Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:10]1([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]([CH3:9])[C:6](=[O:7])[C:11]1[CH2:12][CH2:13][CH2:14][C:10]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:3])[CH3:2]
Reactant: C1=C(N2CCCC2)CCC1
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)C(=O)C1=C(N2CCCC2)CCC1
Yield: 95.2 %

Procedure:
Add dropwise a solution of 1-chloro-1-oxopropan-2-yl acetate (600 g, 3.98 mol) in toluene (1200 mL) to a solution of 1-cyclopent-1-enyl-pyrrolidine (546.7 g, 3.98 mol) and triethyl amine (483.9 g, 4.78 mol) in toluene (2400 mL). Reflux the mixture for overnight. Filter the mixture and concentrate the filtration to give crude 1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-yl acetate (952 g), which is used in next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 5.27 (m, 1H), 3.56 (m, 2H), 3.16 (m, 2H), 2.83 (m, 1H), 2.58 (m, 3H), 2.10 (s, 3H), 1.93 (m, 2H), 1.82 (m, 4H), 1.36 (d, J=7.2, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[NH2:14][C@@:15]1([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.CCN(C(C)C)C(C)C.CCOC(C)=O>CS(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH3:13])[N:3]=[C:2]([NH:14][C@@:15]2([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: CSc1nc(Cl)c(CCO)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(N)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(CCO)c(N[C@@]2(C)CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 110 °C
Reaction time: 42 h
Yield: 65 %

Procedure:
To a solution of 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]ethanol (1.25 g, 5.23 mmol) and tert-butyl(3S)-3-amino-3-methylpyrrolidine-1-carboxylate (1.57 g, 7.84 mmol) in DMSO (13 mL) was added DIEA (4.6 mL, 26.1 mmol) at room temperature. The reaction mixture was stirred at 110° C. for 42 h, whereupon the mixture was poured into EtOAc and washed with water. The water layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via ISCO normal phase silica gel chromatography (80 g column) eluting with a 0-100% gradient of EtOAc/Heptane to give the title compound (1.37 g, 65%) as a light yellow-white foamy solid. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J=17.0 Hz, 1 H), 5.06 (br s, 1 H), 3.75 (dd, J=20.6, 11.2 Hz, 1 H), 3.54 (br s, 2 H), 3.50-3.33 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.44 (s, 3 H), 2.40-2.23 (m, 1 H), 2.03-1.93 (m, 1 H), 1.47 (d, J=11.1 Hz, 3 H), 1.38 (d, J=13.4 Hz, 9 H). m/z (APCI+) for C17H27ClN4O3S 403.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33].C(O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH:22][C:32]([C:31]([CH3:36])([CH3:35])[CH3:30])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 49.1 %

Procedure:
3.36 g (13.1 mmol) of 1,4-dibenzyl-2-aminomethylpiperazine prepared according to a protocol identical to the one used in steps 6.1 and 6.2 of Example 6 are dissolved in 5.5 ml (3 equivalents; 39.3 mmol) of triethylamine and 100 ml of dichloromethane and are treated by rapid dropwise addition of 2.63 ml (1.5 equivalents; 19.6 mmol) of 2,2-dimethylpropanoyl chloride dissolved in 30 ml of CH2Cl2. The solution is refluxed for 4 hours. A few ml of ethanol are then added, after which the solution is washed twice with water, once with saturated NaHCO3 solution and then with water until a neutral pH is obtained. After drying the organic phase (MgSO4), filtration on paper and evaporation of the solvents, the residue is chromatographed on a column of silica gel, eluting with an MeOH/CH2Cl2 mixture (0.5/99.5 v/v). 2.44 g of 1,4-dibenzyl-2-tert-butylcarbonylaminomethylpiperazine are thus obtained in the form of a viscous product. Yield: 49%. Rf═0.36 (95/5 v/v CH2Cl2/MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1ccccc1Cl
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC(C(=O)OCC)c1ccccc1Cl
Temperature: 60 °C
Yield: 100 %

Procedure:
A mixture of ethyl 2-(2-chlorophenyl)acetate (11.32 g, 57.0 mmol), ethyl 4-bromobutanoate (33.3 g, 171 mmol) and Cs2CO3 (55.7 g, 171 mmol) in DMF (Volume: 57.0 ml) was heated at 60° C. overnight. The reaction was cooled to RT and diluted into a mixture of ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography (SG, 0 to 45% EtOAc/Hex) to get diethyl 2-(2-chlorophenyl)hexanedioate (17.82 g, 57.0 mmol, 100% yield). LC-MS (M+H)+=313.2. 1H NMR (500 MHz, CD3OD) δ 7.41 (ddd, J=17.0, 7.7, 1.5 Hz, 2H), 7.33-7.24 (m, 2H), 4.21-4.07 (m, 4H), 2.34 (td, J=7.3, 2.1 Hz, 2H), 2.16-2.05 (m, 1H), 1.82 (dddd, J=13.4, 10.3, 7.7, 5.5 Hz, 1H), 1.70-1.48 (m, 2H), 1.33-1.25 (m, 1H), 1.24 (t, J=7.2, 7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:9]=[C:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[NH:7][C:6]3=[N:8][C:18]=2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:15][CH:16]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1ccc(N)c(N)n1
Product: CC1CCc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2N1

