Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[N:50]/[O:51][CH3:52])/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[S:42][CH:43]=4)=[N:50]\[O:51][CH3:52])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 71.9 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (994 mg: 2 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-methoxyiminoacetic acid (662 mg: 2.2 mMol.) in dichloromethane (16 ml) is added at -30° C. N-methylmorpholine (0.72 ml: 6.6 mMol.) and phenyl dichlorophosphate (0.33 ml: 2.2 mMol.), and the mixture is stirred at the same temperature for 2.5 hours. The reaction mixture is quenched by adding 10% hydrochloric acid (5 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous sodium hydrogen carbonate, and water, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1 containing 0.5% of acetic acid) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-methoxyiminoacetyl]amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (1.07 g). Yield: 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][C:38]=1[NH:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27].CC(C)N=C=NC(C)C>CN(C=O)C>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:25]2[CH:36]=[CH:37][C:38]3[N:39]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:6][NH:7][C:8]([C:10]5([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]5)=[O:9])[CH:17]=[CH:18][C:2]=4[Cl:1])=[N:22][C:23]=3[CH:24]=2)=[O:27])=[CH:30][CH:31]=1
Reactant: CN(C)CCNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(C)CCn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)ccc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide ((222 mg; 0.66 mmol) see Example 59, step (c)), 3-amino-N-(4-bromophenyl)-4-(2-(dimethylamino)ethylamino)benzamide (250 mg; 0.66 mmol), DIC (83 mg; 0.66 mmol) and DMF (4 mL). Yield: 151 mg (34%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.37 (1H, s) 10.22 (1H, s) 8.39 (1H, t, J=5.8 Hz) 8.10 (1H, d, J=1.8 Hz) 8.06 (1H, d, J=1.6 Hz) 7.82-7.71 (3H, m) 7.53-7.46 (3H, m) 7.40 (1H, d, J=8.2 Hz) 6.86 (1H, dd, J=8.2, 1.8 Hz) 4.32-4.21 (4H, m) 2.74-2.68 (2H, m) 2.29 (6H, s) 1.37-1.32 (2H, m) 1.23-1.19 (2H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1)(=O)C.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)Oc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc(O)c3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (300 mg) and commercially available resorcinol monoacetate (0.835 ml) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was crystallized with chloroform to obtain 37 mg of the title compound (yield: 9%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[CH2:31][OH:32])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:27])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH2:25][CH3:26])[CH:13]=1.[CH2:33]([Mg]Br)[CH3:34].[Cl-].[NH4+]>C1COCC1>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([CH3:27])=[CH:10][CH:9]=[C:8]([O:7][CH2:6][C:5]3[CH:28]=[CH:29][C:30]([CH2:31][OH:32])=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:13]=2)=[C:15]([CH2:24][CH2:25][CH3:26])[CH:16]=1)([OH:23])[CH2:33][CH3:34])[CH3:22]
Reactant: CC[Mg]Br
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
890 mg (2 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-methyl-2-propylbiphenyl-4-yl}-1-propanone are placed in 40 ml of dry THF in a round-bottomed flask and under a stream of nitrogen. At 0° C., 4.1 ml (12 mmol) of ethylmagnesium bromide are added. The reaction medium is stirred at room temperature for 1 hour 30 minutes and then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (50/50) to give 550 mg (64%) of {5-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol in the form of white crystals with a melting point of 97° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CC(C)NC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 55.5 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-isopropyl-4-(piperazin-1-yl)benzamide (129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 25-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 15 mL) and dried in vacuum to afford (S)-3-chloro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (122.1 mg, 0.253 mmol, 55.4% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6.57 Hz, 6H) 1.84-2.03 (m, 3H) 2.12-2.25 (m, 1H) 2.50-2.59 (m, 4H) 3.02 (br. s., 4H) 3.35-3.45 (m, 3H) 3.53-3.64 (m, 1H) 3.94-4.09 (m, 2H) 6.98 (d, J=1.52 Hz, 1H) 7.17 (d, J=8.59 Hz, 1H) 7.63 (d, J=1.77 Hz, 1H) 7.77 (dd, J=8.34, 2.02 Hz, 1H) 7.89 (d, J=2.02 Hz, 1H) 8.18 (d, J=7.58 Hz, 1H) 10.45 (s, 1H). [M+H] calc'd for C25H31C1N6O2, 483; found, 483.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4)[C@H]3[C@@H]1CCC2=O

Procedure:
A solution of 1.0 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one in 10 ml of dimethylformamide is stirred with 0.24 ml of pyrrolidine for 2 hours at a bath temperature of 100° C. Then, it is added to saturated sodium bicarbonate solution, extracted three times with methylene chloride, dried on magnesium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol/triethylamine. 367 mg of 11β-fluoro-3-hydroxy-7α-(5-pyrrolidin-1-yl-pentyl)-estra-1,3,5(10)-trien-17-one is obtained as a foam.
Reaction SMILES: [Al].O[N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>O.C(OCC)C.[Hg](Cl)Cl>[NH2:3][CH:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C#N)=NO
Agent: Cl[Hg]Cl
Agent: [Al]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(N)C#N
Reaction time: 0.08 h
Yield: 74.7 %

