Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[N:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]([C:63](O)=[O:64])=[N:55][CH:54]=1>C(Cl)Cl>[F:28][C:26]([F:29])([F:27])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[C:15]([N:9]1[CH2:10][CH2:11][C@H:12]([NH:14][C:63]([C:56]2[C:57]3[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=3)[N:53]=[CH:54][N:55]=2)=[O:64])[CH2:13][C@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(O)c1ncnc2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1)c1ncnc2ccccc12

Procedure:
Analogously to Example 1, 252 mg (1.45 mmol) of (2R,4S)-2-benzyl-1-(3,5-bis-trifluoromethyl-benzoyl)-4-piperidineamine in 5 ml of methylene chloride are reacted with 368 mg (1.45 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride, 440 mg (4.35 mmol) of triethylamine and 566 mg (1.32 mmol) of quinazoline-4-carboxylic acid. The title compound is obtained in the form of white crystals. M.p.: 92-172° C.; TLC: hexane/ethyl acetate (1:1) Rf =0.37, FD-MS: M+ =586; [alpha]D=+1.3 (c=0.98, methylene chloride). ##STR16##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])C#N)=[CH:4][CH:3]=1.OS(O)(=O)=O.O.[C:25]([O-:28])([O-])=[O:26].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[C:25]([OH:28])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCCC1CCC(C#N)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCCC1CCC(C(=O)O)c1ccc(Br)cc1

Procedure:
The oily residue of 2-(4-bromo-phenyl)-4-(1-methyl-pyrrolidin-2-yl)-butyronitrile was hydrolyzed by refluxing for 2 h with concentrated H2SO4 and water (38:28) (4 mL). The mixture was neutralized with Na2CO3, then MeOH (20 mL) was added. The solid was filtered and washed with MeOH (3×10 mL). The combined methanol solution was evaporated to give an oil product. MS: calc'd 326 (MH+), exp 326 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27](=O)[CH3:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27](=[S:42])[CH3:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Solvent: COCCOC
Product: CC(=S)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of N-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]acetamide and 2 mmol of Lawesson's reagent were stirred in 2 ml of DME at 80° C. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-{[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]amino}ethane-1-thione.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.2, 206 mg, 0.5 mmol) and (S)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol) were dissolved in iPrOH (0.5 mL). DIPEA (192 μL, 1.1 mmol) was added and the RM mixture was heated at 140° C. for 1 h in a pressure safe vial. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give residue that was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 20% to 100% EtOAc). Trituration with n-heptane, filtered and dried afforded the title compound as a white crystalline powder. HPLC (Condition 4) tR=5.89 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=464.1 [M+H]+.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[H-].[Na+].[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>CN(C=O)C.CN1C(=O)N(C)CCC1>[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:26]([O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: OCC#CCO
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCN(C)C1=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)C)cn3)ncnc2OCC#CCO)cc1
Temperature: 90 °C
Reaction time: 80 h
Yield: 35.3 %

