Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[F:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>>[F:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Fc1cccc(CBr)c1F
Solvent: NCc1ccccc1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4cccc(F)c4F)CC3)cccc2n1
Yield: 53 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 2,3-difluorobenzyl bromide (77 mg; 0.37 mmol) via Method BB to yield 38 mg. (53% yield). 1HNMR (400 MHz, DMSO-d6) δ 8.26 (br s, 1H), 7.8 (br s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.33 (m, 1H), 7.2 (m, 2H), 6.99 (br s, 2H), 6.9 (d, J=8 Hz, 1H), 6.81 (d, J=8.0 Hz, 2H), 4.07 (d, J=6.4 Hz, 2H), 3.59 (s, 2H), 2.85 (m, 2H), 2.04 (t, J=11.2 Hz, 2H), 1.9 (m, 1H), 1.73 (d, J=10.4 Hz, 2H), 1.33 (m, 2H). MS m/z (ESI) 400 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]O.C([O:11][C:12]([C:15](C(OC(C(OC)=O)(C(F)(F)F)F)(F)F)(F)F)(F)F)(F)(F)F.C(OC(C(C(OC(=C(F)F)F)(F)F)(F)F)(F)F)(F)(F)[F:33]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH:15]=[CH:12][O:11][F:33]
Reactant: COC(=O)C(F)(OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F)C(F)(F)F
Reactant: COCCCO
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Product: COCCCC=COF

Procedure:
In a procedure similar to Example 1, CH3O(CH2)3OH was converted to CF3O(CF2)3OCF(CF3)COOMe bp 123-126° C. and this to CF3O(CF2)3OCF═CF2 bp 62-64° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([C:26](OC)=[O:27])[C:15]=3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([CH2:26][OH:27])[C:15]=3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reaction time: 0.17 h

Procedure:
7.5 mg of lithium aluminum hydride were initially introduced into 1.5 ml of tetrahydrofuran and the mixture was stirred for 10 min. 6 mg of methyl 5-phenyl-1H-pyrazolo[4,3-c]isoquinoline-3-carboxylate (61) in 1.5 ml of tetrahydrofuran were then added dropwise. The mixture was stirred at 80° C. for 3 h, after which water was added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 62. C17H13N3O1 (275.31) MS (ESI) 276 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=2[Br:51])[CH3:55])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CC(O)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccccc4Br)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 76.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (145 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-bromo-α-methylbenzyl alcohol (90 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (101 mg, yield 71%).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:33][CH:32]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3- phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-methoxyphenol (6.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.2 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.6 mg, 37.9% yield) as a thick oil. 1H NMR (400 MHz, CDCl3) δ 7.38-7.14 (m, 8H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.72-6.46 (m, 4H), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.64 (s, 3H), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.37-1.72 (m, 8H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 487.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[C:22]([F:28])[CH:21]=1.Cl>CN(C)C=O.ClC1C=CC=CC=1.O>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:7](=[O:12])[C:8]2=[O:11])=[C:22]([F:28])[CH:21]=1
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Reactant: Fc1cc(Br)ccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccc(Br)cc2F)c2c(Cl)cccc21
Temperature: 25 °C

Procedure:
A suspension of 7-chloroindoline-2,3-dione (15g.) and potassium carbonate (15 g.) in N,N-dimethylformamide (100 ml.) was stirred and treated with a solution of 4-bromo-2-fluorobenzyl bromide (24.7 g.) in chlorobenzene (100 ml.). The mixture was stirred at 90° C. for five hours, cooled to ambient temperature, and diluted with a mixture of water (500 ml.) and petrol ether (b.p 60°-80° C.) (500 ml). The aqueous phase was adjusted to pH3 with 10 M hydrochloric acid. The mixture obtained was separated by filtration. The solid obtained was washed with further petrol ether, then with water, and recrystallised from ethanol to give 1-(4-bromo-2-fluorobenzyl)-7- chloro-indoline-2,3-dione (15.5 g.), m.p. 164°-166° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[C:5]([NH:6][CH3:7])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[CH2:18]([N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[C:21]1[CH:29]=O)[CH3:19].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[C:5]2[N:6]([CH3:7])[C:29]([C:21]3[N:20]([CH2:18][CH3:19])[C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[CH:22]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: CCn1c(C=O)cc2cccnc21
Reactant: CNc1c(OC(F)(F)F)cc(Br)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCn1c(-c2nc3cc(Br)cc(OC(F)(F)F)c3n2C)cc2cccnc21
Temperature: 80 °C
Reaction time: 17 h
Yield: 32.9 %

