Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=1[S:44](Cl)(=[O:46])=[O:45])([O-:34])=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:32]([C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=1[S:44]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:46])=[O:45])([O-:34])=[O:33]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a 20 mL resealable vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.27 g, 0.67 mmol, Example 91, Step 1), DCM (6 mL), triethylamine (0.47 mL, 3.4 mmol) and finally 2,4-dinitrobenzenesulfonyl chloride (0.22 g, 0.81 mmol). The mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous NaHCO3. This was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 70% EtOAc/hexane) afforded 2-(4-(4-((2,4-dinitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.31 g) as a white solid.
Reaction SMILES: COB(OC)OC.C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35](=[O:37])[CH3:36]>O1CCCC1>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C@H:35]([OH:37])[CH3:36]
Reactant: CC(=O)c1cc(Cl)ccc1Br
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 85587.2 %

Procedure:
Trimethylborate (1.74 mL, 15.4 mmol) was added to a stirred solution of (S)-(−)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (3.24 g, 12.8 mol) in tetrahydrofuran (350 mL) at room temperature. After 1.25 h, borane-methyl sulfide complex (70.4 mL of a 2M solution in tetrahydrofuran, 0.141 mol) was added slowly and a gentle effervesence was observed. The resulting solution was cooled to approximately 0° C. and a solution of 1-(2-bromo-5-chlorophenyl)ethanone (3-3) (30.0 g, 0.128 mmol) in tetrahydrofuran (150 mL) was then added uniformly over 1 h. After the addition, the resulting mixture was allowed to warm to ambient temperature and aged overnight. The reaction mixture was concentrated under reduced pressure to approximately one quarter of its original volume, poured into 1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (9% ethyl acetate/hexanes as eluent) afforded 3-4 as a colorless solid (25.8 g; 98:2 S/R enantiomeric ratio).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9]>>[CH2:7]([OH:6])[C@@H:8]([C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The process of claim 1 wherein the acid employed in hydrolysis step (c) is sulphuric acid, the acidic solution of D-(+)-xylose is neutralized with base and the xylose is thereafter reduced in situ to provide xylitol.
Reaction SMILES: C([O-])=O.[NH4+].C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[O:18][C:19]([CH2:22][CH3:23])=[CH:20][N:21]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:22]([C:19]1[O:18][C:17]([CH2:16][CH2:15][NH2:14])=[N:21][CH:20]=1)[CH3:23]
Reactant: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCc1cnc(CCN)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ammonium formate (0.316 g, 5 mmol) is added to a solution of [2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester (step 3) (1.66 mmol) in methanol (15 ml) and 10% Pd on carbon (125 mg) is added under an inert atmosphere. The mixture is stirred at ambient temperature for 2 hours. The catalyst is removed by filtration and the filtrate is evaporated. The residue is diluted with dichloromethane, filtered to remove undissolved solid and the solvent is removed. The residue is dissolved in DCM and treated with 1M aqueous sodium hydroxide solution (5 ml). The organic extract is separated, dried (MgSO4), filtered and the solvent is removed. Crystallisation from ethyl acetate/dichloromethane affords the titled compound.