Procedure:
To a solution of 21.5 g of 2-butyne-1,4-diol in 200 ml of DMF and 50 ml of DMPU was added in portions 5.5 g of NaH 55% in mineral oil. After the evolution of gas had ceased 5.04 g of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was stirred for 80 h at 90° C. The solvent was removed in vacuo and the residue was partitioned between 300 ml of 10% aqueous citric acid and 300 ml of ethyl acetate. The aqueous phase was extracte two more times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate from 1:1 to 1:4 to give 2.0 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a brown solid. LC-MS: tR=4.64 min, [M+1]+=453.28, [M−1]−=451.40.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]N(C)P(=O)(N(C)C)N(C)C.CI>O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][CH3:25])([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 72.5 g of 1-benzyl-4-anilino-4-piperidinemethanol, 11 g of sodium hydride (50% in mineral oil) and 427 g of hexamethylphosphoric triamide is stirred. Then 33 g of methyl iodide is added dropwise to the reaction mixture and the mixture is stirred overnight. The mixture is added to 2500 ml of water, extracted with six 500 ml portions of toluene, dried over anhydrous sodium sulfate and flash evaporated to give an oil. The oil is purified in a Waters Associates Prep LC/System 500, using a PrepPAK-500/SILICA column (40% ethyl acetate in hexane) to give 1-benzyl-4-methoxymethyl-4-anilinopiperidine.
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.O1CCCC1.C(OCC)(=O)C.Cl>O1CCCC1>[CH3:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([CH:14]1[CH2:16][CH2:15]1)=[O:12]
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1ccccc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-methoxy-2,N-dimethylbenzamide (3.55 g) obtained in Step 1 in tetrahydrofuran (40 ml) was added dropwise a solution of 1M cyclopropylmagnesium bromide-tetrahydrofuran (29.7 ml) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added a 4N hydrogen chloride-ethyl acetate solution (10 ml), and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]=O.[OH-].[Na+].O.[CH3:18][C:19]([CH3:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]=[CH:18][C:19](=[O:20])[CH3:21]
Reactant: Cc1nc(Cl)c(C=O)c2c1CCCC2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(Cl)nc(C)c2c1CCCC2

Procedure:
3-Chloro-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carboxaldehyde (4.0 g) was stirred with a few drops of a 2% aqueous sodium hydroxide solution in aqueous acetone (1:2 v/v; 20 ml) at room temperature for 4 hr. the mixture was poured into water which was then extracted with the diethyl ether. The residue obtained after evaporation of the dried (MgSO4) organic extract was purified by column chromatography over silica with dichloromethane elution to give 1-(3-chloro-1-methyl-5,6,7,8-tetrahydroisoquinolin-4-yl)-but-1-en-3-one as white crystals, mp 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[Br:1][C:2]1[C:3]([C:9]([F:10])([F:11])[F:12])=[CH:4][C:5]([OH:8])=[C:6]([N+:18]([O-:20])=[O:19])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)c(C(F)(F)F)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a 0° C. mixture of 4-bromo-3-(trifluoromethyl)phenol (Apollo, 10.8 g, 44.8 mmol) in AcOH (40 mL) was added concentrated sulfuric acid (1.5 mL) followed by fuming nitric acid (5.2 g) and the mixture was stirred for 30 min. Additional concentrated sulfuric acid (9 mL) was added and the temperature was allowed to rise to ambient temperature and stirred for 3 h at rt. The mixture was poured into ice water (500 mL) and the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10-20% EtOAc in petroleum ether) to give 4-bromo-2-nitro-5-(trifluoromethyl)phenol (4.7 g, 36%) as yellow oil. 1H NMR (DMSO-d6, 400 MHz): δ 12.0 (brs, 1H), 8.31 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:15][CH3:16])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O.N>C(Cl)(Cl)Cl>[Cl:19][CH2:14][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[CH2:15][CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C
Agent: N
Solvent: ClC(Cl)Cl
Product: CCc1oc(-c2ccc(Cl)cc2)nc1CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.00 g (4.21 mmol) of the compound from example 36A is dissolved in 15 ml of chloroform, and 1.4 ml (15.15 mmol) of phosphoryl chloride is added carefully. The mixture is heated at reflux and stirred at this temperature for 30 min. The mixture is then cooled to 0° C. and made weakly basic using aqueous ammonia. The reaction mixture is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are washed once with 10 ml of water and then dried over magnesium sulphate. The solvent is removed on a rotary evaporator, and the residue is dried under reduced pressure in a drying cabinet. Without further purification, the product obtained in this manner is used for the subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH2:14]Cl.[I-:16].[Na+]>CC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH2:14][I:16]
Reactant: Fc1c(C(F)(F)F)cc(Cl)c(CCl)c1F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Fc1c(C(F)(F)F)cc(Cl)c(CI)c1F
Yield: 99.7 %

