Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Br:2].[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][CH:3]([CH2:4][O:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:1][Br:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Reactant: BrCC1CO1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(O)CBr
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A 500 ml round bottom flask was charged with epibromohydrin (5.8 g, 42 mmol), linoleyl alcohol (15 g, 56 mmol), a stir bar, and then flushed with nitrogen. Anhydrous DCM (250 ml) was added via cannula, followed by BF3.Et2O (0.53 ml, 4.2 mmol), and stirred at 40° C. for 3 hours. Progress of reaction was monitored by TLC to ensure no epoxide was remaining. The reaction mixture was transferred to a 500 ml separatory funnel with DCM (2×50 ml), washed with NaHCO3 (2×200 ml), water (200 ml), brine (200 ml), dried with MgSO4, and solvent evaporated. The crude product was purified using column chromatography on silica gel (300 g) with 5-15% ether gradient in hexanes to yield 12.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:21](OCC)(OCC)(OCC)[CH3:22]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:21]([CH3:22])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(Cl)ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(Cl)ccc3n12

Procedure:
In the manner given in Example 2, 6-chloro-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-chloro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline of melting point 257°-259° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O)(=[O:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[CH2:1])(=[O:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)OCC(=O)c1ccc(C(C)(C)C)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(COC(C)=O)c1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (8.48 g, 23.7 mmol) in THF (75 ml) was added potassium tert-butoxide (2.66 g, 23.7 mmol) at room temperature. The mixture was stirred at 40° C. for 1 hour. After cooling to room temperature, a solution of 2-[4-tert-butylphenyl]-2-oxoethyl acetate (U.S. Pat. No. 3,526,634, 2.78 g, 11.9 mmol) in THF (25 ml) was added to the mixture. The mixture was heated at reflux for 3 hours. The mixture was concentrated, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with hexane/EtOAc (9:1), to afford the title compound (2.13 g, 77%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.ClCC[I:45]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:45])[N:8]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: ClCCI
Reactant: CC(C)(O)CCn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(O)CCn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 4-(2-chloro-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol (360 mg, 1.1 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.25 mL, 1.7 mmol) in THF (8.1 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (BuLi, 2.0 mL, 5.0 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.51 mL, 5.4 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol as a white foam (390 mg, 78%). LC/MS (ESI+): m/z 452 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:15]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)CCc1ccc(O)cc1
Yield: 92.9 %

Procedure:
Following the same procedure of Example 4 except that 3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol) and glycine ethyl ester hydrochloride (0.94 g, 6.7 mmol) were used, 1.4 g of the title compound was obtained. The compound was finally purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)). The results of analyses of the compound are as follows:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:28])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:28])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CC(C)(CO)CCCCCCCCC(C)(C)CO
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1
Yield: 50.5 %

Procedure:
53.10 Grams (0.3 mole) of nicotinoyl chloride hydrochloride in 150 ml of anhydrous pyridine were reacted with 12.90 grams (0.05 mole) of 2,2,11,11-tetramethyl-1,12-dodecanediol according to the procedure of the above example. 11.8 Grams of the title product, recrystallized from an 80/20 (v/v) mixture of ethanol/water, were obtained, having m.p. 66°-67° C. Yield: 50.5% of theoretical.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2/[CH:36]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 5-chloro-1H-indole-3-carboxaldehyde (0.0515 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and added with methanol (4 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({2-[(5-chloro-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0730 g, 49%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCO)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
MsCl (18.6 g; 164 mmol) was added to a stirred solution of 4-(2-hydroxyethyl)benzonitrile (20 g; 136 mmol) and TEA (20.6 g; 204 mmol) in DCM (200 mL) at 0° C. The reaction mixture was stirred at rt. until tlc indicated that the reaction was complete. Water (200 mL) was added and the organic layer was separated, dried and concentrated to give the sub-title compound in a quantitative yield.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>CN(C=O)C>[CH3:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: Cc1cccc(OCCCCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCCN2C(=O)c3ccccc3S2(=O)=O)c1
Yield: 55 %