Reaction SMILES: C(=S)=S.[CH:4]1([P:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-:23].Cl.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(O)C>[Cl-:23].[CH:17]1([PH+:10]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCO
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Reaction time: 1 h

Procedure:
225 g cyclohexyl chloride and 750 ml diethylether are mixed. 100 ml of this mixture is added to 48.0 g magnesium turnings, and the reaction is started by adding 1 ml 1,2-dibromethane. The remaining cyclohexyl chloride mixture is added to the magnesium turnings within 3.5 hours under cooling at 38-40° C. The suspension is stirred again for one hour, cooled down to room temperature, and the cyclohexyl magnesium chloride solution is decanted from the remaining magnesium turnings. 156.7 g of the Grignard solution obtained in this manner is mixed with 120 ml tetrahydrofuran and slowly added to a mixture of 18.1 g phosphorus trichloride and 60 ml tetrahydrofuran at −20° C., and to an additional 100 ml tetrahydrofuran 20° C. After one hour of stirring at 37° C., the reaction mixture is added to 110 ml of a 15% ammonium chloride solution in water and 70 ml water at 20° C. The lower phase is separated and discarded. To the organic phase is added 10.1 g carbon disulfide. During this process, a reddish-brown precipitate is obtained, which is filtered off after 3 days, and washed three times each with 20 ml petrolether. After drying the solid at 35° C. under vacuum, 25.4 g (54%) of a tricyclohexylphosphine carbon disulfide adduct (CAS-Nr.: 4635-58-9) is obtained as a reddish-brown solid. From a mixture of 17.8 g of the tricyclohexyl phosphine carbon disulfide adduct and 100 ml ethanol, 80 ml of solvent is distilled off at 78-79° C. The oily residue is taken up in 80 ml tert-butylmethylether, and the tricyclohexyl phosphine solution is treated with hydrogen chloride at 20° C. The resulting suspension is diluted with 70 ml tert-butylmethylether. After complete precipitation of the tricyclohexyl phosphine as hydrochloride salt the solvent is evaporated off, and the solid residue is taken up in 100 ml tert-butylmethylether. The solid is filtered off, washed twice with 10 ml tert-butylmethylether each, and dried at 0.02 mbar. 13.1 g of a colorless hygroscopic solid is obtained. It contains 22.5% chloride so that it is assumed that in addition to the hydrochloride an additional equivalent hydrogen chloride is bound in the crystal (calculated for PCy3*2 HCl: 20.1% chloride). If a sample of the solid is left at open atmosphere, it will melt after one hour.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.O=P(Cl)(Cl)[Cl:20].[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[Na+]>ClCCl.O.C(OCC)C>[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[Cl:20][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[CH:4][CH:3]=[N+:2]([CH3:17])[CH3:1]
Reactant: CN(C)C=CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[N+](C)=CC=C(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]-2-propen-1-one (may be prepared as described in Intermediate 2) (1.49 g, 6.13 mmol) in dichloromethane (DCM) (6 ml) was cooled in an ice-water bath before the dropwise addition of POCl3 (0.571 ml, 6.13 mmol). The ice-water bath was removed and the reaction mixture stirred at room temperature for 3 hours. The solvent was removed under vacuum to yield a solid. To the solid was then added to an ice-cold solution of sodium perchlorate (3.75 g, 30.6 mmol) in water (8 mL) and diethyl ether (2 mL). The resulting suspension was stirred in an ice-water bath for 20 minutes. The solid was then collected by filtration, washed with ice-cold water (4 mL), dried by suction for 40 minutes then dried overnight under vacuum to yield the title compound as a solid (2.39 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:16][C:17](=[O:39])[C:18]3[C:23]([F:24])=[C:22]([S:25][C:26]4[S:30][C:29]([NH:31][C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=5)=[N:28][CH:27]=4)[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:41]([O:43][CH2:44][CH2:45][O:46][CH3:47])=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:16][C:17](=[O:39])[C:18]3[C:23]([F:24])=[C:22]([S:25][C:26]4[S:30][C:29]([NH:31][C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=5)=[N:28][CH:27]=4)[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:11][N:12]([C:41]([O:43][CH2:44][CH2:45][O:46][CH3:47])=[O:42])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(Cl)c(Cl)c5)CCNCC4)c3F)s2)c1
