Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>CS(C)=O>[CH3:22][O:21][C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:23]([O-:25])=[O:24])[C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:20]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Dimethyl malonate (6.0 ml) was added to an ice-cold suspension of sodium hydride (2.1 g) in dimethylsulfoxide (15 ml). The reaction mixture was heated to 100° C., stirred for 1 hour and then cooled to room temperature. 2-Chloro-3-methoxycarbonylnitrobenzene (2.15 g) was added in one portion and the mixture was stirred at 100° C. for 1.5 hour. The reaction mixture was then cooled to room temperature and poured into ice water, acidified to pH 5, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3.0 g of the dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(OC([N:21]=[C:22]=S)=O)C.Cl.[NH2:25]O>C(N(C(C)C)C(C)C)C>[CH3:1][O:2][C:3]1[N:8]2[N:25]=[C:22]([NH2:21])[N:9]=[C:7]2[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(-c2ccccc2)c(N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccccc2)c2nc(N)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 230 mg (1.15 mmol) 6-methoxy-3-phenyl-pyridin-2-yl-amine and 142.8 μl ethoxycarbonyl isothiocyanate was stirred at room temperature for 2 h and afterwards evaporated to dryness. The residue was taken up in 20 ml MeOH/EtOH 1:1 and treated with a mixture of 399 mg (5.74 mmol) hydroxylamine hydrochloride and 590 μl N-ethyldiisopropylamine. The mixture was heated to 80° C. for 16 h, concentrated to dryness, taken up in 100 ml water and extracted with 3×150 ml diethyl ether. The combined organic phases were dried with MgSO4 and evaporated to yield 379 mg (80%) of the title compound. 1-H-NMR (300MHz, DMSO-d6): δ=8.05 (d, J=8.49 Hz, 2H, phenyl), 7.73 (d, J=8.31 Hz 1H, H-7), 7.45 (t, J=7.26 Hz, 2H, phenyl), 7.33 (d, t=7.26 Hz, 1H, phenyl), 6.52 (d, J=8.31 Hz, 1H, H-6), 6.08 (s, br, 2H, NH2), 4.09 (s, 3H, OCH3). MS m/e (%): 241.3 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1C)=O.[Cl-].[OH:16][NH3+:17].[C:18]([O-])(=O)C.[Na+]>C(O)C.O>[F:14][C:2]([F:1])([F:13])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:18])=[CH:9][C:10]=1[CH3:11])=[N:17][OH:16]
Reactant: CC(=O)[O-]
Reactant: [NH3+]O
Reactant: Cc1cccc(C)c1C(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=NO)C(F)(F)F)c(C)c1
Yield: 88.4 %

Procedure:
12.6 g (0.062 mol) of 2,2,2-trifluoro-1-(2,6-dimethylphenyl)-ethanone are dissolved in 30 ml of ethanol at 80° C. To the solution are added dropwise 4.6 g (0.066 mol) of hydroxylammonium chloride and 8.7 g (0.106 mol) of sodium acetate dissolved in 15 ml of water. The reaction mixture is refluxed overnight, affording white precipitation. The mixture is poured into ice water, and extracted with ethyl acetate. The organic phase is washed with water, NH4Cl aq, and brine, dried over MgSO4, and concentrated, yielding 11.9 g of crude 2,2,2-trifluoro-1-(2,4-dimethylphenyl)-ethanone oxime as a colorless liquid. The crude product is used in the next reaction step without further purification.
Reaction SMILES: N1C(C)=CC=[CH:3][C:2]=1[CH3:8].OO.C=CC.O=O.[CH2:16]1[O:19][CH:17]1[CH3:18].[C:20](=O)=[O:21]>CO>[CH2:16]1[O:19][CH:17]1[CH3:18].[CH3:20][O:21][CH2:3][CH:2]([OH:19])[CH3:8]
Reactant: Cc1cccc(C)n1
Reactant: O=C=O
Agent: CC1CO1
Agent: O=O
Agent: OO
Solvent: C=CC
Solvent: CO
Product: COCC(C)O
Temperature: 25 °C

