Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:9]1[S:14][CH2:13][CH2:12][CH2:11][S:10]1)[CH2:7][CH3:8].[CH3:15][C:16]([CH3:56])([O:18][C:19]([NH:21][C@H:22]([C:30](N[C@H](C(NC(CC1CCCCC1)C(=O)C(=O)CCC)=O)CC(C)C)=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH3:17]>O1CCCC1>[CH:24]1([CH2:23][C@H:22]([NH:21][C:19](=[O:20])[O:18][C:16]([CH3:15])([CH3:17])[CH3:56])[CH:30]([OH:31])[C:9]2([CH2:6][CH2:7][CH3:8])[S:14][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCCC1SCCCS1
Reactant: CCCC(=O)C(=O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1(C(O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)SCCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium (2.5M, 11.76 ml, 29.4 mmol) was added dropwise at -25° to a 40 ml tetrahydrofuran solution of 2-n-propyl-1,3-dithiane from part A (4.536 g, 28.0 mmol). After stirring for 2 hours at -20° to -25°, the solution was cooled to -78° and (S)-<α-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanepropanal (3.57 g, 14.0 mmol) was added as a 20 ml tetrahydrofuran solution. A chromatography check after 1 hour revealed the formation of a complex reaction mixture. It was warmed gradually from -78° to -50° over a period of 18 hours, quenched with saturated ammonium chloride (50 ml) and the two layers separated upon warming to room temperature. The aqueous layer was diluted with water (75 ml, to dissolve the precipitated ammonium chloride) and reextracted with ethyl acetate (2×50 ml). Combined organic extracts were washed with saturated ammonium chloride (1×75 ml), dried over anhydrous sodium sulfate and concentrated to give 7.9 g crude product which upon flash chromatographic purification yielded 1.517 g of the title B compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-chloro-phenyl)-1-methyl-propyl]-amine (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:18]([NH2:20])=[O:19])[CH3:13].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:18]2[O:19][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[N:20]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:13]
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccncc3)co2)cc1OCC
Temperature: 170 °C
Yield: 2.7 %

Procedure:
In a microwave vial were dissolved 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (134 mg, 0.478 mmol) and 3,4-diethoxybenzamide (100 mg, 0.478 mmol) in DMF (5 ml) and the reaction was heated at 170° C. for 40 min. The reaction mixture was poured in a saturated solution of NaHCO3 and extracted with EtOAc (50 ml×3). The combined organic phases were washed with a saturated solution of NaCl (2×30 ml) and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (95:5) to yield 4 mg (2.7%) of the product. MS (EI) m/z: 311 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[S:10]2(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[F:8].Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[S:10]2(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S1(=O)N(CCCN2CCNCC2)c2ccccc2N1c1ccc(F)c(F)c1
Yield: 89.8 %

Procedure:
A solution of tert-butyl 4-{3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperazine-1-carboxylate (0.16 g, 0.3 mmol) in dichloromethane (10 mL) was treated with hydrogen chloride (6.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(3,4-difluorophenyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.11 g, 81%) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C(N(CC)CC)C.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[N:4]1[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=[C:2]([NH:1][C:21]([CH:18]2[CH2:20][CH2:19]2)=[O:22])[CH:3]=1
Reactant: Nc1cnn2ccccc12
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cnn2ccccc12)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-aminopyrazolo[1,5-a]pyridine (0.74 g, 5.55 mmol) and triethylamine (1.0 ml, 6.95 mmol) in EtOAc (15.0 mL) was added cyclopropanecarbonyl chloride (0.63 mL, 6.95 mmol). The resulting mixture was stirred at room temperature for 48 h and diluted with saturated NaHCO3 solution. More EtOAc and H2O were added and separated. The EtOAc solution was concentrated in vacuo to dryness. The residue was recrystalized from EtOAc to give 0.86 g (77%) of light brown solid as the title compound: mp 159–162° C.; IR (diffuse reflectance) 3207, 3085, 3073, 3044, 2998, 1645, 1596, 1477, 1401, 1356, 1330, 1218, 950, 738, 727 cm−1; MS (EI) m/z 201 (M+); Anal. Calcd for C11H11N3O: C, 65.66; H, 5.51; N, 20.88. Found: C, 65.52; H, 5.48; N, 20.82.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])[CH:5]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2cccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)c2)cc1

