Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9])=[O:6].CC(C)([O-])C.[K+].C(OCC)(=O)C.Cl>O1CCCC1>[CH:4]1([C:5]([C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=2[NH2:9])=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1cccc(C(=O)CCCCl)c1N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)C2CC2)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A mixture of 2-(4-chlorobutanoyl)-6-methylaniline (538 mg) and potassium t-butoxide (285 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 1.5 hour. Ethyl acetate and 0.1 N aqueous hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with water, saturated aqueous sodium bicarbonate and brine successively and dried over magnesium sulfate. Removal of the solvent in vacuo gave 2-cyclopropylcarbonyl-6-methylaniline (445 mg, 100.0%) as a crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14]C)[C:8]([O:12]C)=[N:9]2)=[C:4]([CH2:16][OH:17])[CH:3]=1>C(O)(=O)C.Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:12])[NH:9]2)=[C:4]([CH2:16][OH:17])[CH:3]=1
Reactant: COc1nc2cc(Br)cc(CO)c2nc1OC
Agent: Cl
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Br)cc(CO)c2[nH]c1=O
Temperature: 20 °C

Procedure:
450 mg (1.5 mmol) of 7-bromo-5-hydroxymethyl-2,3-dimethoxy-quinoxaline are dissolved in 30 ml of acetic acid and 10 ml of 2N hydrochloric acid, and the solution is heated at reflux for 2 hours and cooled to 20° C. The solid is filtered off, washed with water and dried.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CCN3C2)cn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CCN3C2)cn1
Yield: 90.1 %

Procedure:
(7R,8aS)-7-{[5-(Prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine (240 mg, 0.512 mmol, Example 116) in ethanol (10 mL) was added to 20% palladium hydroxide on carbon (15 mg, 0.11 mmol). The mixture was stirred at room temperature for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=3:2) to give the title compound (217 mg, 90% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (s, 6H), 1.77 (m, 1H), 1.91 (m, 1H), 2.09 (m, 1H), 2.21-2.42 (m, 4H), 3.01 (m, 2H), 3.56 (m, 1H), 3.66 (m, 1H), 3.84 (m, 1H), 5.22 (m, 1H), 8.02 (m, 5H), 8.20 (m, 1H); MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: N#Cc1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-cyanophenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 28.9, 32.0, 42.6, 60.5, 111.0, 118.7, 127.3 127.0, 127.9, 128.1, 133.0, 140.6, 141.9 and 143.1.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:32])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[F:48][C:49]([C:50]([OH:52])=[O:51])([F:54])[F:53]
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCCNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fmoc-Phe-Gly-NH—(CH2)6NH-Boc (0.7 g) was dissolved in CH2Cl2 (4 mL) at 0° C. under N2 and then trifluoroacetic acid (TFA) (4 mL) was added. The reaction mixture was allowed to warm to RT and stirred for 2 hours under N2. The solvents were removed under reduced pressure and the residue dried at high vacuum to provide 0.71 g of Fmoc-Phe-Gly-NH(CH2)6—NH2.TFA. This crude material was used to prepare without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:23][CH2:22][C@:18]45[C:19]=2[C:20]=1[O:21][C@H:17]4[C:16](=[O:29])[CH2:15][CH2:14][C@@:13]35[OH:30])(=O)=O.[CH3:33][N:34](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([CH2:25][N:24]2[CH2:23][CH2:22][C@:18]34[C:19]5[C:20]6[O:21][C@H:17]3[C:16](=[O:29])[CH2:15][CH2:14][C@@:13]4([OH:30])[C@H:12]2[CH2:11][C:10]=5[CH:9]=[CH:8][C:7]=6[C:33]#[N:34])[CH2:27][CH2:28]1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(OS(=O)(=O)C(F)(F)F)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 120 °C
Yield: 61 %

Procedure:
A mixture of (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-yl trifluoromethanesulfonate [P1](38.0 g, 80.3 mmol), zinc cyanide (18.85 g, 160.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (8.5 g, 7.36 mmol) in DMF (500 mL—degassed with argon for 3 hours) was heated at 120° C. under argon for 3 hours. The reaction mixture was allowed to return to room temperature then diluted with ethyl acetate (1 L) and passed through a pad of celite. The solution was washed with water (3×1 L) and the organic phase dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave crude product that was triturated with methanol to give (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carbonitrile [P2] (17.12 g, 61% yield); LC/MS (r.t. 12.7 minutes [5 to 95% B]), 351 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20]>CN(C)C=O.O>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[CH:3][C:4]2=3)[C:12]1=[O:20]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCCc2[nH]ccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C1=C1CCCc2[nH]ccc21
Temperature: 140 °C
Yield: 11.9 %

