Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[C:13]2[C:18](=[CH:19][C:10]([O:9][CH2:8][CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(OCCC3CCCCN3)ccc12
Product: Clc1ncnc2cc(OCCC3CCCCN3)ccc12
Yield: 95 %

Procedure:
The intermediate 4-piperazinyl-7-(2-piperidylethoxy)quinazoline was prepared using the procedures as generally described in Scheme 1 as follows: Step A To the ethanol solution (15 mL) of 2-amino-4-fluorobenzoic acid (840 mg, 5.41 mmol) was added thionyl chloride (1.18 mL, 16.23 mmol) and the resulting suspension was refluxed overnight. The solvent was evaporated to the residue added EtOAc, washed with 10% NaOH solution, dried, filtered and evaporated to afford desired ethyl ester as a solid 981 mg, 82%). MS (ES) 184(M+H) Step B: To the formamide (6 mL) solution of ethyl-2-amino-4-fluorobenzoate (811 mg, 4.43 mmol) added ammonium formate (0.450 g, 7.14 mmol) and the reaction mixture was heated at 140° C. overnight. After cooling added water and ethyl acetate. The layers were separated, the EtOAc layer was dried, filtered and evaporated to give desired quinazolinone (1 g, quantitative). MS (ES) 165 (M+H) Step C: To the DMF solution (3 mL) of 1-piperidineethanol (0.689 mL, 5.18 mmol) at 0° C. added sodium hydride (0.518 g, 12.95 mmol) and the mixture was stirred for 30 min. To this cold solution added DMF solution (3 mL) of intermediate quinazolinone (0.284 g, 1.73 mmol, from Step B) and the mixture was heated at 75° C. overnight. The solvent was evaporated and the residue purified by RP-HPLC to afford desired product as a creamy solid (0.459 g, 97%) Step D: A mixture of 7-(2-piperidylethoxy)-4-quinazolinone (0.459 g, 1.68 mmol), from Step C) and POCl3 (5 mL) was heated at 75° C. overnight. After cooling excess POCl3 was removed by evaporation and the residue azeotroped with toluene to afford intermediate, 4-chloro-7-(2-piperidylethoxy)quinazoline (600 mg, 95%) Step E: To the isopropanol solution (10 mL) of 4-chloroquinazoline (0.615 g, 2.11 mmol, from Step D) added piperazine (0.727 g, 8.44 mmol) and heated the reaction for 4 h at 100° C. The solvent was evaporated and the residue purified by RP-HPLC to afford 4-piperazinyl-7-(2-piperidylethoxy)quinazoline as a white solid (0.630 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](/[CH:15]=[N:16]/[OH:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].ClN1C(=O)CCC1=O.[CH2:26]=[C:27]1[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:26][C:27]3([CH2:30][CH2:29][CH2:28]3)[O:17][N:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: C=C1CCC1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(/C=N/O)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C2=NOC3(CCC3)C2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl 3-bromo-5-[(E)-(hydroxyimino)methyl]benzoate (5.26 g, 17.5 mmol) in N,N-dimethylformamide (80 mL)) was added N-chlorosuccinimide (2.57 g, 19.3 mmol). The reaction mixture was heated to 50° C. After 1 h, the reaction was cooled to ambient temperature and methylenecyclobutane (6.49 mL, 70.1 mmol) was added. Triethylamine (12.2 mL, 88.0 mol) was added. The mixture was stirred at ambient temperature. After 10 min, saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→90% hexanes/ethyl acetate) gave the title compound (2.86 g). MS 366 (M).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[N:14]([CH:17]1[CH:20](CCO)[NH:19][C:18]1=[O:24])=[N+:15]=[N-:16].N1C=CC=CC=1>C(Cl)Cl>[N:14]([CH:17]1[CH:20]([CH2:2][CH2:3][O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[NH:19][C:18]1=[O:24])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=NC1C(=O)NC1CCO
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: [N-]=[N+]=NC1C(=O)NC1CCOC(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
Trifluoroacetic anhydride (0.2 mol) is added dropwise to an ice-cold, stirred solution of 3-azido-4-(2-hydroxyethyl)-azetidin-2-one (0.2 mol) and pyridine (0.21 mol) in methylene chloride (200 ml). The solution is stirred for 15 more min. at room temperature (25° C.), then washed with water, dried with magnesium sulfate, and filtered. Evaporation of the methylene chloride under vacuum leaves 3-azido-4-(2-trifluoroacetoxyethyl)azetidin-2-one.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: -78 °C