Procedure:
To aluminum foil (25 g) was added a solution of mercury(II) chloride (10 g, 0.37 mol) in water (1 L). The mixture was swirled for 5 min, and then the turbid solution was decanted off. The resulting aluminum amalgam was washed successively with water, methanol and diethyl ether. To amalgam suspended in diethyl ether (500 mL) at 0° C., was added a solution of ethyl 2-hydroxyimino-2-cyanoacetate (100 g, 0.70 mol) in diethyl ether (300 mL), followed by water (50 mL), maintaining a gentle reflux. After 1 h of stirring, the mixture was filtered and the filtrate was washed with water, brine and dried (Na2SO4). Removal of the solvent gave the title compound as a white solid (67 g, 74%). 1H NMR (250 MHz, CD3OD) δ 4.45 (m, 2H), 2.49 (s, 1H), 1.38 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]([CH3:25])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:14]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:30]1[CH:40]=[CH:39][C:33](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:26])[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:36](=[O:37])[CH:35]=[CH:34][C:33]3[CH:39]=[CH:40][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:20]2)[CH:14]=1)([CH3:11])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Reactant: CC(C)c1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1ccc(C=CC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 99 mg, 0.28 mmol) in 2 mL methylene chloride was added 4-isopropyl-trans-cinnamic acid (59 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) and allowed to stir 18 h at ambient temperature. The reaction was concentrated under reduced pressure and the resultant oil flash chromatographed with 30% ethyl acetate/hexanes to yield 89 mg (60%) of 2-(3-{1-[3-(4-Isopropyl-phenyl)-acryloyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][NH2:9])([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([NH:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])[CH3:14]
Reactant: NCCc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In pyridine (33 ml) was dissolved 5.559 g of 3-nitrophenethylamine (Preparation Example 25), followed by dropwise addition of acetyl chloride (2.5 ml) under ice-cooling. After stirring at room temperature for 0.5 hour, the mixture was again ice-cooled. Water was added thereto, followed by extracting with ethyl acetate, The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (6.323 g, 91%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1(C)[O:17][C:16](=O)[CH:15]=[C:14]([CH3:19])[O:13]1.CC(C)=O>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:17])[CH2:15][C:14](=[O:13])[CH3:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: CC(=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
13.8 g (0.1 mol) of 4-nitroaniline were suspended in 20 ml of dry xylene and 14,22 g (0.1 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one were added. The reaction mixture was heated in an oil-bath at 150° C. for 30 minutes while the acetone formed in the reaction was removed by distillation. The reaction mixture was cooled to room temperature, filtered and the residue was washed thoroughly with ethyl acetate. The filtrate was evaporated to obtain 11.65 g (52%) of N-(4-nitrophenyl)-3-oxobutanamide as a white crystalline solid melting at 119°-21° C. (from ethyl acetate-petroleum ether (40°-60° C.)) (lit.* melting at 120°-122° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)C)=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:26]>C(O)(C)C.O>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:26]
Reactant: CC(=O)Nc1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N)cc3)n2)n1C
Yield: 69 %

Procedure:
Sodium hydroxide (1.2 g, 3.0 mmole) was added to a solution of 4-(1,2-dimethyl-imidazol-5-yl)-2-(4-acetamidoanilino)pyrimidine (Example 164; 1.25 g, 3.88 mmole) in isopropanol (12 mL) and water (0.5 mL) and the mixture heated under reflux for 90 minutes. The mixture was allowed to cool and was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was separated and the volatiles evaporated. The residue was purified by column chromatography on silica gel eluting with DCM/7M methanolic ammonia (96:4) to give the title compound (0.75 g, 69%) as a brown solid. NMR: 2.33 (s, 3H), 3.85 (s, 3H), 4.75 (brs, 2H), 6.51 (d, 2H), 6.92 (d, 1H), 7.22 (d, 2H), 7.51 (s, 1H), 8.22 (d, 1H), 8.90 (s, 1H); m/z 281.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 94.6 %