Procedure:
To a solution of 4-bromo-N-methyl-2-nitro-6-(trifluoromethoxy)aniline (1.368 g, 4.34 mmol) and 1-ethyl-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.756 g, 4.34 mmol) in ethanol (20 mL) was added sodium dithionite (2.67 g, 13.03 mmol) in water (10 mL). The mixture was flushed with nitrogen and then heated to 80° C. with stirring for 17 h. LCMS showed ˜52% conversion to the desired product with no starting material remaining. The reaction mixture was partitioned between aqueous hydrochloric acid (0.25 M, 100 mL) and extracted with dichloromethane (3×100 mL). The organics were combined, dried using a hydrophobic frit and evaporated under vacuum to give the crude product as a yellow solid. The sample was loaded in dichloromethane and purified by column chromatography on silica (100 g) using a gradient of 0-30% cyclohexane-ethyl acetate. The appropriate fractions were combined and evaporated in vacuo to give the required product (628 mg, 33%) as a yellow gum which solidified.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([NH2:15])=[O:14])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C:13]([NH2:15])=[O:14])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([NH2:15])=[O:14])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCC(NC(N)=O)c1ccc(F)cc1
Solvent: CO
Product: COC[C@@H](NC(N)=O)c1ccc(F)cc1
Product: COC[C@H](NC(N)=O)c1ccc(F)cc1

Procedure:
The enantiomers of 1-(1-(4-fluorophenyl)-2-methoxyethyl)urea (1.411 g, 6.65 mmol) were separated by SFC (Berger Multigram II SFC, column: Chiral Technology IC-H 2.1×25 cm, 5 uM, mobile phase: 20% to 80% MeOH in CO2(1), flow rate: 70 mL/min, 4 min run time). The fractions were collected and the solvent evaporated in vacuo to afford (S)-1-(1-(4-fluorophenyl)-2-methoxyethyl)urea and (R)-1-(1-(4-fluorophenyl)-2-methoxyethyl)urea. MS ESI calc'd. for C10H13FN2O2 [M+1]+ 213. found 213 (Intermediate 22C) and MS ESI calc'd. for C10H13FN2O2 [M+1]+ 213. found 213 (Intermediate 23C).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1(c2ccc(Br)cc2)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccc(Br)cc2)CCCC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-bromophenyl)-cyclopentylmethyl ester (227) (20 g, 60.01 mmol) in dimethyl sulfoxide (100 mL) were added KI (0.99 g, 6.00 mmol) and NaCN (4.41 g, 90.02 mmol). The reaction mixture was then stirred at 140° C. for 5 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (2×250 mL) and the organic layer was washed with water and brine. It was then dried over Na2SO4, and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give [1-(4-bromophenyl)-cyclopentyl]-acetonitrile (228) (13.9 g, 87%) as a colorless thick liquid.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30](O)(=[O:33])[CH2:31][CH3:32].CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (132 mg) obtained in Example 1, propionic acid (32 mg) and Et3N (0.083 ml) in DMF (5 ml), WSC.HCl (0.15 g) and HoBt.H2O (0.092 g) were added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to obtain the title compound as colorless amorphous.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[F:21][C:22]([F:27])([F:26])[C:23](O)=[O:24]>C(Cl)Cl>[ClH:1].[F:21][C:22]([F:27])([F:26])[C:23]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:24]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)C(F)(F)F
Yield: 60.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.70 ml (4.96 mmol) of anhydrous trifluoroacetic acid under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate ) to obtain the powder which was washed with hexane and dried to obtain 750 mg of the desired compound (free base) (68.4%, pale yellow prisms).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([Cl:32])=[CH:21][N:20]=1>CS(C)=O>[Cl:32][C:22]1[CH:23]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=3)=[CH:29][CH:30]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of potassium carbonate (376 mg), 2-fluoro-4-(trifluoromethyl)pyridine (269 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 120° C. for 2 hr. The mixture was neutralized with sat.NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (484 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:18][C@H:17]([CH2:19][O:20]C(=O)C)[C@@H:12]([O:13]C(=O)C)[C@H:7]([O:8]C(=O)C)[C@H:6]1[NH:24][C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2].CS(C)=[O:30]>>[C:1]([OH:4])(=[O:3])[CH3:2].[C:1]([OH:4])(=[O:3])[CH3:2].[C:1]([OH:4])(=[O:3])[CH3:2].[C:25]([NH:24][C@@H:6]1[C@@H:7]([OH:8])[C@H:12]([OH:13])[C@@H:17]([CH2:19][OH:20])[O:18][C:5]1([OH:4])[OH:30])(=[O:27])[CH3:26]
Reactant: CS(C)=O
Reactant: CC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)O
Product: CC(=O)O