Procedure:
In analogy to example 19, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 4-methoxycarbonyl-phenylboronic acid was prepared the title compound as a yellow foam, MS (ESI+): m/z=450.3 ([M+H]+).
Reaction SMILES: [N:1]([C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[C:2]=[O:3].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(#N)C>[NH2:40][C:26]1[N:27]=[C:28]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([C:2]([NH:1][C@@H:4]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:5]([O:7][CH3:8])=[O:6])=[O:3])[CH2:37]3)=[CH:32][CH:31]=2)[CH:29]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:25]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Methyl (2S)-2-isocyanato-3-phenylpropanoate (12.5 mg, 0.0609 mmol) (Aldrich, Cat. #409731) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (25.0 mg, 0.0576 mmol) and triethylamine (32 uL, 0.23 mmol) in acetonitrile (1.0 mL). After 30 min., the mixture was concentrated, and purified by flash chromatography on a silica gel column with MeOH in dichloromethylene (0-5%) to afford the desired product (30 mg, 98%). Analytic LCMS (M+H)+: m/z=530.2.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:14][CH:11]1[CH2:13][CH2:12]1
Reactant: Cc1cccc(C=O)c1C
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(CNC2CC2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dimethylbenzaldehyde (1 eq.), cyclopropylamine (1.2 eq.) and sodium bicarbonate (1.5 eq.) were heated at reflux in MeOH (0.5 M) for 1 h. The reaction mixture was then cooled in ice and sodium borohydride (1.2 eq.) was introduced portionwise. Following the completion of addition, the reaction mixture was warmed to RT and stirred at RT for 1 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between H2O and CH2Cl2. The organic layer was separated, washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: Cc1cccc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cccc(CBr)c1
Temperature: 25 °C

Procedure:
Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride (20 mL). Add NBS (530 mg, 3 mmol) and irradiate the reaction mixture with a 250 watt sun-lamp with simultaneous heating to reflux for 1 h. Cool to ambient temperature, filter, and concentrate filtrate to dryness to give crude 1-bromomethyl-3-tert-butylbenzene. Dissolve crude 1-bromomethyl-3-tert-butylbenzene (600 mg) in anhydrous DMF. Add portion wise sodium azide (260 mg, 4 mmol) and stir at room temperature for 2 h. Pour the mixture into water (250 mL), extract with EtOAc (3×50 mL), wash combined organic extracts with brine, dry over MgSO4, filter and evaporate solvent to give crude 1-azidomethyl-3-tert-butylbenzene, that was used without further purification. Dissolve crude 1-azidomethyl-3-tert-butylbenzene in methanol containing 10% Pd/C (75 mg) at 5° C., and stir the resulting slurry under 1 atm H2 for 1 h. Filtrate, concentrate in vacuo and purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc, methanol and 2M ammonia in methanol to give the title compound (255 mg, 53% overall). MS (ES+) m/z: 164 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:6]=2[N:5]=[CH:4]1.Cl.[CH3:16]O>>[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:16])=[O:13])=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: CO
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Agent: Cl
Product: COC(=O)c1ccc2c(c1)ncn2C
Yield: 43.6 %

Procedure:
Mass spectrum (FAB, Pos):m/z 177 (M30 +1, as a free base). ##STR11## 1-Methylbenzimidazole-5-carboxylic acid hydrochloride, 20.2 g (including inorganic matters), was added to 300 ml of methanol and 5 ml of conc. hydrochloric acid was added to the mixture followed by heating to reflux for 7 hours. The solvent was distilled off and 200 ml of water was added to the residue. At 5° to 10° C., 1 N sodium hydroxide solution was added to the mixture to adjust pH to 9 to 10 followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure. The resulting crystals were washed with ether to give 4.8 g of methyl 1-methyl-benzimidazole-5-carboxylate (43.6%, based on 1,5-dimethylbenzimidazole).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[NH:7][CH2:8][CH3:9]>CC(O)=O.[Zn]>[Br:1][C:2]1[CH:10]=[C:6]([NH:7][CH2:8][CH3:9])[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: CCNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCNc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
Zinc (8.0 g) was added to a solution of 5-bromo-N-ethyl-2-nitroaniline (3.0 g) in AcOH (60 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The mixture was neutralized with saturated NaHCO3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give the title compound (1.2 g) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[OH-].[Li+]>CO>[Cl:19][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:20])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17][CH3:18]
Reactant: COC(=O)C(C[C@H]1CCCO1)c1ccc(SC)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (0.519 g, 1.65 mmol) in methanol (7 mL) was treated with a 0.8M aqueous lithium hydroxide solution (40.7 mL, 33.0 mmol). The reaction mixture was stirred at 25° C. for 1.5 h and then concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (0.495 g, 95.8%) as a light yellow oil that crystallized upon standing: mp 93-96° C.; [α]23589=−23.70° (c=0.46, chloroform); EI-HRMS m/e calcd for C14H17ClO3S (M+) 300.0587. found 300.0579.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Na+].OP(O)(O)=O>O>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)nc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(-n2cnnn2)nc1

