Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C([O:14][C:15]([C:17]1[C:21]2=[N:22][C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:24][CH:25]=[C:20]2[NH:19][CH:18]=1)=O)C.CO>C1(C)C=CC=CC=1.ClCCCl>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:15]([C:17]1[C:21]2=[N:22][C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:24][CH:25]=[C:20]2[NH:19][CH:18]=1)=[O:14]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)c1c[nH]c2ccc(OC3CCN(C)CC3)nc12
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CN1CCC(Oc2ccc3[nH]cc(C(=O)Nc4ccccn4)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
AlMe3 (0.3 mL, 0.59 mmol, 2 M in PhCH3) is added to a solution of 2-aminopyridine (56 mg, 0.59 mmol) in toluene (1.0 mL) and 1,2-dichloroethane (1.0 mL) at room temperature. The resulting solution is stirred for 30 minutes at room temperature, 5-(1-methyl-piperidin-4-yloxy)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester (60 mg, 0.20 mmol) is then added. The resulting mixture is heated at 100° C. for a period of 3 h. The mixture is cooled to room temperature and Na2SO4.10H2O (285 mg, 0.89 mmol) is added. The mixture is stirred for 30 minutes and MeOH (5 mL) is added. The resulting mixture is filtered through a pad of celite and washed with MeOH (3×5 mL) and CHCl3 (3×5 mL). The filtrate is concentrated and purified by chromatography on silica (gradient elution with 5% MeOH/CHCl3 with 0.1% NH4OH to 8% MeOH/CHCl3 with 0.1% NH4OH to 10% MeOH/CHCl3 with 0.1% NH4OH) to give the title compound as a light yellow solid: (Cmp. #1) 1H NMR (400 MHz, CD3OD) δ 8.29-8.27 (m, 2H), 8.01 (s, 1H), 7.73-7.69 (m, 2H), 7.03 (dd, 1H, J=7.1, 5.4 Hz), 6.63 (d, 1H, J=8.7 Hz), 5.40-5.34 (m, 1H), 2.86-2.80 (m, 2H), 2.57-2.52 (m, 2H), 2.35 (s, 3H), 2.30-2.26 (m, 2H), 1.91-1.86 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 163.9, 159.5, 152.4, 148.1, 139.1, 138.2, 131.6, 125.1, 124.1, 119.5, 114.2, 109.3, 107.2, 70.8, 53.6, 45.7, 30.8; MS (CI) m/z 352.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.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>[C:28]1([CH:27]=[CH:26][C:2]2[CH:7]=[CH:6][C:5]3[CH2:8][C:9]4[C:21]5[NH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:13]=5[C:12]5[C:22](=[O:25])[NH:23][CH2:24][C:11]=5[C:10]=4[C:4]=3[CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(C=Cc2ccccc2)cc1-3
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a solution of 3-bromo-5H, 6H, 12H, 13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), styrene (30 mg, 0.29 mmol) and triethylamine (0.5 mL) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg). The solution was heated in a sealed reaction tube at 100°-110 ° C. for 48 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, then the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 85 mg (80%) of a brown solid. Recrystallization from DMF-Et2O gave the product, Compound I-24, as a tan solid. The melting point was greater than 300 ° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ4.2 (s, 2H), 5.02 (s, 2H), 7.25-7.5 (m, 7H), 7.6-7.75 (m,4H), 7.8 (d, 1H, J=8Hz), 8.2 (s, 1H), 8.6 (s, 1H), 9.4 (d, 1H, J=8 Hz), 12.8 (s, 1H). MS(FAB): m/e 413 (m+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCCN1C(=O)OCc1ccccc1

Procedure:
A solution of 4.3 g (R)-2-Methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester in 20 ml dichloromethane was stirred in the presence of 10 ml TFA for 16 h. The solution was concentrated and the residue codistilled twice with toluene to give the crude hydrotrifluoroacetate. Yield: 6.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:41]=[CH:40][C:22]4[C:23]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:24]([CH2:28]C5C=CC=CC=5)[C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.OC1C=CC2C(C(OCC)=O)=C(CC3C=CC=CC=3)C(=O)OC=2C=1.ClC1C=CC(CN2CCN(CCCCl)CC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:41]=[CH:40][C:22]4[C:23]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:24]([CH3:28])[C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(Cc2ccccc2)c(=O)oc2cc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)ccc12
Agent: CCOC(=O)c1c(Cc2ccccc2)c(=O)oc2cc(O)ccc12
Agent: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Product: CCOC(=O)c1c(C)c(=O)oc2cc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)ccc12