Procedure:
Treat a solution of 1-chloro-2-chloromethyl-3,4-difluoro-5-trifluoromethyl-benzene (1.0 g, 3.8 mmol) in acetone (10 mL) with sodium iodide (2.8 g, 19 mmol) and stir the reaction 1 hr at room temperature. Dilute the reaction in EtOAc (50 mL) and filter. Concentrate the filtrate to afford 1.35 g (100%) of product. 1H NMR (d6-CDCl3) δ 7.39 (d, 1H, J=5.7 Hz), 4.46 (d, 2H, J=2.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].N[CH2:15][CH:16]1[CH2:20][CH:19]([O:21][CH3:22])[O:18][CH:17]1[O:23][CH3:24]>C(Cl)Cl>[CH3:24][O:23][CH:17]1[CH:16]([CH2:15][NH:13][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH2:20][CH:19]([O:21][CH3:22])[O:18]1
Reactant: COC1CC(CN)C(OC)O1
Reactant: NC(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COC1CC(CNC(=O)Nc2ccc([N+](=O)[O-])cc2)C(OC)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
25.1 g (0.15 mol) of 4-nitrophenylurea were dissolved in 150 ml of methylene chloride. The solution was filtered and then 27.0 g (0.17 mol) of 3-aminomethyl-2,5-dimethoxytetrahydrofuran dissolved in 150 ml of methylene chloride were added dropwise at 0° C. The mixture was stirred at room temperature for 1 h and the resulting precipitate was filtered off with suction. 45 g (91%) of the product were obtained. Melting point 172°-174° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:24][CH2:23][C:22]([O:28][P:29](=[O:32])([OH:31])[OH:30])([CH2:25][O:26][CH3:27])[CH2:21][CH2:20]3)=[C:14]([F:33])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].C(O)(=O)C.[Ca+2:42]>>[Ca+2:42].[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:24][CH2:23][C:22]([O:28][P:29](=[O:30])([O-:31])[O-:32])([CH2:25][O:26][CH3:27])[CH2:21][CH2:20]3)=[C:14]([F:33])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COCC1(OP(=O)(O)O)CCN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: COCC1(OP(=O)([O-])[O-])CCN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl)ester (5.0 g, 0.010 mol) anhydrous methanol (50 ml) at 0-5° C., under argon, was added powdered anhydrous calcium acetate carbonate (1.58 g, 0.010 mol). The reaction mixture was stirred at 5-10° C. for 2 hours. The ice-bath was removed and the stirring continued further at 30-35° C. for 1 hour. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. Acetone (25 ml) was added to the residue and triturated. The solvent was decanted. This procedure was repeated twice with acetone (50 ml). Acetone after the third trituration was decanted and the residue dried under reduced pressure to obtain the product as white solid, 5.0 g, in 91% yield, Mp >200° C. (dec); MF: C19CaH24F2N3O8P. Aqueous solubility at pH 7 was ˜0.5 mg/ml.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:11]O)=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[H][H]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: ON=C1CCc2cc(N3CCOCC3)c(F)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 27.2 %

