Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[C:20]([SH:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].N1C=CC=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:21][C:20]2[C:19]([F:22])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=2[F:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1c(F)c(F)c(S)c(F)c1F
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Sc2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (4.96 g) in dry dichloromethane (20 ml) was added dropwise over 15 minutes to a stirred solution of pentafluorothiophenol (5.00 g), pyridine (2.1 ml) and 4-N,N-dimethylaminopyridine (50 mg) in dry dichloromethane (75 ml), the mixture being maintained close to 5° C. by immersion in an ice-bath. The reactants were allowed to reach room temperature overnight and the organic solution was washed successively with aqueous 2M hydrochloric acid, a saturated sodium bicarbonate solution and water. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester (8.79 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C@@H:13]2[CH2:20][C@H:16]3[O:17][CH2:18][CH2:19][C@@:15]3([C:21]([N:23]3[CH2:32][CH2:31][C:30]4[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=4[CH2:24]3)=[O:22])[CH2:14]2)[CH2:11][CH:12]=1)(=O)=O.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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:39]1([C:7]2[CH2:8][CH2:9][N:10]([C@@H:13]3[CH2:20][C@H:16]4[O:17][CH2:18][CH2:19][C@@:15]4([C:21]([N:23]4[CH2:32][CH2:31][C:30]5[N:29]=[CH:28][C:27]([C:33]([F:34])([F:36])[F:35])=[CH:26][C:25]=5[CH2:24]4)=[O:22])[CH2:14]3)[CH2:11][CH:12]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)[C@@]12CCO[C@@H]1C[C@@H](N1CC=C(OS(=O)(=O)C(F)(F)F)CC1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)[C@@]12CCO[C@@H]1C[C@@H](N1CC=C(c3ccccc3)CC1)C2
Temperature: 25 °C

Procedure:
A solution of the product of Step B (50 mg, 0.09 mmol, 1 eq), phenylboronic acid (22 mg, 0.18 mmol, 2 eq), (Ph3P)4Pd (10 mg, 0.009 mmol, 0.1 eq) and 2 M Na2CO3 (0.1 mL) in dimethoxyethane (1 mL) under N2 was warmed to 80 C in a screw-top vial overnight. The solution was cooled to rt, and concentrated. Purification by column chromatography (4 g) eluting with 50 to 100% ethyl acetate/heptane afforded the title compound of Step C. Calculated for C28H30F3N3O2: 498.2 (M+1). found: 498.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([CH3:26])=[N:24][C:23]([CH3:27])=[CH:22][N:21]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:25]([CH3:26])=[N:24][C:23]([CH3:27])=[CH:22][N:21]=3)[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(C)nc2C)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ncc(C)nc3C)n(CCCO)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of the resulting thiourea (435 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (214 mg, 1.12 mmol), and triethylamine (0.16 mL) in tetrahydrofuran (3.0 ml) was stirred at 60° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with ethyl acetate/diisopropyl ether to give methyl 4-chloro-2-[(3,5-dimethylpyrazin-2-yl)amino]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (294 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.[Se](=O)=[O:19].O>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:8]([CH:17]=[O:19])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1NC(C)(C)C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 8-bromo-N-(tert-butyl)-3-methylquinoxalin-2-amine (174a) (137 mg, 0.47 mmol), selenium dioxide (Aldrich; 57.0 mg, 0.51 mmol), and water (0.084 mL, 4.67 mmol) in 1,4-dioxane (5.0 mL) was stirred under argon at 60° C. for 19 h. The reaction mixture was then cooled to RT, diluted with DCM (5 mL), and adsorbed onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (132. mg, 0.43 mmol, 92% yield) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.14 (1H, s), 8.03 (1H, br. s.), 7.99 (1H, d, J=7.4 Hz), 7.88 (1H, d, J=8.4 Hz), 7.22-7.25 (1H, m), 1.64 (9H, s). m/z (ESI, +ve) 308.0/310.1 (M+H)+.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:19][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O