Procedure:
n-Butyllithium (1.6M, 5.3 mL, 8.37 mmol) was added to a solution of thiazole (450 mg, 5.23 mmol) in anhydrous ether (30 mL) stirred −78° C. under nitrogen. After 30 min tri-n-butylstannyl chloride (2.73 g, 8.37 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound a brown oily residue (2.0 g), which was used in the next step without further purification.
Reaction SMILES: [Cl-].[NH2:2][CH2:3][C:4]1([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[NH+:13][CH:14]=[CH:15][N:5]12.[C:23]([O-:26])(O)=O.[Na+]>C(Cl)Cl>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2([CH2:3][N:2]3[CH2:11][CH2:12][CH2:4][CH2:3][C:23]3=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3=[N:13][CH:14]=[CH:15][N:5]23)=[CH:17][CH:18]=1
Reactant: O=C([O-])O
Reactant: NCC1(c2ccc(Br)cc2)c2ccccc2-c2[nH+]ccn21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCCN1CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Reaction time: 0.5 h

Procedure:
To a stirred biphasic mixture of a solution of 5-(aminomethyl)-5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindol-1-ium chloride (25 mg) in CH2Cl2 (3 mL) and aqueous saturated NaHCO3 (3 mL) was added a solution of 5-bromobutyryl chloride (34 mg) in CH2Cl2 (1 mL). After 30 minutes layers were separated. Organic layer was dried over Na2SO4 and concentrated. The residue was then dissolved in DMF (0.5 mL) and NaH (12 mg, 60% in mineral oil) was added and stirred for 30 minutes. The reaction was then quenched with water, diluted with DMF and filtered. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 5-55% MeCN/water containing 0.1% TFA over 20 min at 20 mL/min) afforded title compound as a white solid. HRMS. Found, 408.0718; calcd for (M+H)+, 408.0706. 1H NMR (500 MHz, CDCl3): δ 7.98 (s, 1 H); 7.52-7.43 (m, 4 H); 7.39-7.34 (m, 2 H); 7.16 (d, J=1.54 Hz, 1 H); 7.13-7.09 (m, 2 H); 4.57 (d, J=14.04 Hz, 1 H); 4.38 (d, J=14.28 Hz, 1 H); 2.52-2.46 (m, 2 H); 2.09-1.95 (m, 2 H), 1.62 (p, J=7.47 Hz, 2 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].[Br:45]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:45][CH:22]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=3)[N:30]=2)=[CH:27][CH:28]=1)[CH2:21][NH:20][C:18](/[N:17]=[C:12]1\[S:13][CH2:14][C:15](=[O:16])[N:11]\1[C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCC(Br)c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Yield: 21.8 %

Procedure:
To a dry round-bottomed flask (20 mL) equipped with a magnetic stirrer and a reflux condenser were added (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.20 g, 0.32 mmol), carbon tetrachloride (1 mL), N-bromosuccinimide (0.057 g, 0.32 mmol), and azobisisobutyronitrile (0.0053 g, 0.032 mmol). The reaction was heated to reflux for 2 hours. The reaction was cooled. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a yellow oil (0.049 g, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH:11]([CH2:17][C:18](=O)C)C(OCC)=O)=[CH:5][CH:4]=1.[OH-:22].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][C:17](=[O:22])[CH:18]=2)=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(CC(C)=O)CC(=O)c1ccc(OC)cc1
Agent: [K+]
Solvent: O
Product: COc1ccc(C2=CC(=O)CC2)cc1
Yield: 64.4 %

Procedure:
To ethyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]-4-oxopentanoate (26.2 g) there was added 1000 ml of 1% aqueous potassium hydroxide solution, and the mixture was refluxed for an hour. Next, potassium hydroxide was added so that the aqueous potassium hydroxide solution reached a concentration of 10% (adding a solution of 146 g of potassium hydroxide in 200 ml of water), and the mixture was further refluxed for 2 hours. After allowing the reaction solution to cool, extraction was performed with ethyl acetate and water washing was then followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to produce crude crystals which were then washed with diethyl ether to give 11.4 g of 3-(4-methoxyphenyl)-2-cyclopenten-1-one (64.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[Mg].C1O[C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12]C1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13](=[O:12])[CH2:14][CH:15]=1
Reactant: Clc1ccccc1I
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CC=C(c2ccccc2Cl)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 7, using 9.5 grams (0.040 mole) of 1-chloro-2-iodobenzene, 1.1 grams (0.044 mole) of magnesium turnings, 6.2 grams (0.040 mole) of 1,4-cyclohexanedione mono-ethylene ketal, and about 100 mL of aqueous 10% hydrochloric acid in about 95 mL of tetrahydrofuran, yielding 1-(2-chlorophenyl)-1-cyclohexen-4-one.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:12]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][C:6]2[CH:17]=[CH:18][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[NH:11]1
Reactant: O=C1Nc2cc(CO)ccc2Oc2ccccc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)NC(=O)c1ccccc1O2
Reaction time: 0.17 h
Yield: 83 %

