[S:41]1[CH:42]=[C:38]([C:36](=[O:37])[CH2:35][NH:34][C:12]([C:10]2[S:11][C:7]3[C:6]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:14])[C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]1=2
Reactant: NCC(=O)c1csc2ccccc12
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3csc4ccccc34)nc12
Reaction time: 48 h
Yield: 44.1 %

Procedure:
0.30 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.19 g 1,1′-carbonyl-diimidazole in 6 ml DMF were stirred at room temperature for 4 hours. 0.26 g 2-amino-1-benzo[b]thiophen-3-yl-ethanone hydrochloride and 0.–16 ml triethylamine were added and stirring was continued for two days at room temperature. 100 ml water was added and the mixture was extracted with ethylacetate. The precipitate was filtered to yield 0.21 g (44%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-amide as a yellow solid; M.p.: 256–258° C.; MS (ISP): m/e=468 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[CH3:11][C:12]1[C:13]([O:15][C:16](=O)[C:17]=1[CH3:18])=[O:14]>C(O)(=O)C>[C:7]([C:4]1[S:3][C:2]([N:1]2[C:13](=[O:14])[C:12]([CH3:11])=[C:17]([CH3:18])[C:16]2=[O:15])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)N(c2nnc(C(C)(C)C)s2)C1=O
Yield: 91 %

Procedure:
2-Amino-5-tert-butyl-1,3,4-thiadiazole (1.57 g) and 2,3-dimethylmaleic anhydride (1.51 g) were refluxed for 5 hours in glacial acetic acid (30 ml). After the reaction, acetic acid and the excess of the 2,3-dimethylmaleic anhydride were evaporated. The residue was dissolved in dichloromethane (50 ml), and the solution was washed with a 10% aqueous solution of potassium carbonate (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the desired N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2,3-dimethylmaleinimide (2.41 g), mp. 87°-91° C.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>C(Cl)Cl>[F:8][C:9]([F:18])([F:19])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[N:7][S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[S@](N)=O
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N=Cc1ccc(C(F)(F)F)cc1
Reaction time: 36 h

Procedure:
(R)-2-methylpropane-2-sulfinamide (31.6 g, 260 mmol), 4-(trifluoromethyl)-benzaldehyde (22.7 g, 130 mmol) and cupric sulfate (83.2 g, 521 mmol) were added to 300 mL DCM and the mixture was stirred for 36 h. The mixture was filtered through a pad of celite and the filtrate was evaporated and purified via silica plug filtration. (R)—N-(4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=2[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=2[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1Oc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2C(=O)Oc2ccccc2)cc1
Yield: 91.8 %

Procedure:
9 g of phenyl 2-(4'-nitrophenoxy)benzoate, prepared as described in Example 1, are contacted with hydrogen in 50 cm3 of ethanol, in the presence of 5% palladium (100 mg) on coal. After recrystallization in 100 cm3 of a methanol-water mixture (50--50 by volume), 7.52 g of phenyl 2-(4'-aminophenoxy)benzoate (m.p. 102° C.) are obtained (yield: 92%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[C:5]=1[CH2:15][CH3:16].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[CH2:15]([C:5]1[C:6]2[NH:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][C:12]=2[S:13][C:4]=1[CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[C:22]3[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=3[O:25][N:24]=2)[CH2:31][CH2:30]1)[CH3:16]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCc1c(CCCl)sc2c1NC(=O)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CCN2CCC(c3noc4cc(F)ccc34)CC2)sc2c1NC(=O)CCC2
Temperature: 100 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
A mixture of 1.0 g of 2-(2-chloroethyl)-3-ethyl-4,6,7,8-tetrahydro- 5H-thieno[3,2-b]azepin-5-one, 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 4.0 g of potassium carbonate and 1.5 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 100° C. for 3 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and recrystallized from isopropyl alcohol to give 0.45 g of 3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one 3/4 hydrate, m.p. 115°-117° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[CH3:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][NH2:22])[N:19]=1>CO>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:22][O:21][CH2:20][C:18]2[N:19]=[C:15]([CH3:14])[S:16][CH:17]=2)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: Cc1nc(CON)cs1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Solvent: CO
Product: Cc1nc(CON=C(C(=O)O)c2csc(NC=O)n2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)glyoxylic acid (1.10 g.) and 2-methylthiazol-4-ylmethoxyamine (0.99 g.) in methanol (17 ml.) was stirred at room temperature for 3 hours. The precipitates were collected by filtration and washed with methanol to give 2-(2-formamidothiazol-4-yl)-2-(2-methylthiazol-4-ylmethoxyimino)-acetic acid (syn isomer, 1.17 g.).
Reaction SMILES: [C:1]1([C:7]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:17]([O:21][CH3:22])(=[O:20])[C:18]#[CH:19]>>[CH2:6]1[C:1]2=[C:7]3[CH:8]([CH:19]=[C:18]([C:17]([O:21][CH3:22])=[O:20])[CH:2]2[CH2:3][CH2:4][CH2:5]1)[O:9][C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:12]3
Reactant: C1=C(C2=COc3ccccc3O2)CCCC1
Reactant: C#CC(=O)OC
Product: COC(=O)C1=CC2Oc3ccccc3OC2=C2CCCCC12