Procedure:
2,500 ml of benzene was added to 1,423 g of N-(1'-hydroxy-2',2',2'-trichloroethyl)-2-hydroxy benzamide and then 833 g of thionyl chloride was added thereto and heated under reflux at 70°-80° C. for 4 hours to obtain N-(1',2',2',2'-tetrachloroethyl)-2-hydroxy benzamide (white crystal, melting point of 113°-113.5° C., Anal. Found: C,35.74; H,2.12; N,4.70 Calcd. for C9H7Cl4NO2 : C,35.68; H,2.33; N,4.62 and the resultant reaction mixture, without separation of the crystals, was cooled to below 30° C. and mixed with 1,250 g of methanol and heated under reflux for 2 hours at 55°-60° C. followed by removing the solvent and the residue was poured into water, filtered and dried to obtain 1,380 g (yield 92.4%) white crystals of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-hydroxy benzamide.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[C:10]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCCOc1c(OCc2ccccc2)cccc1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCOc1c(O)cccc1C(=O)OCC
Yield: 97 %

Procedure:
A mixture of ethyl 3-benzyloxy-2-(3-ethoxycarbonylpropyloxy)benzoate (2.5 g) and palladium on charcoal (0.25 g) in ethanol (12.5 ml) was hydrogenated under hydrogen atmosphere. The catalyst was filtered off. The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1:3) to give colorless oil of ethyl 3-hydroxy-2-(3-ethoxycarbonylpropyloxy)benzoate (1.86 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1I.Cl>C1(O)CCCCC1.[Cu]>[F:11][C:10]1[C:2]([NH:1][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: Fc1ccccc1I
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: OC1CCCCC1
Product: O=C(O)c1cccc(F)c1Nc1ccccc1F
Yield: 71.2 %

Procedure:
A mixture of 14.0 g (90.2 mmol) of 2-amino-3-fluorobenzoic acid (XIV), 12.5 g (90.4 mmol) of potassium carbonate, 21.0 g (94.6 mmol) of 2-fluoroiodobenzene (XV) and a spatula-tipfull of copper powder in 85 ml of cyclohexanol was heated at reflux for 12 hours. The solvent was then removed by steam distillation, and the aqueous residue obtained was subjected to centrifugation. The soluble centrifugate was acidified with diluted hydrochloric acid, and the resulting precipitate was filtered off and dried. Fractional sublimation of the solid under high vacuum yielded 16.0 g (71% of theory) of 3-fluoro-2-(2-fluorophenylamino)benzoic acid (XVI) as a yellow powder with a melting point of 176° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]5[CH2:21][CH2:22][CH:23]([C:25](OCC)=[O:26])[CH2:24][C:19]=5[S:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.C([AlH]CC(C)C)C(C)C.[Cl-].[NH4+]>O1CCCC1>[OH:26][CH2:25][CH:23]1[CH2:22][CH2:21][C:20]2[C:13]3[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)=[N:17][CH:16]=[N:15][C:14]=3[S:18][C:19]=2[CH2:24]1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Nc3ncnc4sc5c(c34)CCC(CO)C5)cc2s1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A mixture comprising 4.42 g (10.36 mmol) (RS)-ethyl 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate (prepared according to example 1) 350 mL tetrahydrofuran and 62.1 mL hydrido(diisobutyl)aluminum (1M in tetrahydrofuran) was stirred at 23° C. overnight. 40 mL saturated ammonium chloride was added carefully and stirring was continued for 0.5 hours. The precipitate was filtered off and washed with ethyl acetate. The product crystallized from the filtrate and was washed with water and a mixture of dichloromethane and methanol to give 3.13 g (79%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:15](=[O:17])[CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>CCOCC>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:12][C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][C:15](=[O:17])[CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2cc(=O)cc(-c3ccccc3)o2)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Product: O=c1cc(C=Cc2ccc(O)cc2)oc(-c2ccccc2)c1

Procedure:
The ether linkage of 2-[2-(4-methoxyphenyl)ethenyl]-6-phenyl-4H-pyran-4-one was cleaved with boron tribromide as described in Example 47 to give the title product as orange needles (mp 198°-201° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])[CH:5]=[CH:4][N:3]=1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccnc(Cl)n2)c1
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccnc(Cl)n2)c1

Procedure:
A solution of 2-chloro-4-(2-fluoro-5-nitrophenyl)pyrimidine (800 mg, 3.2 mmol) in ethanol (300 mL) was reduced under 40 p.s.i. hydrogen with platinum(IV) oxide (100 mg) for 30 minutes then filtered to give a solution of 3-(2-chloro-pyrimidin-4-yl)-4-fluorophenylamine: m/z (ES+) 224 (M++H).
Reaction SMILES: [NH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].Cl.[N:15]([O-])=O.[Na+].N(O)=O.N([O-])=O>>[N:15]1[N:4]2[C:5]3[C:10]([C:11](=[O:13])[NH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=N[O-]
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Agent: Cl
Agent: O=NO
Agent: [Na+]
Product: O=c1[nH]c2nnnn2c2ccccc12
Reaction time: 1 h

