Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[O:11][CH2:10]2.I[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[O:11][CH2:10]2
Reactant: COc1ccc(CNc2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Reactant: ICCN1CCOCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CN(CCN2CCOCC2)c2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Temperature: 85 °C

Procedure:
A mixture of 3-[5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (100 mg, 0.24 mmol), 4-(2-iodo-ethyl)-morpholine (90 mg, 0.37 mmol), N,N-diisopropylethylamine (63 mg, 0.49 mmol) and silver triflate (75 mg (0.29 mmol) in 1,4-dioxane (5 ml) was heated at 85° C. under nitrogen for 16 hours. Purification of the mixture by silica gel chromatography, eluted with a gradient of MeOH in CHCl3 led to 3-{5-[(2,4-dimethoxy-benzyl)-(2-morpholin-4-yl-ethyl)-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (40 mg, 31%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=3)[N:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].CCO.O>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)n1ccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)n1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Yield: 83.1 %

Procedure:
To a mixture of 3-cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (1.08 g, 3.32 mmol), ammonium chloride (88.8 mg, 1.66 mmol) in 4:1 EtOH/water (15 mL) was added iron powder (1.85 g, 33.2 mmol) and the mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was mixed with in EtOAc/water and filtered through GF/F paper. The organic phase was separated and concentrated under reduced pressure to provide 3-cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (0.815 g, 83% yield) as a yellow solid.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].C(N(CC)CC)C.[ClH:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([CH:37](Cl)[CH2:38][CH3:39])[CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[ClH:24].[ClH:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:32][CH2:33][N:34]([CH2:37][CH2:38][CH2:39][N:3]3[CH2:4][CH:5]4[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[CH2:35][CH2:36]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCC(Cl)N1CCN(c2cccc(Cl)c2)CC1
Reactant: C1CC2CCC1CNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1cccc(N2CCN(CCCN3CC4CCC(CC4)C3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-azabicyclo[3.2.2]nonane, (4 g, 0.032 mol), sodium carbonate (4 g, 0.045 mol) and triethylamine 3 mL in 50 mL of dimethylformamide is added 4-(3-chlorophenyl)-1-piperazinylpropylchloride hydrochloride (4 g, 0.0115 mol). The reaction mixture is stirred at room temperature overnight, the solvent is removed under vacuum and the remaining solid is extracted in 3×100 mL methylene chloride. The methylene chloride extracts are collected, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[CH3:20][C:21]1[S:22][C:23]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([NH2:36])=[CH:33][CH:34]=3)[CH:29]=[N:28]2)=[CH:24][N:25]=1>>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:36][C:32]1[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=1)[N:27]([CH2:26][C:23]1[S:22][C:21]([CH3:20])=[N:25][CH:24]=1)[N:28]=[CH:29]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Cc1ncc(Cn2ncc3cc(N)ccc32)s1
Product: Cc1ncc(Cn2ncc3cc(Nc4ncnc5cccc(O[C@H](C)C(=O)N(C)C)c45)ccc32)s1
Yield: 61.5 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (261 mg, 1 mmol) and 1-[(2-methyl-1,3-thiazol-5-yl)methyl]-1H-indazol-5-amine (269 mg, 1.1 mmol) were reacted to give the title compound as a white solid (300 mg, 61%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 2.62 (s, 3H), 3.07 (s, 3H), 3.15 (s, 3H), 5.43 (q, 1H), 5.71 (s, 2H), 6.82 (d, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.61 (m, 2H), 7.86 (dd, 1H), 8.05 (s, 1H), 8.42 (s, 1H), 8.62 (s, 1H); Mass spectrum 488.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:24])[CH:18]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a stirred mixture of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (300 g, 1.46 mol), and TEA (300 g, 3 mol) in DCM (4 L) was added 6-chloropyrimidine-4-carbonyl chloride (250 g in 2 L of DCM) slowly at −60° C. over 1 h. After the addition was complete, the mixture was then allowed to warm to 10° C. Stirring was continued for 1 h, at which time TLC showed the reaction was completed. The reaction was quenched by addition of water (2 L). The organic phase was collected, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give the desired product as a pale yellow solid. Four batches were run in parallel and produced a combined product weight of 970 g, yield: 49%. 1H NMR (400 MHz, MeOD-d4) δ 8.73 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.2 Hz, 1H), 7.17-7.06 (m, 3H), 7.00 (d, J=7.2 Hz, 1H), 5.51 (s, 1H), 4.12 (q, J=6.0 Hz, 1H), 3.74 (s, 2H), 3.64-3.53 (m, 2H), 2.94 (q, J=5.6 Hz, 2H), 2.92-2.81 (m, 2H), 2.78-2.64 (m, 2H); LCMS (m/z): 347.2 [M+H]+
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CN(C)[CH:21]=[O:22]>>[CH:21]([C:14]1[S:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:16][CH:15]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: c1ccc(-c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 75 mL of dimethylformamide was cooled to 0° C., and 15 mL of phosphorus oxychloride was added with stirring. The solution was allowed to warm to room temperature, and then a solution of 20.4 grams (0.127 mole) of 2-phenylthiophene in 20 mL of dimethylformamide was added in one portion. The reaction mixture was heated to 80° C. where it stirred for 24 hours. It was then poured into 250 mL of an aqueous, 10% sodium hydroxide solution containing 50 grams of ice. The resulting slurry was extracted with chloroform, and the extract was washed in succession with an aqueous solution saturated with sodium chloride and water. The organic phase was dried over anhydrous magnesium sulfate and filtered. TThe filtrate was concentrated under reduced pressure to a brown residue. Purification of this residue by column chromatography on silica gel, eluting with ethyl acetate:n-hexane (15:85) yielded 18.0 grams of 2-formyl-5-phenylthiophene.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([CH3:17])[NH:12]3)[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19]([N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([CH3:17])[NH:12]3)[CH2:4][CH2:3]1)=[O:20]
Reactant: Cc1cc2c(N3CCN(C)CC3)cccc2[nH]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(N3CCN(C(=O)OCC(Cl)(Cl)Cl)CC3)cccc2[nH]1
Yield: 85 %