Reactant: COCCOC(=O)Cl
Product: COCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Following the procedure given for example 81, N-((4-(3,4-dichlorophenyl)piperidin-4-yl)methyl)-3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamide (compound example 48) was reacted with 2-methoxyethyl chloroformate to give the title compound. LC/MS (M+H)+: 705. Ret. time: 2.06 min. (Condition I); analytical HPLC Ret. time: 9.77 min (Condition H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[C:5]([OH:14])(=O)[CH:6]([CH:8]([C:10]([OH:12])=O)[OH:9])[OH:7]>[V].[Mn].[Fe].[Mo]>[N+:1]([O-:4])([OH:3])=[O:2].[O:7]=[CH:6][C@@H:5]([C@H:10]([C@@H:8]([C@@H:6]([CH2:5][OH:14])[OH:7])[OH:9])[OH:12])[OH:14]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [Fe]
Agent: [Mn]
Agent: [Mo]
Solvent: O=[N+]([O-])O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A variety of different processes for the oxidation of carbohydrates using nitric acid are known. For example, U.S. Pat. No. 2,380,196 (the '196 patent) describes the nitric acid oxidation of carbohydrates to dibasic acids, particularly tartaric acid. The '196 patent describes a cyclic process in which in each cycle, fresh carbohydrate and residue from a previous oxidation is oxidized with nitric acid. A catalyst, such as vanadium, manganese, iron and molybdenum, is employed to increase the yield of tartaric acid. According to the '196 patent, good yields are obtained when the molar ratio of nitric acid to glucose is 5:7.5, preferably 6:7.5. The '196 patent also describes that when mixing the ingredients, the temperature should be maintained at 20° C. or lower. Following mixing, the temperature is raised gradually or allowed to rise spontaneously to about 30° C. to 35° C. (this is the induction or heating-up stage). When the temperature reaches 30° C. to 35° C., an autocatalytic strong exothermic reaction called the “blow” sets in. The “blow” stage is maintained at a temperature of about 50° C. to 75° C., preferably 65-70° C. for anywhere from 45 to 120 minutes. The final temperature stage of the oxidation is the “fume-off” stage at which the last of the nitric acid is reacted and passed off as lower nitrogen oxides. During the “fume-off” stage, the reaction mixture is maintained at a high temperature somewhat below the boiling point of the mixture, at approximately 90° C. to 95° C. until nitrogen oxide is no longer detectable by the fumes. Oxalic and tartaric acids are recovered from the oxidized reaction mixture by direct precipitation and crystallization.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:17]=[CH:16][C:10]2[O:11][C:12]([F:15])([F:14])[O:13][C:9]=2[CH:8]=1.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C.[OH-].[Na+].Cl>C(OCC)C>[F:14][C:12]1([F:15])[O:11][C:10]2[CH:16]=[CH:17][C:7]([O:23][B:22]=[O:21])=[CH:8][C:9]=2[O:13]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: O=BOc1ccc2c(c1)OC(F)(F)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl lithium (1.15 mL, 1.95 mmol) in anhydrous diethyl ether (5 mL) was cooled to −78° C. under nitrogen. 5-bromo-2,2-difluoro-benzo[1,3]dioxole (180 mg, 0.760 mmol) in diethyl ether (0.80 mL) was added, and the reaction was stirred for 1 h at −78° C., followed by the addition of triisopropylborate (0.37 mL, 1.60 mmol) under nitrogen. The reaction allowed to stir for 1.5 h while allowing to warm to ambient temperature. The reaction was poured into 4 N aqueous sodium hydroxide (5 mL), stirred, and adjusted to pH ˜1 by the dropwise addition of concentrated aqueous hydrochloric acid, and the product extracted with ethyl acetate (10 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and the solvent removed under vacuum to afford 140.2 mg of I-187 as a brown solid, which was taken on without further purification.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:47])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:47]=[O:16])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C)c3c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1
Temperature: 76 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