Procedure:
The title compound was prepared from 6-methylpyridine-2,3-diamine and 1,2-bis(4-fluorophenyl)ethane-1,2-dione analogously to Intermediate E;
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].CCOCC>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5])=[O:13]
Reactant: CC(O)C(N)=NO
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C(N)=NOC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.45 g crude N′,2-dihydroxypropanimidamide was cooled on an ice-bath with 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g 3-chlorobenzoyl chloride was added. The mixture was warmed to r.t. and stirred for 2 h. Addition of Et2O (200 mL), washing with sat. aq. NH4Cl and re-extraction of the aq. layer gave after combining and concentration of the org. layers followed by drying in vacuo 27.24 g of crude title compound, which was used directly in the next step for 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol. LC-MS (M++1): 243
Reaction SMILES: ClC1C=CC2C=CC3C=CC=CC=3C(=O)C=2C=1.CNN(CC)NC.Cl[C:26]1[CH:27]=[CH:28][C:29]2[CH:35]=[CH:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[C:31](=[N:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[C:30]=2[CH:46]=1.[C:47]([O-:52])(=[O:51])[C:48]([O-:50])=[O:49]>>[C:47]([OH:52])(=[O:51])[C:48]([OH:50])=[O:49].[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][N:40]=[C:31]1[C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH:34]=[CH:35][C:29]2[CH:28]=[CH:27][CH:26]=[CH:46][C:30]1=2
Reactant: O=C([O-])C(=O)[O-]
Reactant: CN(C)CCN=c1c2ccccc2ccc2ccc(Cl)cc12
Agent: CCN(NC)NC
Agent: O=c1c2ccccc2ccc2ccc(Cl)cc12
Product: CN(C)CCN=c1c2ccccc2ccc2ccccc12
Product: O=C(O)C(=O)O

Procedure:
from 3-chloro-5H-dibenzo[a,d]cyclohepten-5-one and N,N-dimethylamino-ethylamine, there is obained 3-chloro-N-(2-dimethylamino-ethyl)-5H-dibenzo[a,d]cyclohepten-5-imine, melting point 173°-175° C. (oxalate);
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc(F)ccc1F
Product: COc1ccc(/C(C#N)=C/c2cc(F)ccc2F)cc1OC
Yield: 73.1 %

Procedure:
2,5-Difluorobenzaldehyde (1.42 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.20 g, yield: 73%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc(-c2ccc3oc(C)nc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc2cc(-c3ccc(C(=O)O)cc3)ccc2o1
Reaction time: 1 h

Procedure:
A room temperature solution of Example 54A (80 mg, 3.0 mmol) and LiOH (630 mg, 15.0 mmol) in a mixture of THF (15 mL), water (4 mL), and methanol (4 mL) was stirred for 1 hour, poured into 1M HCl, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12][C:11](N(N=O)C)=[N:10]2)=[CH:5][CH:4]=1.CN(C)C=O.CC(C)([O-])C.[K+].[N+:31]([CH3:34])([O-:33])=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12]/[C:11](=[CH:34]/[N+:31]([O-:33])=[O:32])/[NH:10]2)=[CH:7][CH:8]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C2(C)COCC(N(C)N=O)=N2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)COC/C(=C/[N+](=O)[O-])N2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 100 mmol of [5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-N-nitroso-N-methylamine, 200 ml of N,N-dimethylformamide, 50 ml of nitromethane and 115 mmol of potassium tert-butoxide is stirred at room temperature for 15 minutes. It is quenched by adding 20 ml of glacial acetic acid and diluted with dichloromethane and water. The organic phase is separated off, washed with water, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C@H:4]([CH3:7])[C:5]#[N:6].[CH2:8]([OH:10])[CH3:9]>>[ClH:1].[CH2:8]([O:10][C:5](=[NH:6])[C@H:4]([O:3][CH3:2])[CH3:7])[CH3:9]
Reactant: CO[C@H](C)C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)[C@@H](C)OC
Yield: 100 %