Procedure:
A 100 mL Parr reactor equipped with a magnetic stir bar is charged with 34 grams of methanol, 200 mg. of 2,6-lutidine and 250 mg. of Ts-1 titanium silicalite containing 2.1 weight % Ti (calcined at 540-550° C. before use). After stirring for several minutes at ambient temperature, 8 grams of 30% aqueous hydrogen peroxide is added. The closed reactor is then charged with 14 grams of propylene from a Hoke pressure vessel using 400 psig of nitrogen. The reactor is heated at 40° C. for 30 minutes and cooled to 20° C. using an ice bath. The gasses from the reactor are vented into a gas bag. The reactor is pressurized to 400 psig with nitrogen and the gasses vented into another gas bag. The gas bags are analyzed by GC for oxygen, propylene oxide, propylene and CO2. The volumes of the bags are measured using a wet test meter. The liquid phase is analyzed by GC for oxygenated products using acetonitrile as a standard and by LC for carboxylic acids. The hydrogen peroxide conversion is measured by reaction of an aliquot of the recovered liquid with sodium iodide and titration with sodium thiosulfate. The above reaction gave propylene oxide and propylene glycol monomethyl ether isomers in 98.5 and 0.8% selectivity, respectively. The selectivities were based on observed products on a propylene basis. The hydrogen peroxide conversion was 74%.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[Br:8][CH2:9][CH2:10][CH2:11][NH2:12]>C1(C)C=CC=CC=1>[Br:8][CH2:9][CH2:10][CH2:11][NH:12][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4]
Reactant: COCC(Cl)C=O
Reactant: NCCCBr
Solvent: Cc1ccccc1
Product: COCC(C=O)NCCCBr
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. γ-Bromopropylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-γ-bromopropylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [OH:1][CH:2]([C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][C:16]=1[CH3:17])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.[BrH:24].N([O-])=O.[Na+].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CO.CC(C)=O.O>[Br:24][CH:30]([CH2:31][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][CH:2]([OH:1])[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])=[CH:6][CH:7]=1)[C:29]([O:33][CH3:34])=[O:32]
Reactant: Br
Reactant: C=CC(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1C(O)COc1ccc(N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)C(Br)Cc1ccc(OCC(O)c2nc(-c3ccccc3)oc2C)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
4-[2-Hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]aniline (18.5 g) was dissolved in methanol (50 ml)-acetone (150 ml), and 47% aqueous HBr (41.0 g) was added to the solution. Then, a solution of NaNO2 (4.5 g) in water (10 ml) was added dropwise to the mixture at a temperature of not higher than 5° C. The whole was stirred at 5° C. for 15 minutes, and methyl acrylate (30.4 g) was added to the mixed solution, followed by warming at 38° C. Cuprous oxide (2.0 g) was added in small portions to the reaction solution with vigorous stirring, and stirring was continued until evolution of nitrogen gas stopped. After concentration, the residue was made basic with aqueous ammonia, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) concentrated to give methyl 2-bromo-3-{4-[2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl}propionate as a crude oily material (27.0 g, 98.5%). IR (Neat) cm-1 : 3300, 1735. NMR δ (ppm) in CDCl3 : 2.40(3H, s), 3.0(1H, broad), 3.11(1H, d.d, J=14 and 7 Hz), 3.39(1H, d.d, J=14 and 7 Hz), 3.68(3H, s), 4.0 to 4.5(3H, m), 5.05(1H, d.d, J=8 and 5 Hz), 6.0 to 7.2(4H, m), 7.4 (3H, m), 7.9(2H, m).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[C:11](=[O:14])([O-])[O-].[K+].[K+].O[C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[C:19]=1[C:20]#[N:21].Cl>CN(C)C(=O)C>[C:4]([C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([O:14][C:11]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=2[C:4]#[N:5])[C:19]=1[C:20]#[N:21])#[N:5]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(F)cccc1F
Reactant: N#Cc1c(O)cccc1O
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1c(F)cccc1Oc1cccc(Oc2cccc(F)c2C#N)c1C#N
Yield: 639.3 %