Procedure:
Enzymatic hydrolysis: The beads containing immobilized lipase as obtained above were placed in the reactor and the solution of 10 g of 2-acetamido-2-deoxy-β-D-glucose tetracetate in 250 ml of 0.1 M tris-HCl buffer of pH 7.5 containing 10% dimethyl sulfoxide was recycled using an assembly as described in FIG. 1 till all the starting material was hydrolyzed. After the reaction, the reactants were drained and extracted with ethyl acetate {3×50 ml). The product, 2-acetamido-2-deoxy-1-hydroxy-β-D-glucose triacetate, was recovered (8.5 g) as a sticky gum after removal of ethyl acetate by evaporation. 1H NMR (CDCl3): δ 6.22 (d, 1H, NHα, j=10 Hz), 5.77 (d, 1H, NHβ, j=8.6 Hz), 5.32 (t, 1H, H3α, j=9.4 Hz), 5.22 (d, 1H, H1 α, j=4 Hz), 5 13 (dt, 2H, j=9), 4.74 (d, 1H, H1β, j=8.4 Hz), 4.38–3.91(m, 4H), 3.77–3.68 (m, 1H), 2.10 (s, 3H, acetyl), 2.09 (s, 3H, acetyl), 2.02 (s, 3H, acetyl). 1.97 (s, 3H, acetyl). 13C NMR (CDCl3) 91.60, 71.30, 68.70, 67.45, 62.49, 52.58 ppm. [α]23 D=+49.1 (c 1, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([NH:20][CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([N:20]([C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19]
Reactant: C=C(C)CNCC
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C)CN(CC)c1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 41.3 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.29 mmol), N-ethyl-2-methylallylamine (Aldrich Chemical Company) (0.19 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by preparative TLC on silica gel with 1:1 EtOAc:hexanes as eluant to give 36.7 mg (42%) of the title compound as off-white solid. An analytical sample was obtained by recrystallization from EtOAc. Mp: 148-150° C. 1H NMR (CDCl3; 500 MHz): δ 1.32 (t, 3, J=7.1), 1.95 (s, 3), 2.59 (s, 3), 3.78 (q, 2, J=7.1), 4.20 (s, 2), 5.18 (s, 1), 5.24 (s, 1), 6.74 (s, 1), 7.35-7.48 (m, 3), 7.55 (d, 2, J=7.4), 8.47 (br s, 1). MS m/z: 307 (M+1), 305 (M−1). Anal. Calcd for C19 H22N4: C, 74.48; H, 7.24; N, 18.28. Found: C, 74.36; H, 7.27; N, 18.19.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9]Cl.Cl[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([NH2:22])[C:17]=1[C:18]([O:20][CH3:21])=[O:19].N1C=CC=CC=1>ClCCl>[Cl:9][C:15]1[CH:14]=[CH:13][CH:12]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16]=1[N:22]=[S:7]([CH3:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(N)cccc1Cl
Reactant: ClCl
Reactant: CSc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Cl)c1N=S(C)c1ccccc1