Procedure:
A solution of 4-methyl-1-(2-methyl-1H-indol-4-yl)piperazine (0.510 g, 2.22 mmol) and 2,2,2-trichloroethyl chloroformate (5 mL) was heated at 100-110° C. for 48 hours. The reaction solution was cooled, and methylene chloride (200 mL) followed carefully by a saturated solution of sodium hydrogen carbonate (20 mL) were added. The organic layer was removed, dried (potassium carbonate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 300 g) using elution with 10% ethyl acetate in hexanes to afford 4-(2,2,2-trichloroethoxycarbonyl)-1-(2-methyl-1H-indol-4-yl)piperazine as a white amorphous solid (0.74 g, 1.89 mmol, 85%): FAB LRMS (m/z, relative intensity) 394 (9), 392 (27), 390 ([MH+ with 35Cl], 32), 358 (18), 356 (29), 216 (99), 194 (100). This compound was used directly as outlined below.
Reaction SMILES: C(O)(=O)C.Cl[CH2:6][C:7](=[O:30])[C@@:8]1([OH:29])[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][C:9]1=[CH2:28]>C(OCC)(=O)C.[Zn]>[OH:29][C@@:8]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][C:9]1=[CH2:28])[C:7](=[O:30])[CH3:6]
Reactant: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@]1(O)C(=O)CCl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@]1(O)C(C)=O
Reaction time: 16.5 h