Procedure:
Hydrogen chloride gas was passed into an icecold solution of (R)-2-methoxy-propionitrile (prepared according to the method of Example 1, Step A, 9.91 g, 116.5 mmol) in anhydrous ethanol (100 mL) until the solution was saturated with the gas. The reaction was stored in a refrigerator over night. The excess ethanol was removed under vacuum to obtain the title compound of Example 1, Step B as a deliquescent solid (19.5 g, 100% yield); [α]D+46.4 (c=1, methanol); 1H NMR (CDCl3, 300 MHz) δ1.4 (d, 3H), 3.4 (s, 1H), 3.7 (q, 2H), 4.8 (q, 1H), 6.2 (b, 1H).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][NH:6][C:5]2=[O:10].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21]C)(=[O:20])=[O:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[CH3:11][N+:2]1[CH:1]=[C:9]2[N:4]([C:5](=[O:10])[NH:6][CH2:7][CH2:8]2)[CH:3]=1
Reactant: O=C1NCCc2cncn21
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Product: C[n+]1cc2n(c1)C(=O)NCC2
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 60 °C
Reaction time: 3.33 h

Procedure:
A stirred suspension of 7,8-dihydroimidazo[1,5-c]pyrimidin-5(6H)-one (699.7 g) in DMF 2.45 litres) was heated to ca. 60° C. A solution of methyl 4-methylbenzenesulfonate (1058.2 g.) in DMF (0.7 litres) was added over 100 min at ca. 60° C., and rinsed in with DMF (0.35 litres). The white suspension was stirred at ca. 60° C. for 200 min. when the reaction was complete by nmr. The reaction mixture was allowed to cool to ca. 40° C. and TBME (5.25 litres) was added. The product was cooled to ca. 22° C., aged at this temperature for 17 h, and filtered. The cake was washed with TBME-DMF (3:1, 1.4 litres), then with TBME (2×1.4 litres), the cake was pulled dry, and the product was dried in vacuo at ca. 50° C. to yield the title compound, 1583.5 g.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[C:9]1(/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH2:23].CC(C)=O.C(#N)C>[O-][Os](=O)(=O)=O.O=[Os](=O)(=O)=O>[C:9]1([C@@H:15]([OH:5])[C@@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:23])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=[Os](=O)(=O)[O-]
Solvent: CC#N
Solvent: CC(C)=O
Product: O[C@H](c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Resin-OsO4 (0.01 Eq. Wt.), Hydroquinidine 1,4-phthalazinediyl diether (DHQD)2PHAL (0.01 Eq. Wt.) and N-methylmorpholine-N-oxide (1.5 Eq. Wt.) were stirred in the mixed solvent of water/acetone/acetonitrile (in the volume ratio of 1:1:1). To this mixture was added trans-stilbene (1.0 Eq. Wt) and stirred at room temperature for 6 hours. After the reaction, supported osmate catalyst was filtered off and washed with methanol. The combined filtrates were concentrated under reduced pressure. The chiral ligand was recovered from the aqueous layer after acidification (1N HCl). The pure product was obtained by removing the solvent at reduced pressure followed by column chromatography. (R,R)-(+)-1,2-diphenyl-1,2-ethandiol of more than 99.0% of enantiomeric excess was obtained (yield 96%) [∝]D +92.44 (c1.0, EtOH): e.e.=99.4%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][C:41]3=[N:42][O:43][N:44]=[C:40]3[CH:39]=2)O1>CN(C=O)C.O>[N:42]1[O:43][N:44]=[C:40]2[CH:39]=[C:38]([C:2]3[CH:3]=[C:4]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=3[O:8][CH2:9][CH:10]3[CH2:12][CH2:11]3)[CH:46]=[CH:45][C:41]=12
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(Br)c1
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nonc3c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.5 g, 1.240 mmol) in a mixture of DMF (20 mL) and water (5 mL) were added Cs2CO3 (1.4 g, 4.342 mmol), Pd(TPP)4 (286 mg, 2.480 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzo[c][1,2,5]oxadiazole (355 mg, 1.364 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of Celite™ was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (250 mg) as an off white solid.
Reaction SMILES: F[S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=1[CH3:18])(=[O:4])=[O:3].[OH-:19].[K+:20]>O>[K:20][CH:5]([S:2]([OH:19])(=[O:4])=[O:3])[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=1[CH3:18]
Reactant: [OH-]
Reactant: CC(=O)Nc1ccc(C)c(NCCS(=O)(=O)F)c1
Reactant: [K+]
Solvent: O
Product: CC(=O)Nc1ccc(C)c(NCC([K])S(=O)(=O)O)c1