Procedure:
In a sealed tube, 500 mg of 2-(1-cyclohexenyl)-1,4-benzodioxin and 1.4 ml of methyl propiolate are stirred for 22 hours 30 minutes at 70° C. The regioisomers are separated by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 98:2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[N+:12]([CH:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]3)[CH:23]=2)[CH:18]=1)[CH3:16])([O-:14])=[O:13].[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:43][O:42][C:38](=[O:41])[CH2:39][CH2:40][C:15]([N+:12]([O-:14])=[O:13])([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]([F:37])([F:36])[F:35])[CH2:32][CH2:33]3)[CH:23]=2)[CH:18]=1)[CH3:16]
Reactant: CC(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a mixture of potassium carbonate (78 mg, 0.56 mmol, Fisher), tetrabutylammonium hydrogen sulfate (10. mg, 0.029 mmol, Aldrich) and N,N-dimethylformamide (2.00 mL, Acros) was added 2-(1-nitro-ethyl)-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalene (0.159 g, 0.433 mmol). The mixture was stirred and methyl acrylate (50 μL, 0.56 mmol, Aldrich) was added. The mixture was stirred at room temperature. After 2 h, ethyl acetate was added and the solution was washed with saturated ammonium chloride, then saturated sodium chloride. The organics were dried over Na2SO4, filtered, concentrated. The residue was taken up in DCM, and silica gel was added. The solvent was removed and the residue was purified by silica gel chromatography (0-25% EtOAc in hexanes). Isolated was 98 mg (50%) of product (Rf=0.19 in 7:1 hexanes/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC.CCCCCC>[CH2:12]([NH:19][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccn1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(NCc1ccccc1)c1cc(Cl)ccn1

Procedure:
A mixture of 5 g of methyl 4-chloropicolinate and 3.44 g of benzylamine is heated at 100° for 16 hours. Cooling and trituration with ether/hexane affords N-benzyl-4-chloro-pyridine-2-carboxamide. This material is heated with 5 g of sodium azide in 50 ml of dimethylformamide at 100° for 10 hours. After dilution with water the product is extracted with ether. Drying and removing the solvent affords 4-azido-N-benzyl-pyridine-2-carboxamide as an oil. This material is stirred under 1 atom of hydrogen in 50 ml of ethanol with 1.0 g of 10% palladium on carbon catalyst for 4 hours. Filtration and removal of solvent affords 4-aminopyridine-2-(N-benzyl)-carboxamide as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[CH2:7][NH2:8].[OH-].[Na+].C(O)C.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>O>[CH3:2][O:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[CH2:7][NH:8][CH2:23][CH2:22][C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: C=CC(=O)OCC
Reactant: COCc1cccc([N+](=O)[O-])c1CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCNCc1c(COC)cccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Methoxymethyl-6-nitrobenzylamine hydrochloride (20.4 g., 0.114 mole) is dissolved in a minimum volume of water and the solution is made strongly basic by the addition of 10% sodium hydroxide. The clear oil which forms is extracted into two 120-ml. portions of ether. The ether is dried with 10 g. of anhydrous sodium sulfate, filtered, and finally dried over Drierite. The dried solution is filtered and evaporated, leaving a yellow oil. The oil is dissolved in 100 ml. of absolute ethanol and 11.4 g (0.114 mole) of freshly distilled ethyl acrylate is added. This solution is allowed to stand overnight and the solvent removed by distillation from a steamcone. The oily residue is dissolved in 200 ml. of dry ether, the solution is cooled in an ice bath, and treated with dry hydrogen chloride. When precipitation is complete, the solid is filtered and dissolved in 120 ml. of boiling absolute ethanol. The hydrochloride crystallizes from this solution on cooling yielding the title product. By concentrating and cooling the mother liquor, additional title product g. is obtained. ##SPC43##
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O.B(O)(O)O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:8][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: Nc1ccccc1O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: c1c[nH]c(-c2nc3ccccc3o2)c1
Yield: 51.6 %