Procedure:
Zinc dust (0.030 mg) and glacial acetic acid (0.13 ml) is added to a solution of 21-chloro-17β-hydroxy-16-methylenepregn-4-ene-3,20-dione (III, EXAMPLE 40B, 0.050 g) in ethyl acetate (1.5 ml). The reaction system is purged with nitrogen and warmed to 45°. After stirring for 16.5 hr, THF (5 ml) is added and the mixture is filtered thru celite to remove the remaining zinc. The filtrate is then partitioned between water (5 ml) and ether (5 ml). The organic extract is washed with sodium bicarbonate (5%) and water, dried over sodium sulfate and concentrated to give the title compound, NMR (CD2Cl2) 0.87, 1.17, 2.20, 3.40, 5.10 and 5.65 δ.
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[CH:5]2.[N:15]1C2C(=CC=CC=2)C=C[CH:16]=1>>[CH3:14][C:3]1[C:2]([C:16]#[N:15])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: c1ccc2ncccc2c1
Reactant: Cc1c(Br)ccc2[nH]c(C(=O)O)cc12
Product: Cc1c(C#N)ccc2[nH]ccc12
Temperature: 230 °C

Procedure:
4.71 g (18.5 mmol) of 5-bromo-4-methyl-1H-indole-2-carboxylic acid and 5.03 g (56.2 mmol) of cuprous cyanide were dissolved in 35 ml of quinoline and the solution heated at 230° C. for 90 minutes. The reaction mixture was then cooled down to ambient temperature and poured onto crashed ice. The pH was adjusted to pH 2-3 and the mixture subsequently extracted 3 times with ether. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a crude product which was purified by chromatography (silicagel, eluent: gradient of n-heptane/ethyl acetate) to yield 2.36 g of 4-methyl-1H-indole-5-carbonitrile as light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[C:10]3[C:7](=[CH:2][CH:3]=[CH:4][CH:9]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCCCCC
Product: Brc1ccc(-c2cccc3ccccc23)cc1

Procedure:
An Rf value of the objective substance by a silica gel thin layer chromatography (TLC) (developing solvent, hexane) was 0.38 and that of 4-bromoiodobenzene was 0.57.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:22]([O:29][C:30](=[O:47])[N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](Br)[N:41]=1)[CH2:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:47])[N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[N:41]=1)[CH2:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)NC(=O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Product: CC(C)NC(=O)CN(Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared by using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.92 g, 0.30 mmol) and benzyl[(6-bromopyridin-2-yl)methyl][2-(isopropylamino)-2-oxoethyl]carbamate (0.12 g, 0.30 mmol) as the starting materials.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]3[CH:33]=2)=[CH:19][CH:18]=1.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>O1CCCC1.CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:33]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([O:14][CH2:13][CH2:12][CH2:11][O:10][S:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=4)(=[O:8])=[O:9])=[CH:22][CH:21]=3)[N:24]=2)[CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCO)cc1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(OCCCOS(=O)(=O)c4ccc(C)cc4)cc3)cn2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 45.1 %