Procedure:
To a suspension of ethyl [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (30.0 g, 129 mmol) in 150 mL of water was added 28 mL of 5M aq NaOH (141 mmol) over 5 min while cooled in a water bath. A very mild exotherm to +22° C. was observed. The mixture was stirred for 40 min at rt whereupon 106 mL of 2M aq H3PO4 was added over 30 min at rt. The resulting suspension was filtered, and the filter cake was washed with 2×50 mL water and dried on the frit under a stream of nitrogen overnight to afford [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid. This material was identical by H NMR to that synthesized according to method 1 above.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
{2-[4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2200 mg, 1.135 mmol, 1 eq) was dissolved in dichloromethane (4 ml) and stirred at 0° C. for 5 min. TFA (3084 ml, 40.273 mmol, 7 eq) was added and stirring was continued at rt overnight. Reaction mixture was diluted with NaHCO3 (sat.) and extracted with DCM (3×). Organic layers were combined and evaporated to give 2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethylamine as white solid (1.6 g, yield=99%, purity 99%). [M+H]+=283.26 1H NMR (DMSO-d6, 300 MHz): 2.83-2.91 (m, 2H), 3.03-3.13 (m, 2H), 7.13-7.19 (d, 2H), 7.20-7.24 (d, 1H), 7.30-7.36 (d, 2H), 7.86 (bs, 2H), 8.19-8.25 (m, 1H), 8.53 (s, 1H)
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH2:19][OH:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[CH:44][C:45]=1[F:46]>>[F:39][C:40]1[CH:41]=[C:42]([CH:43]=[CH:44][C:45]=1[F:46])[O:20][CH2:19][C:16]1[CH2:17][S:18][C@@H:13]2[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:37](=[O:38])[N:14]2[C:15]=1[C:21]([O:23][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:22]
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(F)c(F)c3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 7-phenoxyacetamido-3-hydroxymethyl-3-cephem-4-carboxylate and 3,4-difluorophenol, to afford 326 mg of the title compound as a powder.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[Si](C)(C)C.C([Li])CCC.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19](=O)[CH2:18]1>O1CCCC1.C(OCC)C>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19](=[C:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[CH2:18]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CC1(C)CCCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCCC(=C2SCCCS2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1,3-dithian-2-yl)trimethylsilane (5.0 g) in tetrahydrofuran at −78° C. was added n-butyllithium (1.6M, 16.24 mL). After stirring for 30 minutes, 3,3-dimethylcyclohexanone (3.3 g) was added as a solution in tetrahydrofuran and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with diethyl ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 0.13% to 2.5% ether/hexanes gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:25][C@H:24]1[OH:37].CS(Cl)(=O)=O.C(N(CC)CC)C.[C:50]([O-])(=[O:52])[CH3:51].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C@H:25]1[CH2:24][O:37][C:50](=[O:52])[CH3:51]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c4c(=O)cc(-c5ccccc5Cl)oc34)[C@H](O)C2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c4c(=O)cc(-c5ccccc5Cl)oc34)[C@@H]2COC(C)=O)cc1

Procedure:
Compound of example 122 (1.7 g, 3.2 mmol) was subjected to ring contraction as described in example 3, method A using methanesulfonyl chloride (0.448 g, 0.3 mL, 3.9 mmol), triethylamine (0.66 g, 0.95 mL, 6.5 mmol). The sulfonyl ester was treated with anhydrous sodium acetate (1.06 g, 13 mmol) to furnish the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][CH2:26][CH:27]([CH2:29]O)[OH:28].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(8-cyclohexyloctylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])=[CH:21][C:20]=3[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[CH:11][C:10]([OH:36])=[CH:9][C:5]=12.[Cl:37]N1C(=O)CCC1=O>O1CCCC1>[O:1]=[C:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])=[CH:21][C:20]=3[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[C:11]([Cl:37])[C:10](=[O:36])[CH2:9][C:5]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(O)cc3c2C2CCC3C2O)c(C(C)(C)CC)c1
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(OCCCNC(=O)C2=C(Cl)C(=O)CC3=C2C2CCC3C2=O)c(C(C)(C)CC)c1

Procedure:
The above (4.9 g) synthesized in (3) above was dissolved in tetrahydrofuran (60 ml), and N-chlorosuccinimide (2.9 g) was added thereto, followed by reacting the reaction for 6 hours. Thereafter, the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 3,6-dioxo-4-[3-(2,4-di-t-pentylphenoxy)propylcarbamoyl]-5-chlorobenzonorbornene. (Yield: 5.0 g (95.7 %).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[N:16]=[C:15]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[N:30]=2)[N:14]=1>CS(C)=O>[CH3:5][O:4][CH2:3][CH2:2][O:25][C:21]1[CH:20]=[C:19]([CH2:18][N:17]2[C:13]([CH3:12])=[N:14][C:15]([C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:39])([F:41])[F:40])=[CH:33][CH:32]=4)[N:30]=3)=[N:16]2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1cccc(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)cs3)nc2C)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-bromo-2-methoxyethane (3.2 mg, 0.023 mmol), Cs2CO3 (9.4 mg, 0.029 mmol) and 3-((5-methyl-3-(4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (5.0 mg, 0.012 mmol; synthesized in analogous manner to Example 59, using 2-(5-methyl-1H-1,2,4-triazol-3-yl)-4-(4-(trifluoromethoxy)phenyl)thiazole, Example 87, Step 4) in DMSO (0.2 ml) was stirred at 50° C. for 20 minutes. The mixture was purified by prep-HPLC to give the title compound; MS (ES+) C23H21F3N4O3S requires: 474. found: 475 [M+H]+.