Procedure:
A mixture of 680 mg 1,5,6,7-tetrahydro-4H-indol-4-one and 1.33 g oxindole in 3 ml dimethylforamide was heated at 140° C. for 50 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water and then brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified on a silica gel column using hexanes/ethyl acetate as the eluent to provide 150 mg of 1′,5′,6′,7′-tetrahydro-1H-[3,4′]biindolyliden-2-one as a yellow solid.
Reaction SMILES: [NH:1]([C:29]([O:31]CC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:18]([N:20]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([NH2:24])=[O:23])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4]C(=O)N>C(O)(=O)C.[Pd]>[NH:1]1[C:29](=[O:31])[CH2:4][CH2:3][C@H:2]1[C:8]([NH:10][C@H:11]([C:18]([N:20]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([NH2:24])=[O:23])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCCC[C@@H]1C(N)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)[C@H]1CCCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Yield: 37.4 %

Procedure:
2.63 g (5 mmoles) of Z-Gln-His-D-Pip-NH2 are dissolved in 50 ml of acetic acid, 0.5 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is heated to 60°-70° C., maintained at this temperature for 30 minutes, and then evaporated in vacuo. The residue is dissolved in water, the solution is passed through Dowex 2 ion exchange resin in the OH cycle, and then evaporated. The resulting crude product is applied onto the top of a silica gel column, and the column is eluted with solvent mixture (1). The fractions which contain the pure product are combined and evaporated. The residue is dissolved in water, the solution is decolourized, filtered, and the clear filtrate is evaporated. The amorphous residue is dried in vacuo over phosphorous pentoxide. 704 mg (51%) of Glp-His-D-Pip-NH2 are obtained; Rf4 =0.10; [α]D25 =+16.0° (c=1%, in water). Amino acid analysis: Glu: 1.03 (1.0), His: 1.00 (1.0), Pip: 0.96 (1.0).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: C1COCCO1
Product: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 53 %

Procedure:
In a manner similar to that of Example 1(g), starting with 220 mg (0.5 mmol) of N-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methyloctanamide in 10 ml of dioxane, 120 mg (53%) of the desired product, with a melting point of 36° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=O)[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]([OH:48])([CH3:47])[CH3:46])[CH2:41][CH2:40]1.CC(O)=O.C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][N:39]2[CH2:44][CH2:43][CH:42]([C:45]([OH:48])([CH3:47])[CH3:46])[CH2:41][CH2:40]2)[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:32][CH2:33]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCC=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCN4CCC(C(C)(C)O)CC4)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (49 mg, 0.093 mmol) was taken up in TIIF (1 mL) and 2-(piperidin-4-yl)propan-2-ol (26.6 mg, 0.186 mmol), AcOH (5.32 μl, 0.093 mmol), and sodium cyanoborohydride (11.69 mg, 0.186 mmol) were added. The reaction was stirred at room temperature overnight. The reaction mixture was quenched with 2M K3PO4 solution and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-100% EtOAc/DCM then flushed with 10% MeOH/DCM; 24 g column). 2-((2-chloro-5-cyano-4-(3-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)propyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (43 mg) was obtained as a yellow glass.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]([CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COC(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a stirred mixture of methyl 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.24 g, 0.94 mmol) and K2CO3 (0.156 g, 1.13 mmol) in 10 mL of DMF was added chloromethyl pivalate (0.17 g, 1.13 mmol) drop-wise at room temperature. Then the mixture was stirred at room temperature for 16 hours. The mixture was then poured into 30 mL of water, extracted with ethyl acetate (90 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4 to give a crude product, which was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.276 g, 79.5%) as a pale yellow solid. LCMS: (M+H)+=370; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.38 (s, 1H), 6.21 (s, 2H), 3.96 (s, 3H), 1.15 (s, 9H).
Reaction SMILES: S(Cl)(Cl)=O.[N+](C1C=CC(COC(=O)CO)=CC=1)([O-])=O.[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N+:39]([C:42]1[CH:80]=[CH:79][C:45]([CH2:46][O:47][C:48](=[O:78])[CH:49]([N:51]2[C@H:54]([S:55][C:56](=[O:74])[CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]3[CH:70]=[CH:69][C:68]([N+:71]([O-:73])=[O:72])=[CH:67][CH:66]=3)=[O:62])[C@@H:53]([O:75][CH3:76])[C:52]2=[O:77])Cl)=[CH:44][CH:43]=1)([O-:41])=[O:40]>O1CCCC1.C(Cl)Cl.C(N(CC)CC)C>[N+:39]([C:42]1[CH:43]=[CH:44][C:45]([CH2:46][O:47][C:48](=[O:78])[C:49]([N:51]2[C@H:54]([S:55][C:56](=[O:74])[CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]3[CH:70]=[CH:69][C:68]([N+:71]([O-:73])=[O:72])=[CH:67][CH:66]=3)=[O:62])[C@@H:53]([O:75][CH3:76])[C:52]2=[O:77])=[P:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:79][CH:80]=1)([O-:41])=[O:40]
Reactant: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(CO)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 24, 0.12 ml of thionyl chloride and then 0.23 ml of triethylamine in 0.23 ml of absolute tetrahydrofuran are added to a solution of 606 mg of 2-[(3S,4R)-4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 4.5 ml of absolute tetrahydrofuran. After reacting and working up, 0.54 g of triphenylphosphine is added to the resulting crude 2-[(3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 1.15 ml of absolute tetrahydrofuran. Working up and chromatography over silica gel produce the title compound with the following IR spectrum (CH2Cl2):
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@H:8]([OH:10])[CH3:9])([CH3:4])[CH3:3].O[C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([O:10][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])[CH3:9])([CH3:3])[CH3:4]
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 16 h
Yield: 80.1 %