Procedure:
To a solution of 554 mg (corresponding to 2.40 mmol) of 1,3-propanediol mono-p-toluenesulfonate in 10 mL of tetrahydrofuran, 260 mg (corresponding to 1.08 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine and 636 mg (corresponding to 2.42 mmol) of triphenylphosphine were added. Further, 5 mL of N,N-dimethylformamide was added thereto to completely dissolve the contents. To the reaction mixture, 0.48 mL (corresponding to 2.42 mmol) of diisopropylazodicarboxylate was added. After the resulting mixture was stirred at room temperature for 23 hours, the reaction solution was concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform/ethyl acetate=19/1), further purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name: manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), and further purified again by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=35/65) to obtain 220 mg (corresponding to 0.487 mmol) of 6-methoxy-2-[4′-(3″-p-toluenesulfonyloxypropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1, Step 7).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CCc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 27 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-4-phenylbutanoic acid (310.3 mg) and ethyl 4-aminophenylacetate hydrochloride (201.6 mg) were condensed in THF (5 ml) in the presence of triethylamine (421.2 μl) and pivaloyl chloride (153.6 μl), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (117.6 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[C@@H:7]([CH3:18])[CH2:8][N:9]2[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][N:47](C(OC(C)(C)C)=O)[CH:48]=2)O1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:21]1([C:19]([N:6]2[C:5]3[C:10](=[CH:11][C:2]([C:44]4[CH:45]=[N:46][NH:47][CH:48]=4)=[CH:3][CH:4]=3)[N:9]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][C@@H:7]2[CH3:18])=[O:20])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(Br)cc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Temperature: 90 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
A 50-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-isopropyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.801 g, 2.1 mmol), dioxane (11 mL), and water (4.6 mL). Cesium carbonate (2.053 g, 6.30 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (0.927 g, 3.15 mmol) were then added. The reaction was purged with nitrogen and bis(triphenylphosphine)palladium (II) dichloride (0.177 g, 0.252 mmol) was added. The mixture was heated at 90° C. with vigorous stirring for 5 h and then cooled to ambient temperature. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic extracts were concentrated to afford a viscous oil and purified via column chromatography (gradient elution with 75-100% ethyl acetate-hexanes). The resulting material was triturated with diethyl ether (2×10 mL) to afford (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.55 g, 71% yield) as a solid. MS (ESI, pos. ion) m/z 369 [M+1]+.
Reaction SMILES: [Br:1][CH2:2][C:3](OCC)([O:38]CC)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:38])[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (6.5 g) in methylene chloride (60 ml) was added conc. hydrochloric acid (6 ml) at 3° to 5° C., and the mixture was stirred from under ice-cooling to at ambient temperature for 8 hours. After methylene chloride (100 ml) was added to the reaction mixture, it was heated with water and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain benzhydryl 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.5 g).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[NH2:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[NH2:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(N)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(N)=O
Reaction time: 24 h

Procedure:
Ethyl 8-carbamoyl-12-acetoxyheptadecanoate (5.50 g., 0.0138 mole) is added to a solution of sodium hydroxide (1.66 g., 0.0414 mole) in water (8 ml.) and methanol (72 ml.). The resulting solution is allowed to stand 24 hours at 25° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C1N=CN([C:15]([N:17]2C=N[CH:19]=[CH:18]2)=[O:16])C=1>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:15]([NH:17][C:18]2[CH:19]=[C:4]([CH3:5])[N:3]=[C:2]([CH3:7])[CH:1]=2)=[O:16])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(N)cc(C)n1
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)Nc2cc(C)nc(C)c2)cc(C)n1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
2,6-Dimethyl-pyridin-4-ylamine (1.22 g, 10 mmol) is dissolved in dry dioxane (30 mL) and CDI (891 mg, 5.5 mmol) is added. The mixture is heated at 80° C. for 1 h. Further CDI (160 mg) is added and stirring is continued for 15 h. The mixture is evaporated and purified by FC (SiO2, EtOAc-MeOH) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.[C:13]1([O:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:22]2)=[O:12]
Reactant: C#CCOc1ccccc1
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Resin bound 4-amino-3-iodo-benzoic acid methyl ester was suspended in DMF and treated with 15.6 g of phenyl propargylether, 60 ml of triethylamine and catalytic amounts of CuI and bis(triphenylphosphine)palladium(II) chloride. The resin was shaken for 6 h at 50° C. and washed subsequently with DMF, isopropanol/water and diethylether.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1.C(N(CC)CC)C>ClCCl>[C:9](/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)([OH:11])=[O:10]
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)/C=C\C(=O)Nc1ccc(/C=C/C(=O)O)cc1

Procedure:
The method of Example 1 was employed using 4-aminocinnamic acid hydrochloride (10.0 g, 0.0501 mol) and maleic anhydride (5.00 g, 0.0509 mol). Triethylamine (7.00 ml, 0.0502 mol) in dichloromethane (100 ml) was added to generate the free amine. The yellow maleamic acid was obtained. H.p.l.c. 100%. 1H-n.m.r. (DMSO): δ 10.51 (1H, s, NH); 7.65 (4H, bs, ar H's); 7.55 (1H, d, pH-CH); 6.44 (2H, t, HO2C CH=CH; CO, PhCH=CH); 6.30 (1H, d, HO2C CH=CH CO).