Procedure:
2-Hydrazino-quinazolin-4-one (IIIb) (17.6 g; 0.1 mole), was suspended in 2 N-hydrochloric acid (78 ml; 0.156 mole) in a 600 ml beaker equipped with a thermometer and efficient stirrer. 15% w/v aqueous NaNO2 solution was added at such a rate that the temperature remained between 20° and 25° C., cooling with a water bath when necessary, until a small permanent excess of nitrous acid was present. The volume of the nitrite solution used was 63 ml (=9.45 g NaNO2 ; 0.137 mole). The reaction mixture was then stirred for 1 hour, filtered, and the solid washed acid free with water. After pulling as dry as possible on the filter, the product was dried completely in a vacuum desiccator over phosphorus pentoxide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:36])[C:23]([CH3:35])=[C:24]([C:33]#[N:34])[C:25]=1[C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:20])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:36])[C:23]([CH3:35])=[C:24]([C:33]#[N:34])[C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:28][CH:27]=1)=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(C)n1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(C)n1C
Temperature: 0 °C

Procedure:
Add trifluoromethanesulfonic anhydride (1.2 Eq.) to 4-cyano-3-(4-hydroxy-phenyl)-1,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-238) and pyridine (1.5 Eq) in methylene chloride dropwise with stirring at 0° C. Stir the reaction mixture for 2 hours and then allow the reaction to warm to room temperature. Wash the organic layer with 1.0 N HCl, water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the residue by silica gel chromatography (Chromatotron™) eluting with methylene chloride to provide the title compound as a yellow solid. Mass spectrum (m/e): 417.1 (M*+1): (Bruker 300) 1H NMR (CDCl3) δ 7.29-7.32 (2H, d), 7.27-7.29 (2H, d), 4.01-4.11 (2H, dd), 3.85-3.89 (3H, s), 2.43-2.47 (3H, s), 0.90-1.00 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]([F:25])([F:24])[CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8]>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]([F:24])([F:25])[CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Reaction time: 2 h

Procedure:
A solution of tert-butyl 5-chloro-4-((3,3-difluorocyclohexyl)methoxy)-2- fluorobenzoate (64.4 mg) in dichloromethane (0.34 mL) and trifluoroacetic acid (0.17 mL) was stirred at 0° C. for 10 min then at rt for 2 h. The contents were concentrated. The residue was re-dissolved with dichloromethane and concentrated. The crude was dried under vacuum and used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][C:15]1=[O:21].C(N(CC)CC)C.CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:16]2[C:17](=[O:20])[CH2:18][CH2:19][NH:14][C:15]2=[O:21])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCNC(=O)C1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCNC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (5.8 g) in dry dichloromethane (10 ml) was added over 5 minutes to a stirred solution of piperidine-2,4-dione (3.0 g) and triethylamine (5.5 ml) in dry dichloromethane (100 ml) and the mixture was stirred at ambient temperature for 3 hours. Acetone cyanohydrin (0.5 ml) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was washed successively with 2N hydrochloric acid (50 ml) and water (2×100 ml), dried over sodium sulphate and evaporated under reduced pressure to give a solid residue which was recrystallised from ethyl acetate (70 ml) to give 3-(4-chloro-2-nitrobenzoyl)piperidine-2,4-dione (1.6 g), mp 161°-164° C., as a light brown crystalline solid.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([CH3:20])([CH3:19])[CH:17]=O)=[CH:15][C:10]=2[O:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:20][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[O:7][CH2:8][O:9][C:10]=2[CH:15]=1)([CH:17]=[CH2:1])[CH3:19]
Reactant: CC(C)(C=O)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(C)(C)c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of methyl triphenyl phosphonium bromide (325 mg, 0.95 mmol) and t-BuOK (87.5 mg, 0.78 mmol) in dry tetrahydrofuran (1 mL) was stirred at 0° C. for 1 hour. To this mixture at 0° C., a solution of Compound I (50 mg, 0.26 mmol) in dry tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours and then refluxed for 5 hours. It was then cooled to 0° C. and quenched by NH4Cl solution with stirring for 30 minutes. The reaction mixture was then extracted with diethyl ether. The ether layer was washed with distilled water, dried over anhydrous sodium sulfate, filtered and evaporated. Purification on silica gel column using petroleum ether followed by with 20:1 petroleum ether-ethyl acetate afforded desired Compound No. 14 (1 mg) as colourless oil.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Cl-].[K+].[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[CH:33]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32]2.COC1C=CC(C=O)=CC=1>C(O)C>[OH:38][C@@H:34]1[C:35]2[C:31](=[CH:30][C:29]([F:28])=[CH:37][CH:36]=2)[CH2:32][C@@H:33]1[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)C1Cc2cc(F)ccc2C1=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1Cc2cc(F)ccc2[C@H]1O
Reaction time: 48 h
Yield: 84.2 %