Procedure:
Into a 500 mL 3-neck round bottom flask equipped with stir bar, condenser, nitrogen inlet, and addition funnel was charged, 2,6-difluorobenzonitrile (50.0 g, 35.9 mmol), potassium carbonate (29.80 g, 28.8 mmol), and N,N-dimethylacetamide (DMAc, 100 mL). A solution containing 2,6-dihydroxybenzonitrile (12.2 g, 9.00 mmol) and DMAc (75 mL) was added dropwise over 6 hours at 70° C. The mixture was stirred at 70° C. for 72 hours. The reaction mixture was then poured into 2 M HCl (600 mL), and the precipitate was collected by filtration and washed with water. After air drying, the solid was dissolved with acetone (600 mL). The mixture was stirred at room temperature for 3 hours, followed by filtration to remove insoluble impurities. The filtrate was evaporated to dryness on a rotary evaporator. The resulting solid was extracted with hot toluene to afford 21.48 g (64.0%) of a brown solid (3CN trimer; 4 in FIG. 1), m.p. 216.1-218.4° C. 1H-NMR (DMSO-d6): 7.18-7.22 (m, 4H, Ar—H), 7.41-7.45 (t, 2H, Ar—H), 7.78-7.86 (m, 3H, Ar—H). 13C-NMR (DMSO-d6): 93.61, 93.80, 97.30, 110.58, 111.48, 112.40, 112.79, 114.86, 115.40, 136.77, 136.94, 137.04, 157.41157.76, 161.88, 164.44.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](Cl)=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22])=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(Cl)c1-c1nc(Cl)n(-c2ccc(Br)cc2)n1
Reactant: COCCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1nc(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 35.4 %

Procedure:
To a solution of 1-(4-bromophenyl)-5-chloro-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazole (Intermediate-3, 0.100 g, 0.257 mmol) in DMF (3.0 mL) was added 3-methoxypropan-1-amine (0.035 g, 0.386 mmol) and DIPEA (1.0 mL). The reaction mass was stirred at 80° C. for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.040 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.92 (d, J=5.4 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 3.28 (s, 3H), 3.56-3.64 (m, 2H), 5.69 (m, 1H), 7.06-7.15 (m, 1H), 7.22-7.49 (m, 2H), 7.54 (d, J=10.2 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H). MS (m/z): 441.19 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:31][CH3:32])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CO>[CH3:32][O:31][CH:5]([CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Yield: 90.3 %

Procedure:
0.184 g of 2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester (0.40 mmol) was dissolved in 1 ml of THF/MeOH=1/1 and treated with 0.670 ml of 3N NaOH. The reaction mixture was kept over night at RT and then quenched by pouring onto crashed ice/HCl. Twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product, which was purified by crystallisation from AcOEt/hexane to yield 0.158 g of the title compound as white solid, mp.121-122°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:26](O)(=O)[CH3:27]>>[CH2:26]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH3:23])[CH3:27]
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (16 mg, 0.049 mmol) and NaBH4 pellets (large excess, >10 equiv) in 5 mL acetic acid (0.01 M stirred at rt for 12 h, to afford 18 mg (100%) of (3R)-4-ethyl-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (18 mg, 0.050 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 2.5 mL acetic acid and 2.5 mL concentrated HCl and heated at 90° C. for 4 h to afford 9 mg (57%) of Compound 103, after purification by column chromatography (3:1 hexanes: EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 12.02 (bs, 1H), 7.12 (s, 1H), 7.04 (d, J=8.8, 1H), 6.97 (d, J=9.3, 1H), 4.10 (dd, J=10.2, 3.4, 1H), 4.02 (dd, J=10.3, 2.9, 1H), 3.53 (m, 1H), 3.43 (m, 1H), 3.32 (m, 1H), 1.22 (d, J=6.9, 3H), 1.18 (t, J=7.1, 3H).
Reaction SMILES: S(=O)(=O)(O)O.C(=O)=O.[N+:9]([O-:12])(O)=[O:10].[Cl:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:22]>C(Cl)Cl>[Cl:13][CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([N+:9]([O-:12])=[O:10])[CH:18]=[CH:17][N+:16]=1[O-:22]
Reactant: Cc1ccc[n+]([O-])c1CCl
Reactant: O=[N+]([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])cc[n+]([O-])c1CCl
Reaction time: 2 h