Procedure:
ethyl 7-{3-{4-[(4-chlorophenyl)-methyl]-1-piperazinyl}-propoxy}-3-phenylmethyl-2H-1-benzopyran-2-one-4-carboxylate from ethyl 7-hydroxy-3-phenylmethyl-2H-1-benzopyran-2-one-4-carboxylate and 3-{4-[(4-chlorophenyl)-methyl]-1-piperazinyl}-propyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[N:19]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH2:33]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH2:12][CH:13]1[NH:19][C:14](=[O:33])[CH2:15][CH2:16][CH2:17][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(CC2CCCCC2=NO)cc1OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCCCC(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)N1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-benzyloxy-4-nitrobenzyl)-cyclohexanone oxime (250 mg, 0.706 mmol) in chloroform (5 mL) at −50° C. is added PCl5 (148 mg, 0.71 mmol). The mixture is stirred at −50° C. for 2 h then water is added. The mixture is extracted with methylene chloride and the organic phase is washed sequentially with 5% NaOH, water and brine. The organic solution is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by flash chromatography using a gradient of 50-100% EtOAc/hexanes to afford the title compound: (M+1)+=355.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]3[CH:36]=[CH:35][NH:34][C:31]3=[N:32][CH:33]=2)O1>>[CH3:13][NH:12][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([C:28]3[CH:29]=[C:30]4[CH:36]=[CH:35][NH:34][C:31]4=[N:32][CH:33]=3)=[N:7][C:6]=2[CH:8]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CNCc1cc2nc(-c3cnc4[nH]ccc4c3)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine and 5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine were reacted according to the General Procedure A to give 437. NMR (DMSO, 400 MHz), 2.35 (3H, s), 3.78-3.82 (4H, m), 3.99-4.06 (6H, m), 6.54 (1H, s) 7.36 (1H, s), 7.48-7.51 (1H, m), 8.97 (1H, s), 9.28 (1H, s). MS: (ESI+): MH+=381
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1)#[N:2].O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: COc1cc(C#N)ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1OC
Yield: 367.8 %

Procedure:
A solution of 4-cyano-2-methoxy benzoic acid (1.0 g, 5.65 mmol, Biogene) in methanol was reacted with p-toluenesulfonic acid monohydrate (285.6 mg, 1.479 mmol) and heated to reflux for 16 hrs. The solvent was removed and the reaction residue was extracted with EtOAc, and washed with saturated sodium carbonate, water, and saturated NaCl, and dried over Na2SO4 to give 4-Cyano-2-methoxy-benzoic acid methyl ester (1.04 g, 96%). This ester (1.01 g, 5.28 mmol) in methanol (50 mL) was reacted with Raney Ni (3 spatula tips full, exact amount unknown, Aldrich) under 50 psi H2 in a Parr apparatus for 16 hrs. After filtering through Celite and concentrating, the crude mixture was purified by silica gel chromatography using methanol and methylene chloride to give 4-aminomethyl-2-methoxy-benzoic acid methyl ester (385.7 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:29]
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(N)cc3n2CC)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(C#N)c(-c3ccc(OCC)cc3)n(CC)c2c1

Procedure:
6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example 1BR, step B is treated with ethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to furnish, after purification using column chromatography, [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethyl ester (30 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[C:18](O)=[O:19].ClC(OCC(C)C)=O.C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[CH2:18][OH:19]
Reactant: O=C(O)c1c(-c2cccs2)c(=O)[nH]c2ccc(Br)cc12
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1[nH]c2ccc(Br)cc2c(CO)c1-c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 6-bromo-2-oxo-3-(thiophene-2-yl)-1,2-dihydroquinoline-4-carboxylic acid (1.00 g, 2.86 mmol) in tetrahydrofuran (11.4 ml) were added isobutyl chloroformate (0.364 ml, 2.86 mmol) and triethylamine (0.398 ml, 2.86 mmol) at 0° C. The reaction was allowed to stir at room temperature for 30 min. The reaction was then filtered to remove solids and placed in an ice bath at 0° C. Sodium borohydride (0.119 g, 3.14 mmol) was added to the reaction mixture followed by methanol (3 ml). This mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was diluted in ethyl acetate (50 ml) and extracted with 1 N sodium hydroxide (3×40 ml) and sodium chloride (1×40 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford 6-bromo-4-(hydroxymethyl)-3-(thiophen-2-yl)quinolin-2(1H)-one as a crude, yellow oil. Compound used without further purification. LCMS (M+H)=337.7.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH2:11](I)[CH:12]=[CH2:13]>O1CCCC1>[CH2:13]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH:12]=[CH2:11]
Reactant: CCc1ccccc1Br
Reactant: C=CCI
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccccc1CC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 8.53 g (350 mmoles) of magnesium in 270 mL in dry tetrahydrofuran was added 50 g (270 mmol) of 1-bromo-2-ethylbenzene. The temperature was maintained at 50° C. during addition, then was heated under reflux. After 1 h, the solution was cooled to -78° C. under N2, and 54.42 g (324 mmoles) of allyl iodide was added dropwise. The mixture was allowed to warm to room temperature, stirred for an additional 2 h, then cooled to 0° C. The reaction was quenched by addtition of 2M HCl and 500 mL of ether and the layers were separated. The organic layer was washed with 30 mL of saturated NaHCO3 solution and brine, dried over MgSO4, and concentrated. The oily residue was filtered through silica gel with 20% ethyl acetate-hexane and the eluate was concentrated to afford the crude 1-allyl-2-ethylbenzene as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1.C(=O)([O-])O.[K+]>COCCOC.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:29][C:28]([C:23]3[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=3)([C:30]([F:31])([F:33])[F:32])[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C=NO)cc1Cl
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
In a solution of 10.6 g of 3-chloro-4-methylbenzaldoxime in 60 mL of 1,2-dimethoxyethane, 9.2 g of N-chlorosuccinimide was added, and stirred at 70° C. for 2 hours. Then, the reaction mixture was left and cooled to room temperature, 11.3 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 1, 15.6 g of potassium hydrogen carbonate and 10 mL of water were added, and continued to stir at room temperature further for 20 hours. After the completion of the reaction, the reaction mixture was diluted with 70 mL of ethyl acetate, washed with water (50 mL×1), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and then the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 13.8 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]Br.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Product: COC(=O)[C@H](CCN1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97 %