Procedure:
A solution of 4-(2-keto-1-benzimidazolinyl)piperidine (10.0 g, 46 mmol), ethyl bromoacetate (5.1 mL, 46 mmol) and N,N-diisopropylethylamine (8.8 mL, 50.6 mmol) in acetonitrile (200 mL) was heated at reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was suspended in water (˜200 mL). The suspension was made basic with the addition of a saturated aqueous solution of sodium bicarbonate. The resultant solid was collected by filtration, washed with water and dried in vacuo to give the ethyl (4-(2-keto-1-benzimidazolinyl)piperidin-1-yl)acetate as a colorless solid (13.2 g, 94%). MS m/z 304 (MH+); NMR(CDCl3): δ 1.32 (t, 3 H), 1.84 (br d, 2 H), 2.40-2.66 (m, 4 H), 3.13 (br d, 2 H), 3.31 (s, 2 H), 4.23 (q, 2 H), 4.45-4.49 (m, 1 H), 6.99-7.10 (m, 2 H), 7.12-7.19 (m, 1 H), 7.27-7.34 (m, 1 H) and 10.54 (br s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([NH:18][S:19]([N:22]2[CH2:26]COC2=O)(=[O:21])=[O:20])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([CH:32]1[CH2:37]NC[CH2:34][N:33]1[C:38]([OH:40])=[O:39])(C)(C)C>>[C:1]([O:40][C:38]([N:33]1[CH2:32][CH2:37][N:22]([S:19](=[O:20])(=[O:21])[NH:18][C@:8]2([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:9]2[CH3:17])[CH2:26][CH2:34]1)=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1[C@H](c2ccccc2)[C@]1(NS(=O)(=O)N1CCOC1=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)C1CNCCN1C(=O)O
Product: C[C@@H]1[C@H](c2ccccc2)[C@]1(NS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Yield: 158.8 %

Procedure:
Under argon atmosphere, this (1S,2R,3R)-2-methyl-1-(2-oxo-oxazolidine-3-sulfonylamino)-3-phenyl-cyclopropanecarboxylic acid t-butyl ester (0.61 mmol) and t-butyl-1-piperazinecarboxylic acid (0.14 g, 0.73 mmol) were mixed, and the mixture was refluxed for 18 hours under heating. The obtained solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:0 to 5:1) to give the title compound (0.24 g, yield 79%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[NH:33]1[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]3)(=[O:29])=[O:30])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: C=CS(=O)(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Reactant: O[C@@H]1CCNC1
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CCN3CC[C@@H](O)C3)s2)cc1C#N
Temperature: 80 °C
Yield: 25.8 %

Procedure:
Prepared using General Procedure 13. To a solution of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide (40 mg, 0.5 mmol) in DMF (0.5 mL) was added (R)-pyrrolidin-3-ol (18.7 mg, 0.21 mmol) and the reaction was heated to 80° C. for 18 h. The product was purified by preparative HPLC to give 30 mg (56%) of N-((S)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethanesulfonamide 37 as an off-white solid. LCMS-ESI (m/z) calculated for C27H31N5O4S2: 553.2; found 554.2 [M+H]+, tR=2.52 min.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][C:8]=2[CH3:12])[C:3]1=O.[CH3:15][Li].Cl.O>C(OCC)C>[CH3:15][CH:3]1[C:4]2[C:9](=[C:8]([CH3:12])[CH:7]=[CH:6][C:5]=2[CH3:13])[C:10]([CH3:11])=[C:2]1[CH3:1]
Reactant: [Li]C
Reactant: Cc1ccc(C)c2c1C(=O)C(C)C2C
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC1=C(C)C(C)c2c(C)ccc(C)c21
Reaction time: 8 h
Yield: 44.8 %

Procedure:
In a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus and a reflux condenser 2,3,4,7-tetramethyl-1-indanone (35) (19.52 g, 0.1 mol) was dissolved in dry diethyl ether (300 ml) under an argon atmosphere. The mixture was cooled with ice and methyllithium (45 ml, 3 M solution in diethoxymethane, 0.135 mol) was added dropwise via a syringe, then the mixture was refluxed for 3 h. When the yellow reaction mixture had cooled a mixture of concentrated HCl (20 ml) and H2O (60 ml) was added via an addition funnel. The resulting mixture was transferred to a separation funnel and extracted with diethyl ether (3×200 ml). The combined organic layers were stirred overnight with 15 ml concentrated HCl. After this time the reaction mixture was carefully adjusted to pH 7 with a saturated aqueous solution of sodium carbonate. The reaction mixture was transferred into a separation funnel. The organic layer was washed with H2O (3×100 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure to give a yellow liquid. This residue was purified via column-chromatography [(SiO2, 25×9 cm) eluent: cyclohexane] to afford 1,2,3,4,7-pentamethylindene (38) (8.35 g, 44%) as a yellow liquid; then (35) (starting material) (9.60 g, 49%) (eluent: cyclohexane:ethylacetate (10:1)) as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][C:4](=[O:8])[CH:5]=[CH:6][CH3:7].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]([C:4](=[O:8])/[CH:5]=[CH:6]/[CH3:7])[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]=1
Reactant: CC=CC(=O)C=C(C)CCC=C(C)C
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 10 g. of 6,10-dimethyl-4-oxo-2,5,9-undecatriene prepared according to the method of paragraph c) herebelow, 100 ml. of benzene and 1 g. of boron trifluoride etherate was heated to the reflux until the vapour phase chromatographic analysis of a sample showed that practically all the starting material had disappeared. The solution was cooled and stirred with ice-water. The organic layer was removed and treated as usual. Distillation of the residue of evaporation gave a 50 % yield of trans-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene of about 60 % purity as shown by the vapour phase chromatographic analysis.