Procedure:
2-(Pyrrol-2-yl)benzoxazole was prepared as follows: A mixture of 5.55 g (0.05 mol) of pyrrole-2-carboxylic acid and 5.46 g (0.05 mol) of o-aminophenol and 3.09 g (0.05 mol) boric acid in 50 mL of xylene was heated under reflux for 3 days while removing water which was generated from reaction using a Dean-Stark trap. The cooled reaction mixture was diluted with 100 mL of ethyl acetate, washed with 150 mL of 5% sodium hydroxide solution and then with 150 mL of water. The separated organic layer was dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography on silica gel with 20% hexane in chloroform as eluant. The desired product, 2-(pyrrol-2-yl)benzoxazole (4.75 g, 52%), was obtained as a white solid. m.p. 149°-150° C.; 1H NMR (CDCl3) δ6.38-6.40 (m, 1H, ArH), 7.05-7.06 (m, 1H, ArH), 7.11-7.13 (m, 1H, ArH), 7.29-7.36 (m, 2H, 2xArH), 7.53-7.56 (m, 1H, ArH), 7.65-7.69 (m, 1H, ArH), 10.9 (bs, 1H, NH).
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25](C(OCC5C6C=CC=CC=6C6C5=CC=CC=6)=O)[CH2:24]4)=[CH:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].Cl.[C:49]([C:51]1([C:54]([OH:56])=O)[CH2:53][CH2:52]1)#[N:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C>[CH:13]1[C:14]2[N:19]3[C:20]([C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:54]([C:51]5([C:49]#[N:50])[CH2:53][CH2:52]5)=[O:56])[CH2:24]4)=[CH:21][N:22]=[C:18]3[CH:17]=[N:16][C:15]=2[NH:11][CH:12]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc([C@@H]4CCCN(C(=O)OCC5c6ccccc6-c6ccccc65)C4)n23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#CC1(C(=O)N2CCC[C@@H](c3cnc4cnc5[nH]ccc5n34)C2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 9.3 %

Procedure:
To a solution of (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate (0.20 g, 0.32 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.97 mL, 1.9 mmol). The reaction mixture was heated at about 100° C. for about 3 h before it was allowed to cool to ambient temperature. The reaction was neutralized with 4N HCl in 1,4-dioxane (0.5 mL) and was concentrated under reduced pressure. To the residue was added MeCN (25 mL) before it was concentrated under reduced pressure. This procedure was repeated before the addition of 1-cyanocyclopropanecarboxylic acid (0.072 g, 0.65 mmol), HATU (0.111 g, 0.291 mmol) and DMF (2 mL) followed by DIEA (0.170 mL, 0.971 mmol). After stirring at room temperature for about 3 h, the reaction was partitioned between EtOAc (2×50 mL) and aqueous NaHCO3 (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction was purified by RP-HPLC (Table 2, Method j). The combined product-containing fractions were concentrated under reduced pressure to remove MeCN and then lyophilized to give (R)-1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile as a white solid (0.010 g, 9%): LC/MS (Table 2, Method a) Rt=1.67 min; MS m/z: 335 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([C:20](OC)=[O:21])[CH2:5]1)([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O>[CH:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([CH2:20][OH:21])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N1C[C@H](CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 89.3 %

Procedure:
8 grams of 6-isopropyl-8β-methoxycarbonylergoline was added to a mixture of 8 g of sodium borohydride in 200 ml of methanol. The reaction mixture was heated under reflux for 2 hrs; then a second 2 g batch of sodium borohydride was added. The mixture was cooled after 3 hrs, diluted with water, and the precipitate was filtered to give 6.5 g of 6-isopropyl-8β-hydroxymethylergoline, m.p. 192°-194° C., after crystallization from methanol. A solution of 13 g of 4-toluenesulfonyl chloride in 87 ml of pyridine was added slowly to a cooled solution of 6.5 g of 6-isopropyl-8β-hydroxymethylergoline in 250 ml of pyridine. After 15 hrs the mixture was poured over iced water and the precipitate was filtered to give 7.4 g of 6-isopropyl-8β-toxyloxymethylergoline melting at 180°-184° C. after crystallization from acetone.