Procedure:
Colletotrichum gloeosporioides is cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H2O (0.5 gram), NaNO3 (2 grams), FeSO4.7H2O (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of 5-fluoro-2-carboethoxy-1-indanone is dissolved in 2 ml of 95% ethanol, the resulting solution is added to the culture, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.7 grams of (1S,2S)-1-hydroxy-2-carboethoxy-5-fluoroindane as a yellow oil. The chiral purity of the product is greater than 98% as judged by chiral chromatography.
Reaction SMILES: [CH:1]1([NH:7][S:8](=[O:11])(=O)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C1C=CC=CC=1>[CH:1]1([NH:7][S:8]([Cl:13])(=[O:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)NC1CCCCC1
Solvent: c1ccccc1
Product: O=S(=O)(Cl)NC1CCCCC1
Yield: 90.7 %

Procedure:
To a solution of cyclohexylsulfamic acid (5 g, 27.9 mmol) in benzene (30 mL) was added dropwise phosphorus pentachloride (6.4 g, 30.7 mmol), and the mixture heated at reflux for 4 h. After the solvent was removed, the residue was distilled under reduced pressure to give the title compound (5 g, 91%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:8])[CH:4]=[CH:5][CH2:6][OH:7].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:9]([O:7][CH2:6][CH:5]=[CH:4][CH2:3][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC=CCO
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: C(=CCOCc1ccccc1)COCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 114.5 %

Procedure:
To 48% aqueous sodium hydroxide 127.8 g was added tetra-n-butylammonium bromide 3.3 g (10 mmol), and the mixture was heated to 60° C. To the mixture was added 2-butene-1,4-diol (14) 30.0 g (340 mmol), to which was added dropwise benzyl chloride 94.8 g (743 mmol) at 80±15° C. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled down, and separated after addition of water 90 ml. To the organic layer was add sulfuric acidic brine. The solution was neutralized by aqueous sodium hydrogen carbonate, separated, mixed with ethyl acetate, and concentrated under reduced pressure to yield the oil residue 104.5 g (quantitative) of the objective (15).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>O1CCCC1>[CH3:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:32][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(F)cc2)cc1
Reactant: Cc1ccc(O)cc1C
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C)c(C)c1)c1ccc(OCCOc2ccc(F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-fluorophenoxy)ethoxy]phenyl}acetate (0.017 mole) is reacted with 3,4-dimethylphenol (0.017 mole) in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:16][CH:15]=[N:14][CH:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:27]Br.[O-]S([O-])=O.[Na+].[Na+]>O1CCCC1.CN1CCCN(C)C1=O.CCOCC>[Br:27][C:13]1[N:14]=[CH:15][O:16][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=1[F:1]
Reactant: BrBr
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cnco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S([O-])[O-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cc(C(F)(F)F)ccc1-c1ocnc1Br
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A solution of Example 5A (6.46 g, 27.9 mmol) in tetrahydrofuran (48 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (36 mL) was cooled to −78° C., and then treated slowly with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 34 mL, 34 mmol). The reaction was stirred for 1 hour and then treated dropwise with bromine (1.43 ml, 27.9 mmol). The reaction stirred for another hour at −78° C., and then was poured into 900 mL ether and 270 mL 10% Na2SO3 solution. The phases were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. The crude material was purified by chromatography (5 to 20% ethyl acetate-hexane) to afford the title compound as a yellow oil (4.58 g, 53% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.02 (m, 2H), 7.81 (m, 1H). MS (DCI+) m/z 312 (M+H)+.