Procedure:
A solution of 3.0 g (24 mmol) of methyl phenyl sulfide in 30 mL of dichloromethane was cooled to -10° C. and 1.7 g (24 mmol) of chlorine was sparged in with cooling and stirring. To this was added with cooling and stirring 4.5 g (24 mmol) of solid methyl 6-chloroanthranilate and then 3.8 g (48 mmol) of pyridine. The product mixture contained the title compound and methyl 6-chloroanthranilate in a 60:40 ratio as determined by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[C:17]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][O:19][N:20]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClC(Cl)C.CN(C1C=CN=CC=1)C>[C:22]([NH:21][C:17]1[C:16]([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=2[Cl:1])=[N:20][O:19][N:18]=1)(=[O:24])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)Nc1nonc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nonc1NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
173 mg (0.5 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid and 191 mg (0.505 mmol) of N-(4-amino-1,2,5-oxadiazol-3-yl)acetamide are dissolved in 5 ml of dichloroethane at RT and treated with 0.071 ml (0.5 mmol) of triethylamine, 31 mg (0.25 mmol) of DMAP and 483 mg (0.76 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 24 h at RT and subsequently filtered through a glass frit. The residue is washed twice using in each case 1 ml of CH2Cl2. The filtrate is passed over a silica-gel-filled SPE cartridge and eluted twice using in each case 5 ml of a mixture of ethyl acetate/methyl tert-butyl ester (1:1). The organic phase is dried over Na2SO4 and evaporated. The residue is purified by preparative HPLC using acetonitrile/water. Yield 16 mg (9%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[F:11].N#N.[CH3:14][CH2:15][OH:16].[Li][CH:18](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[F:11][C:3]1[C:4]([F:10])=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[CH2:14][C@H:15]([OH:16])[CH3:18]
Reactant: Fc1cc(F)c(F)c(Br)c1F
Reactant: CCO
Reactant: [Li]C(C)CC
Agent: FB(F)F
Agent: N#N
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)Cc1c(F)c(F)cc(F)c1F
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of 1-bromo-2,3,5,6-tetrafluorobenzene (4.58 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.57 in EtOAc/hexane 3:7) to give (2R)-1-(2,3,5,6-tetrafluorophenyl)propan-2-ol (2.57 g, 62%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 6.96 (m, 1H), 4.11 (m, 1H), 2.89 (m, 2H), 1.47 (d, J=5.46 Hz, 1H), 1.29 (d, J=6.21 Hz, 3H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH:14]([N:17]([CH:36]([CH3:38])[CH3:37])[C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)([CH3:16])[CH3:15]>CC(C)=O>[CH:36]([N:17]([CH:14]([CH3:16])[CH3:15])[C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:3])=[O:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)([CH3:38])[CH3:37]
Reactant: CC(C)N(C(=O)COc1ccc(-c2ccc(C=O)cc2)cc1)C(C)C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)N(C(=O)COc1ccc(-c2ccc(C(=O)O)cc2)cc1)C(C)C
Reaction time: 7 h

Procedure:
0.85 ml of Jones' reagent were introduced under an inert gas atmosphere into a solution of 741 mg of the product of stage B in 10 ml of acetone and the mixture was stirred for 7 hours. The precipitate formed was filtered off and dried to obtain 620 mg of the expected product with a Rf=0.5 (dichloromethane/methanol 9/1).