Procedure:
The title compound was synthesized analogously to 83.8 (see experimental below), using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 1-(4-bromobutoxy)-3-methylbenzene (146 mg, 0.6 mmol) in DMF (anhydrous, 1 mL). The crude product obtained after workup was purified by flash column chromatography on silica gel (25% ethyl acetate-petroleum ether) to give 83.6 as a viscous liquid in 55% yield (95 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][CH2:13][C:14]1[C:15]([NH:22][CH2:23][CH3:24])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1.[H-].[Na+].[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N:12]1[CH2:13][C:14]2[C:15](=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)[N:22]([CH2:23][CH3:24])[C:27]1=[O:28]
Reactant: CCNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2Cl)Cc2cnc(SC)nc21
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Into a solution of 1.00 g (2.71 mmol) of {5-[(2-chloro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-ethyl-amine in 7 mL of dry DMF cooled to 5° C. was added 0.271 g (6.78 mmol) of sodium hydride as a 60% mineral oil suspension. The ice bath was removed, and the reaction was stirred for 1 hour. To the reaction was then added 1.32 g (8.13 mmol) of 1,1′-carbonyldiimidazole. After stirring a further 2 hours, the reaction was concentrated in vacuo. The residue was partitioned between dichloromethane and a saturated solution of ammonium chloride. The aqueous layer was washed twice with dichloromethane. The dichloromethane layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane, added silica gel, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane/ethyl acetate (9:0.5 v/v), to give 0.7507 g (70%) of the title compound: mp 189-191° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O>[S:21]([O:8][CH2:7][C:3]1([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CCC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 0 °C

Procedure:
3-ethyl-3-hydroxymethyloxetane (trade name of product, OXT-101®, manufactured by To a Gosei Co.; 116 g) was added to pyridine (500 mL) and cooled to 0° C. while stirring. p-Toluene sulfonyl chloride (190 g) was added divisionally for several times. After stirring for 5 hours while keeping at 0° C., the reaction mixture was poured to iced water (1 L). It was extracted with diethyl ether (500 mL), the pH was rendered acidic with 3% hydrochloric acid, and extracts were washed with water. Then, the extracts were washed with a saturated solution of sodium carbonate and water successively and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3-[(tosyloxy) methyl]3-ethyloxetane (243 g).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.CN1CCOCC1.[CH3:17][CH:18]([CH2:20][C@H:21]([NH2:26])[C:22]([O:24][CH3:25])=[O:23])[CH3:19].Cl>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[C:21]([NH2:26])([C:7]([C:3]1[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=1)=[O:9])[CH2:20][CH:18]([CH3:19])[CH3:17]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1cccnc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C(N)(CC(C)C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
To a solution of niacin (1.35 g, 11.0 mmol) in DCM (20 mL) were added N-methyl morpholine (3.34 g, 33.00 mmol) EDCI.HCl (4.2 g, 22.02 mmol), and L-leucinemethyl ester hydrochloride (2.0 g, 11.0 mmol). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL), washed with water (3×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain required product as white solid (2.0 g, 72%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[CH:17]=[C:18]([S:22]([N:25]([CH:27]2[CH2:31][CH2:30][C:29](=O)[CH2:28]2)[CH3:26])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.[F:33][C:34]([F:42])([F:41])[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[OH-].[Na+]>ClCCCl>[CH3:15][C:16]1[CH:17]=[C:18]([S:22]([N:25]([CH3:26])[C@H:27]2[CH2:31][CH2:30][C@@H:29]([N:38]3[CH2:39][CH2:40][CH:35]([C:34]([F:42])([F:41])[F:33])[CH2:36][CH2:37]3)[CH2:28]2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(S(=O)(=O)N(C)C2CCC(=O)C2)c1
Reactant: FC(F)(F)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cccc(S(=O)(=O)N(C)[C@H]2CC[C@@H](N3CCC(C(F)(F)F)CC3)C2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.9 %

Procedure:
Sodium triacetoxyborohydride (340.4 mg, 1.61 mmol) was added to a solution of 3-((3,N-dimethyl)benzenesulfonamido)cyclopentan-1-one (280.7 mg, 1.05 mmol), and 4-trifluoromethylpiperidine (194.8 mg, 1.27 mmol) in 1,2-dichloroethane (10 ml). The resulting mixture was stirred at room temperature overnight (20 hours). 1M Aqueous sodium hydroxide (25 ml) was added and the mixture extracted with dichloromethane (2×10 ml). The combined extracts were dried (K2CO3) and evaporated. The residue was purified by medium pressure silica chromatography, eluting with 2.5% methanol in dichloromethane, to afford cis-3,N-dimethyl-N-(3-(4-trifluoromethylpiperidin-1-yl)cyclopentyl) -benzenesulfonamide (93.1 mg, 22%). A portion of this material was dissolved in ethyl acetate, warmed and treated with hydrogen chloride in diethyl ether to afford the title compound as a white crystalline solid; δH (400 MHz, CD3OD) 1.68 (2H, m), 1.83 (4H, m), 2.06-2.18 (4H, m), 2.44 (3H, s), 2.60 (1H, m), 2.79 (3H, s), 2.99 (2H, m), 3.51 (1H, m), 3.63 (1H, m), 3.69 (1H, m), 4.43 (1H, m), 7.47 (2H, m), 7.63 (2H, m); m/z (ES+) 405 ([M+H]+, 100%).
Reaction SMILES: Cl.[F:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][O:10]2)=[C:5]([I:14])[C:4]=1[O:15]COC>C1COCC1.CC(OC)(C)C>[F:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][O:10]2)=[C:5]([I:14])[C:4]=1[OH:15]
Reactant: COCOc1c(F)c(F)c2c(c1I)CCCO2
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Oc1c(F)c(F)c2c(c1I)CCCO2
Temperature: 20 °C
Reaction time: 18 h