Procedure:
A solution of 6-fluoro-5-morpholin-4-ylindan-1-one (200 mg), hydroxylammonium chloride (102 mg) and sodium acetate (241 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 218 mg of 6-fluoro-5-morpholin-4-ylindan-1-one oxime. Next, 10% palladium-carbon (water content: 48%, 200 mg) was added to a solution of the resulting 6-fluoro-5-morpholin-4-ylindan-1-one oxime (218 mg) in ethanol (5.0 mL), and the reaction solution was stirred in a hydrogen atmosphere (0.4 MPa) at room temperature for 9 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 56.0 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:10](=[N:1]/[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1)\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(/N=C/c2ccccc2)cc1F
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred solution of 4-amino-2-fluorophenol (1.27 g, 10 mmol) in 30 mL of toluene at room temperature under nitrogen in a Dean Stark apparatus was added benzaldehyde (1.01 ml, 10 mmol) followed by p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The mixture was heated to reflux for 4 hours. The reaction was cooled to room temperature and a solid crystallized out of the reaction mixture. The mixture was cooled to 0° C. and then filtered and the solids rinsed with toluene. The isolated tan crystals were dried under high vacuum (1.5 gm, 70% yield).
Reaction SMILES: C([NH:18][C:19]([C@@H:21]1[CH2:25][C@H:24]([F:26])[CH2:23][NH:22]1)=[O:20])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>C(NCC)C.ClCCl>[F:26][C@@H:24]1[CH2:23][NH:22][C@H:21]([C:19]([NH2:18])=[O:20])[CH2:25]1
Reactant: O=C(NC(=O)[C@@H]1C[C@H](F)CN1)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCNCC
Product: NC(=O)[C@@H]1C[C@H](F)CN1
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
(2S,4S)—N-Fmoc-4-fluoropyrrolidine-2-carboxamide (Fa) (354 mg, 1 mmol) was dissolved in 12 ml of a 1:1 mixture of diethylamine and dichloromethane at room temperature. After the mixture was stirred for 1.5 h, all the volatiles are removed. To the obtained residue was added ethyl acetate (10 ml) and water (5 mL), and the mixture was stirred and left. The aqueous layer was separated, washed with 10 ml of ethyl acetate, and evaporated to dryness by a vacuum pump. The residue was dissolved in 2 ml of isopropanol and mixed with ether. The precipitated solid was washed with ethyl acetate and dried in vacuo, giving 118 mg (yield 90%) of (2S,4S)-4-fluoropyrrolidine-2-carboxamide as crystals: 19F-NMR (D2O) δ −172.40 (m, 1 F): 1H-NMR (D2O) δ 2.0-2.5 (m, 2H), 2.95 (dd, 1H, J=38.8, 3.42 Hz), 3.20 (dd, 1H, J=21.6, 1.7 Hz), 3.0 (dd, 1H, J=10.3, 4.1 Hz), 5.16 (dt, 1H, J=53.2, 4.1 Hz): 13C-NMR (D2O) δ 37.52 (d, J=21.7 Hz), 52.68 (d, J=23.1 Hz), 58.49, 94.63 (d, J=171.2 Hz, 4-C), 177.71 (CO).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([CH3:17])[CH2:13]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H]1CNCCN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C)C1

Procedure:
To a solution of 3.0 g (R)-2-Methyl-piperazine-1-carboxylic acid benzyl ester hydrotrifluoroacetate in 17 ml dichloromethane were added at 0° C. 3.5 ml triethylamine and 1.2 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation purified by chromatography on silica using heptane/ethyl acetate 2/1 as eluent. Yield: 3.0 g.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.Cl.[NH2:21][C@H:22]([CH3:26])[C@H:23]([OH:25])[CH3:24].[Na+].[Cl-]>C(#N)C>[Cl:8][C:9]1[N:14]=[C:13]([NH:21][C@H:22]([CH3:26])[C@H:23]([OH:25])[CH3:24])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C[C@@H](N)[C@@H](C)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H](O)[C@@H](C)Nc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
4.8 ml (34.8 mmol) of triethylamine are added dropwise to 3.78 g (17.4 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 2.19 g (17.4 mmol) of (2R,3R)-3-amino-butan-2-ol hydrochloride in 70 ml of acetonitrile at 0° C. The mixture is slowly warmed to room temperature and then stirred for 48 hours. The mixture is added to half-concentrated NaCl solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is purified by HPLC. 1.45 g (5.4 mmol; 31% yield) of the product are obtained.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:17][OH:18].C[O-].[Na+].CCOCC>CO>[OH:18][N:17]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NO
Reactant: O=C(O)CCC(=O)CCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(O)CCC(CCc1ccccc1)=NO
Yield: 89.7 %

Procedure:
The ketone 99 (3.0 g, 13.6 mmol) and hydroxylamine hydrochloride (1.98 g, 27 mmol) were dissolved in methanol (20 mL) then sodium methoxide (2.9 g) was added. The solution was stirred and refluxed for 2 hr then cooled. Ether was added and the organic layer was washed twice with 2M HCl, brine and dried over MgSO4. Removal of solvent gave the oximes 100 (2.7 g 90%) as a mixture of E:Z isomers in the ratio 1.5:1.