Procedure:
N-(2-Fluorosulfonylethyl-2-methyl-5-acetamidoaniline (13.7 g, 0.05 m) is stirred with water (100 ml.) and potassium hydroxide (5.0 g) at room temperature for 2 hrs. when thin-layer chromatography shows reaction to be complete. The aqueous solution is used in the coupling reaction without further isolation.
Reaction SMILES: C([OH:3])C.Cl.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[N:20]=[C:19]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[Cl:29][C:30]1[N:35]=[C:34](Cl)[CH:33]=[CH:32][N:31]=1>C(N(CC)CC)C>[OH2:3].[Cl:29][C:30]1[N:35]=[C:34]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=4)[N:20]=3)=[O:22])[CH2:28][CH2:27]2)[CH:33]=[CH:32][N:31]=1
Reactant: CCO
Reactant: COc1ccc(-c2cccc(C(=O)N3CCNCC3)n2)cc1OC
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccnc(Cl)n4)CC3)n2)cc1OC
Product: O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To an ethanol (6 ml) solution of 327 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazine monohydrochloride were added 0.28 ml of triethylamine and 148 mg of 2,4-dichloropyrimidine, followed by 2 hours of stirring at an oil bath temperature of 90° C. After the solvent was evaporated, water was added thereto, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) and further, recrystallization was carried out from acetonitrile-diisopropyl ether to obtain 70 mg of 2-chloro-4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrimidine monohydrate as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reaction time: 24 h
Yield: 52.6 %

Procedure:
A mixture of 100.0 g of methyl 2-methyl-3-nitrobenzoate, 100.0 g of N-bromosuccinimide, 3.0 g of dibenzoyl peroxide and 1000 ml of carbon tetrachloride was refluxed for 24 hours. The reaction mixture was cooled, 3.0 g of dibenzoyl peroxide added, and refluxing continued an additional 24 hours. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The crude reaction product was dissolved in ether and the organic solution washed sequentially with saturated sodium sulfite (500 ml), water (2×500 ml), 2.5% sodium hydroxide (500 ml), water (2×500 ml) and saturated brine (500 ml). The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated in vacuo giving a pale yellow oily solid. Recrystallization from 350 ml of 1-chlorbutane/cyclohexane (2:1) gave 73.9 g of methyl 2-bromomethyl-3-nitrobenzoate, m.p. 67°-70°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:32](OC(=O)C)=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][CH2:14][N:15]([CH:32]=[O:33])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CC(=O)OC=O
Reactant: CCOc1cc([C@@H](CCNO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Solvent: ClCCl
Product: CCOc1cc([C@@H](CCN(O)C=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reaction time: 1 h
Yield: 24.1 %

Procedure:
To a solution of (1R)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (350 mg, 0.82 mmol) in methylene chloride (3 mL) was added a solution of acetyl formate (84 mg) in methylene chloride (1 mL) at 0° C. After 1 h, the mixture was extracted with ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with brine (20 mL) and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with prep HPLC to give (1R)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (90 mg, 24% yield): mp: 96-98° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.81-2.83 (m, 2H, CH2), 3.56 (t, J=6 Hz, 2H, CH2), 3.85 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 5.25 (t, J=8 Hz, 1H, NCH), 6.82 (d, J=8 Hz, 1H, Ar), 7.06-7.09 (m, 2H, Ar), 7.45 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 7.72 (s, 1H, CH), 8.75 (d, J=8 Hz, 1H, Ar), 9.49 (s, 1H, NH); 13C NMR (CDCl3) δ 14.73, 24.95, 28.35, 46.61, 51.92, 55.93, 64.46, 111.37, 112.79, 115.21, 118.05, 120.63, 124.90, 130.33, 131.09, 136.02, 137.47, 148.48, 149.40, 155.73, 167.72, 169.27, 170.07; Anal Calcd for C23H25N3O7+0.3 H2O: C, 59.95; H, 5.60; N, 9.12; H2O, 1.17. Found: C, 59.94; H, 5.59; N, 8.98; H2O, 1.22.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH:11][CH2:12][C:13](=O)[CH3:14]>>[OH:11][CH2:12][CH:13]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([F:9])[C:2]=1[F:1])[CH3:14]
Reactant: CC(=O)CO
Reactant: Nc1ccc(F)c(F)c1F
Product: CC(CO)Nc1ccc(F)c(F)c1F

Procedure:
2,3,4-trifluoroaniline was reductively alkylated in the presence hydroxyacetone using a Raney Nickel catalyst. Raney nickel (14 ml of 50% aqueous Raney nickel catalyst was slurried in 100 ml of absolute methanol. The mixture was allowed to settle and 90-95% of the liquid was decanted. The process was then repeated three times. 2,3,4-Trifluoroaniline (7.3 g, 0.05 mole) was charged into a glass autoclave liner containing the catalyst. Hydroxyacetone (3.7 g, 0.05 mole) was then added and the mixture was purged with nitrogen. Hydrogenation was initiated at 65° C. and continued to a maximum temperature of 85° C. Hydrogen uptake continued for 0.5 hour between 430 and 450 psi at which time 75% of the alkylated product (3) was obtained with the remainder being unreacted 2,3,4-trifluoroaniline and hydroxyacetone.