AIBN (22.2 mg, 0.135 mmol) was added to a stirring solution of NBS (88 mg, 0.49 mmol) and methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)benzoate (163 mg, 0.451 mmol) in CCl4 (40 mL) and was heated to 76° C. The mixture was allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (63 mg, 0.54 mmol) and subjected to MW irradiation (150° C.) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2× followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (34 mg, 0.091 mmol, 20% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.31 (1H, s), 8.79 (1H, d, J=2.44 Hz), 8.74 (1H, d, J=2.44 Hz), 8.28 (1H, s), 8.16-8.25 (2H, m), 8.00-8.13 (2H, m), 7.72 (1H, t, J=7.78 Hz), 7.49-7.57 (2H, m), 3.92 (3H, s). LC-MS retention time: 1.72 min., m/z (MH+): 376. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[B:17](OC)([O:20]C)[O:18]C.Cl>O1CCCC1.O.II>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:17]([OH:20])[OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
62 g (0.236 mol) of 3-benzyloxybromobenzene, 6.64 g (0.277 mol) of magnesium and 0.3 g of iodine are reacted in 800 ml of tetrahydrofuran at 60° C. for 2 hours to give the solution of the corresponding Grignard compound, which is subsequently added dropwise to a solution, cooled to 0° C. of 28.77 g (0.277 mol) of trimethyl borate in 300 ml of tetrahydrofuran. The mixture is stirred at 0° C. for 1 hour, 74 ml of 37% strength hydrochloric acid in 300 ml of water are added, and the reaction mixture is subsequently partitioned between water and ether. The organic phase is washed twice with water, dried over sodium sulfate, evaporated and recrystallized from hexane, giving 33.65 g of 3-benzyloxybenzeneboronic acid. ##STR13##
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:14]([N:16]1[CH2:20][C:19]([F:22])([F:21])[C:18]([F:24])([F:23])[CH2:17]1)=[O:15])[C@H:10]([CH3:13])[CH2:11][CH3:12])(C)(C)C>>[NH2:8][C@@H:9]([C@H:10]([CH3:13])[CH2:11][CH3:12])[C:14]([N:16]1[CH2:20][C:19]([F:21])([F:22])[C:18]([F:24])([F:23])[CH2:17]1)=[O:15]
Reactant: CC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)C(F)(F)C1
Agent: Cl
Product: CC[C@@H](C)[C@H](N)C(=O)N1CC(F)(F)C(F)(F)C1

Procedure:
(2S,3R)-2-amino-3-methyl-1-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-pentan-1-one was prepared by HCl treatment of [(1S,2R)-2-methyl-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester as analogously described in Step 2 of Example 1. (mp>250° C.).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[CH2:21]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:28])=[O:3])=[O:8])[CH:13]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid (0.7 g, 0.00237 mol) in DMF (4 mL) was added DIPEA (1.226 g, 0.00948 mol), HOBt (0.4 g, 0.0029 mol) and EDCI.HCl (0.57 g, 0.0029 mol) at ambient temperature. After 5 minutes glycine ethyl ester hydrochloride (0.347 g, 0.0024 8 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (65% ethyl acetate in hexane) afforded 0.66 g (73%) of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester. To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester (0.65 g, 0.00171 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL) was added LiOH.H2O (0.215 g, 0.00512 mol) at ambient temperature. The resulting mixture was stirred overnight. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 0.56 g of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid. LCMS: 353.11 (M+1)+, 60.4%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[C:28]1([N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:10][CH2:11]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:25])[CH2:38][CH2:39]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: NC1CCN(c2ccccc2)CC1
Agent: [Li+]
Product: O=C(NC1CCN(c2ccccc2)CC1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (70 mg, 0.18 mmol) and 1-phenylpiperidin-4-amine (39 mg, 0.22 mmol). Yield: 34 mg (34%).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](=[S:17])[S-:16])[CH3:13].C([NH2+]CC)C>C(=S)=S>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](=[S:16])[S:17][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CCN(CC)C(=S)[S-]
Agent: CC[NH2+]CC
Solvent: S=C=S
Product: CCN(CC)C(=S)SC(C[N+](=O)[O-])c1ccccc1

Procedure:
As in Example 17, reaction of β-nitrostyrene with diethylammonium diethyldithiocarbamate in the presence of carbon disulfide gave α-(nitromethyl)benzyl diethyldithiocarbamate melting at 81° C.-82.5° C. when recrystallized without heating from acetone-2-propanol solution.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2s1)C1CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
A suspension of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.17 g, 5.00 mmol), 1,2-difluoro-4-nitrobenzene (0.96 g, 6.00 mmol) and cesium carbonate (3.26 g, 10.0 mmol) in dimethyl sulfoxide (10 mL) was stirred at 50° C. for 5 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (1.22 g, 65%) as a pale-yellow solid.