Procedure:
10.4 ml of conc. HCl are added to a solution of 20.2 g (56.7 mmol) of 7,8-difluoro-5-iodo-6-methoxymethoxychroman in 100 ml of THF, and the mixture is stirred at 20° C. for 18 h. The batch is diluted with MTBE, and the solution is washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:MTBE=1:1), giving 7,8-difluoro-5-iodochroman-6-ol as a pale-brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[Cl:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A solution of 2.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8) and 3.58 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione in 50 ml of benzene was heated under reflux for 1.5 hours, whilst the water being formed during the reaction was continuously removed. At the end of this time, the benzene used was removed by distillation under reduced pressure. The resulting residue was dissolved in 100 ml of absolute methanol, and then 3 g of sodium borohydride were added to the resulting solution. The reaction mixture was allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure, and the concentrate was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate, followed by a 10:1 by volume mixture of ethyl acetate and ethanol, as the eluent. The product was recrystallized from ethyl acetate, to give 0.74 g of the title compound as crystals, melting at 100°-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:7]([NH2:8])=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([NH:8][C:7]1[C:6]([C:15]([F:16])([F:17])[F:18])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:10][C:9]=1[C:11]([F:12])([F:13])[F:14])(=[O:21])[CH3:20]
Reactant: Nc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
A mixture of 8.2 g. of 4-nitro-2,6-bis-trifluoromethylaniline, 3.6 g. acetic anhydride, and 20 ml. of pyridine is heated for 48 hours on a steam bath. The reaction mixture is poured onto ice water and the solid material is filtered, dried and recrystallized from isopropanol affording 4-acetylamino-3,5-bis-trifluoromethylnitrobenzene.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:9]=2)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:42]1(=[O:52])[N:46]([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:9]=3)[CH:4]=2)[C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCN(CCC)CCCc1ccc2cc(CO)ccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN(CCC)CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The compound (453 mg) obtained in Example 121-9 was added with triphenylphosphine (516 mg) and phthalimide (245 mg), and then dissolved in anhydrous THF (10 ml). The solution was added with a 40% diethylazodicarboxylate/toluene solution (0.892 ml) in an ice bath and stirred at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (439 mg) as a white solid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C(Cl)Cl>[F:7][CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS(=O)[C@H]12
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
To a solution of 0.483 g (3.0 mmoles) of diethylaminosulfur trifluoride in 10 ml of CH2Cl2 at -78° under N2 was added a solution of 1.61 g (3.0 mmoles) of benzhydryl 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in 50 ml of CH2Cl2 and the mixture was stirred at -78° for 0.5 hr, then poured into 100 ml of water. The CH2Cl2 layer was dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel with 9:1 CH2Cl2 -acetone to yield 0.095 g of benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in fractions 12-15, rf = 0.60 on tlc with 9:1 CH2Cl2 -acetone; mp 205.5°-207.5° d; ir (CHCl3) 3450 (amide N--H), 1805 (β -lactam C=O), 1725 (ester C=O), 1680 (amide C=O), 1495 ("amide II" band), and 700 (aromatic) cm-1.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[NH2:6])[CH2:3][CH2:2]1.F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][CH:5]([NH:6][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=2)[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(CC1CC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(CC2CC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
A mixture of 2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethanamine (90 mg, 0.30 mmol), methyl 6-fluoronicotinate (68.7 mg, 0.443 mmol) and potassium carbonate (122 mg, 0.885 mmol) in DMF (5 mL) was stirred for 12 h at 120° C. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by preparative TLC to give methyl 6-(2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethylamino)nicotinate (60 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.85-7.88 (m, 1H), 7.62-7.60 (m, 4H), 7.49 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.18 (d, J=8.8 Hz, 1H), 5.80 (br, 1H), 4.74-4.72 (m, 1H), 3.78 (s, 3H), 1.83-1.56 (m, 2H), 0.71-0.60 (m, 1H), 0.50-0.33 (m, 2H), 0.18-0.05 (m, 2H).