Procedure:
(S)-4-Bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (0.10 g, 0.34 mmol) (prepared as in Example 120, Steps A-D) and piperidine (1 mL) were heated to 50° C. for 16 hours and then cooled to room temperature and concentrated under reduced pressure. The residue was azeotroped with toluene (3×10 mL) and then chromatographed eluting with MeOH/dichloromethane (1:9) to provide 93 mg of colorless oil (97% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[N:31][CH:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3cncnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M97) (0.43 g, 0.84 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light red solid (230 mg, 69%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][N:31]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CNCC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@H](O)[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*)-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f39) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:21][C:5]1([CH3:20])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: O=C(Cl)CCc1ccccc1
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Yield: 99.7 %

Procedure:
N-(3,3-Dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (1.17 g) is synthesized from A8 (807 mg) and freshly prepared 3-phenyl-propionyl chloride (0.5 ml; 3,3 mmol) as described in Example 1a.
Reaction SMILES: Br[C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[Li]CCCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[CH2:15]([C:3]1[C:2]([C:26]([OH:28])=[O:27])=[CH:14][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]=2[CH:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C=O
Reactant: CCCCCCc1cc2c(cc1Br)CCCCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc2c(cc1C(=O)O)CCCCC2(C)C
Reaction time: 0.67 h

Procedure:
This 3.21 g of 2-bromo-3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene were placed in 30 ml of abs. tetrahydrofuran under Ar and treated at -78° with 6.75 ml of 1.55M nBuLi (hexane) (1.1 eq.). The metal/halogen exchange was followed by gas chromatography (GC). After 40 min., a large excess of CO2 gas was introduced and the cooling bath was removed. After 10 min., the mixture was poured on to ice/NH4Cl solution, extracted with diethyl ether, washed with H2O, dried over Na2SO4 and the solvent was removed in a vacuum. Flash chromatography on SiO2 (hexane/ethyl acetate=8/2) yielded 2.26 g of 3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid as white crystals of m.p. 74°-75°.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH3:26][NH:27][CH3:28]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([N:27]([CH3:28])[CH3:26])[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.05 g) was heated with 40% aq. dimethylamine (2 ml) in ethanol (1 ml) for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. The residue was triturated with ethyl acetate/isohexane mixtures and the title product collected by filtration as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[CH3:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:29][C:28]1[CH:30]=[CH:31][C:25]([F:24])=[C:26]([CH3:32])[CH:27]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)ccc1F
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1ccc(F)c(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 4-fluoro-3-methylaniline. After completion, the reaction mixture was extracted with HCl and washed with a saturated NaHCO3 solution. The organic was dried (Na2SO4), filtered and concentrated. The product was used without further purification. tR: 1.37 min (LC-MS 2); ESI-MS: 508.1/510.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23].O.C(=O)(O)[O-].[Na+:30]>O>[CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([O-:24])=[O:23].[Na+:30]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Yield: 95 %

Procedure:
25 gms of cephalexin monohydrate was suspended in 75 ml of water. To this under stirring, 5.75 gms of sodium bicarbonate was added. The solution were filtered and lyophilized to afford 24 gms of crystalline cephalexin sodium.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]([OH:17])=[O:16].C(O)C>O>[OH:3][N:2]=[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=NO)c1cccs1

Procedure:
A cooled solution of hydroxylamine hydrochloride (0.884 g) and sodium bicarbonate (1.08 g) in water (20 ml.) was added to a cooled (0° ) solution of thien-2-yl-glyoxylic acid (2.0 g) and sodium bicarbonate (1.08 g) in water (20 ml.). After two days at 20° the solution was extracted with ether, cooled and acidified with concentrated hydrochloric acid. The resulting white solid was filtered off (0.564 g) and the filtrate was then thoroughly extracted with ether. The combined extracts were washed with brine, dried and concentrated. The solid residue was triturated with benzene to give the exime (synisomer) (1.05 g; 51%), m.p. 132°, λmax. (ethanol) 284 nm (Ε9,500),νmax. (Nujol) 2590 and 1706 (SO2H) and 1655 cm-1 (C=N), τ (DMSO-d6), -2.5 to -0.5 (broad multiplet; N-OH and COOH), 2.36 (multiplet; thienyl C-5 H) and 2.82 (multiplet; thienyl C-3 H and C-4 H).