Procedure:
300 ml of concentrated sulphuric acid are added slowly while cooling with dry ice to 230 ml of concentrated nitric acid (68%; d=1.41), whereby the temperature of the mixture does not exceed 5°. A solution of 38.7 g (0.25 mol) of 2-chloromethyl-3-methylpyridine 1-oxide is added thereto and the mixture is stirred at 80° for 2 hours. The reaction mixture is poured on to a mixture of ice and methylene chloride, the aqueous phase is washed several times with methylene chloride and the methylene chloride solution is extracted with 10% sodium bicarbonate solution. The organic phase is dried with sodium sulphate and concentrated. The residue is recrystallized from ethyl acetate, there being obtained 2-chloromethyl-3-methyl-4-nitropyridine 1-oxide. The product exhibits a melting point of 126°-129°.
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].Cl.C(O)(C(F)(F)F)=[O:18]>O.O.CO>[OH:18][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 66 %

Procedure:
To a 250 mL flask were added 3-chloro-2-nitrobenzoic acid (10 g, 49.6 mmol) and a potassium hydroxide solution (40 g, 727 mmol) in water (70 mL). The thick slurry was heated to reflux for 12 hours. The solution was cooled in ice and cautiously brought to pH 3 with concentrated HCl. The aqueous mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The crude product mixture was dissolved in dichloromethane and the resulting yellow precipitate was filtered to afford Intermediate A-15A (6 g, 32.8 mmol, 66.0% yield). HPLC: RT=0.85 min (H2O/MeOH with TFA, Sunfire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS (ES): m/z=206 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.56-7.35 (m, 1H), 7.23 (dd, J=7.9, 1.5 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:22]([O:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH2:5][Cl:6])[O:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24][C:22](=[O:23])[C@H:18]([CH:19]([CH3:21])[CH3:20])[NH:17][C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)COC(=O)OCCl
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Chloromethyl chloroformate (1.50 mL, 16.6 mmol) was added to a solution of the alcohol (2.74 g, 8.12 mmol) from step (a) and pyridine (4.9 mL, 61 mmol) in 40 mL dry CH2Cl2, in an ice bath. After stirring for 1 h, the mixture was diluted with CH2Cl2 and washed successively with water, saturated NaHCO3, and brine. The organic phase was dried over anhydrous Na2SO4 and concentrated, coevaporating several times with toluene on a rotavapor. Flash column chromatography (silica, 2/1 petroleum ether-ethyl acetate) gave 3.31 g (95%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1COCC1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26](F)[CH:25]=1>CS(C)=O.O>[F:23][C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2cc(F)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-hydroxyphenyl)acetamide (1.00 g, 6.5 mmol) in DMSO (12 ml) was added 1M t-BuOK/THF solution (7.13 ml, 7.13 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 30 minutes under N2 flow. 1,3-Difluoro-5-nitrobenzene (0.89 ml, 7.8 mmol) was added at room temperature, and then the mixture was stirred at room temperature for 2 hours and at 50° C. for 2 hours under a N2 flow. The reaction mixture was cooled to room temperature, diluted with H2O, and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound as a pale brown solid, which was purified by washing with i-Pr2O to give the desired product as slightly brown crystal (1.73 g, 92%).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H-].[Na+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-hydroxybenzimidazole (4.00 g, 29.8 mmol) and tert-butyl bromoacetate (5.53 g, 28.3 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.31 g of a 60% dispersion in mineral oil, 32.8 mmol). The mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H2O (300 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:26])([F:27])[O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.460 g, 2.0 mmol), 3-(4-trifluoromethoxy-phenyl)-propylamine (0.438 g, 2.0 mmol), and K2CO3 (0.500 g, 3.6 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-trifluoromethoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.248 g, 37%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.97 (m, 2H), 2.70 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.09 (d, 2H), 7.23 (t, 2H), 7.42-7.56 (m, 3H), 7.86 (d, 1H). GC-MS: m/z 335 (M)+.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reaction time: 8 h

Procedure:
To a solution of [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride (82 mg, 0.22 mmol) in dichloromethane (2 ml) were added triethylamine (4.2 eq, 0.13 ml) and methanesulfonyl chloride (1.4 eq, 0.02 ml). The mixture was stirred overnight, diluted with dichloromethane and washed with 1N aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase extracted with dichloromethane, and the combined organic phases washed with brine and dried over magnesium sulfate. The crude product was purified by column chromatography on silica gel (1:0 to 5:1 dichloromethane/methanol eluant) to afford the title compound as an off-white solid. MS (m/z): 449.2 (M+H)+.