Procedure:
(2R)-1-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}propan-2-ol (3.31 g, 17.4 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g, 11.6 mmol) in THF (50 mL) at 0° C. followed by addition of triphenylphosphine (4.57 g, 17.4 mmol) then DIAD (3.43 mL, 17.4 mmol) and the reaction was warmed to RT and stirred for 16 h. The reaction was quenched with water (100 mL) and diethyl ether (400 mL) and the organic layer was separated then dried (MgSO4) and evaporated. Purification by column chromatography, eluting with 1:15 to 1:5 ethyl acetate:hexane, afforded the title compound as a colourless oil (4.00 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:7]=1)=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][Br:20])[N:8]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)n(-c2c(Cl)cccc2Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CBr)n(-c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2 L flask was charged with 44.6 g of 1-(2,6-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (133 mmol), 28.43 g of N-bromosuccinimide, 0.80 g of benzoyl peroxide and 1 L of carbon tetrachloride. The resulting solution was placed under a high intensity lamp for 2 hours. The resulting solution was allowed to cool to room temperature, filtered through a pad of celite. The filtrate was then concentrated in vacuo and the crude bromide was passed through a plug of silica using 40% EtOAc:hexane and recrystallized from heptane-ethanol to afford 5-bromomethyl-1-(2,6-dichlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester was recovered as a tan solid (19.3 g, 38%); 1H NMR (400 MHz, CDCl3): δ 7.45 (m, 4H), 7.05 (s, 1H), 6.77 (s 0.2H starting material), 4.43 (q, J=7.07 Hz 2H), 4.27 (s, 2.16H), 2.14 (s, 0.6H starting material); 1.41 (t, J=7.07 Hz 3H), MS (ES): 399 [M+Na]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH3:31])[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[CH3:21]>>[CH3:31][N:19]([CH3:18])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:24][CH:23]=1)[CH3:21]
Reactant: CC(c1ccc(B(O)O)cc1)N(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)N(C)C)cc1
Yield: 60.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.5 g, 4.8 mmol) was reacted with 4-[1-(dimethylamino)ethyl]phenylboronic acid (1.5 g, 6.3 mmol) to afford the desired product (1.1 g, 58%) as a white solid: ESI MS m/z 379 [C22H22N2O2S+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:5][N:4]=[CH:3]1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: Cn1cncc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cncc1C(=NO)c1ccccc1
Reaction time: 3 h
Yield: 47.2 %

Procedure:
A solution of (1-methyl-1H-imidazol-5-yl)(phenyl)methanone (14.0 g, 75 mmol) and hydroxylamine hydrochloride (13.1 g, 188 mmol) in pyridine (60 mL) was stirred for 72 h at room temperature, and for 3 h at 50° C. After removal of the solvent in vacuo, addition of water (600 mL) and extraction with ethyl acetate (4×150 mL), the combined organic layers were washed with water (150 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow solid was washed with pentane to afford N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-phenylmethanimine [7.12 g, yield 42%; HPLC/MS: m/z=202 (M+H); log P(HCOOH)=0.41]. Further extraction of the neutralised combined aqueous layers afforded a second crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-phenylmethanimine [5.75 g, yield 34%; HPLC/MS: m/z=202 (M+H); log P(HCOOH)=0.41], combined yield 76%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12]CC.CN(C)CCN(C)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:11]([C:3]1[C:2](=[O:10])[N:1]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2)[CH3:12]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1=c2ccccc2=NC1=O
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under N2 was cooled to −25° C. and treated drop wise with n-butyl lithium (2.5M in hexanes, 240 ml, 0.6 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min. iodoethane (48 ml, 0.6 mol) was added and the reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was poured into aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford the crude product (24.5 g, 51%). A sample (3 g) was recrystallized from EtOAc/hexane to obtain 3-ethyl-indol-2-one (1.4 g), m.p. 100–101° C.; 1H-NMR (DMSO-d6) δ 0.76 (t, 3H, J=7.5 Hz), 1.8–2.0 (m, 2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 1H, J=7.69, 0.45 Hz), 6.93 (dt, 1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m/z 270 [M+H].