Procedure:
8-(hydroxymethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (0.241 g, 1 mmole) in acetonitrile was added to the molecular sieves (1 g) under N2 at room temperature then 4-methylmorpholine N-oxide (0.175 g, 1.5 mmole) was also added into the reaction mixture. After stirring the mixture for 10 minutes, tetrapropylammonium perruthenate (0.0176 g, 0.05 mmole) was added and the reaction followed by t.l.c. until complete. Dilute the reaction mixture with 10 ml of ethyl acetate and flashed it through a small silica gel column. Collected all the ethyl acetate that contains desired material, extracted the organic layer with 1N HCl and also washed it with brine. Dried the organic layer over sodium sulfate and filtered and concentrated. Obtained the desired compound (white solid) in 83% yield.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCCC1
Reactant: O=C(O)c1cccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1SC1CCCCC1
Reaction time: 0.5 h

Procedure:
2-Mercapto-nicotinic acid (0.5 g, 3.22 mmol) was dissolved in DMF (5 mL), and the solution was cooled to 0˜5° C. NaH (0.64 g, 16.11 mmol) was added slowly thereto, and the mixture was stirred at 0˜5° C. for 30 minutes. Bromo-cyclohexane (1.19 mL, 9.66 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and the residue was diluted with water. 3N HCl was used to adjust the pH of the solution to 2˜3, and the solution was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnn(CCc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1-phenethyl-1H-pyrazole (90 mg, 0.41 mmol) in ethyl acetate (2 mL) and ethanol (2 mL) was added 10% Pd—C (20 mg), and the resulting mixture was stirred under hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound as red oil. 1H NMR (CDCl3, 400 MHz): δ=2.36 (br s, 2H), 3.11 (t, J=7.5 Hz, 2H), 4.21 (t, J=7.5 Hz, 2H), 6.83 (d, J=0.8 Hz, 1H), 7.10-7.12 (m, 2H), 7.18 (d, J=0.8 Hz, 1H), 7.20-7.28 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][S:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:23]=1[C:29]([F:32])([F:31])[F:30].CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[C:23]([C:29]([F:30])([F:31])[F:32])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][S:15][CH2:16][CH3:17]
Reactant: CCSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCSC[C@H](Oc1cccc(Cl)c1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethylsulfanyl-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 mg, 40 μmol) was dissolved in DMF (174 μL). NaH (1.3 mg, 54.5 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorobenzotrifluoride (21.6 mg, 109 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (890 μL, 1.1 mmol) and stirred overnight at room temperature. The product was concentrated and the crude product was dissolved in 1:1 AcOH/H2O (1.5 mL) then purified by preparative HPLC to yield the title compound as a mono-TFA salt (3.4 mg, purity 97%). MS m/z: [M+H]+ calcd for C15H19ClF3NOS, 354.08. found 354.0.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12]Br)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CC(C)n1nc(Br)c2ccc(CN3CCN(C)CC3)cc2c1=O
Reaction time: 1 h
Yield: 80 %

Procedure:
4-Bromo-7-bromomethyl-2-isopropyl-2H-phthalazin-1-one (0.2 g, 0.56 mmol) was dissolved in tetrahydrofuran (THF) (1 ml), to this was added N-Methyl piperazine (0.14 g, 1.4 mmol) as a solution in THF (1 ml) and the reaction mixture was stirred for 1 hour. Whereupon LC-MS indicated complete consumption of starting material, the solvent was removed under vacuum and the residue was purified by flash column chromatography (elution: 90% ethyl acetate, 10% methanol) to give the title compound (0.17 g, 84% yield) as a light yellow solid.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:37][C:38]3[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:40][C:41]([CH3:48])=[CH:42][C:43]=3[C:44]([CH3:47])([CH3:46])[CH3:45])[O:21][C:22]3[C:23]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:24][C:25]([CH3:32])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Cc1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 0.9 grams of 4,4'-isopropylidenebisphenol (0.004 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.19 gram (0.008 mol) of sodium hydride, as a 50 weight percent dispersion mineral oil was added to the 4,4-isopropylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,6-di-t-butyl-4-methylphenyl) phosphorochloridite (4.0 grams, 0.008 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,6-di-t-butyl-4-methylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 3.72 grams. The molecular weight, FD/MS was 1164. NMR data obtained was, (CDCl3): 1.44 (S, 72H), 2.23 (S, 12H), 6.01 (d, J=8.4, 4H), 6.69 (d, J=8.4, 4H), 7.02 (S,8H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[O:25][CH:26]=1>>[CH3:35][C:32]1[CH:31]=[CH:30][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:23]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Product: Cc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1
Yield: 72.4 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) and (E)-4-chloromethyl-2-[2-(4-methylphenyl)ethenyl]oxazole(257 mg), the same reaction as Example 1 was carried out to yield the titled compound (331 mg) as colorless crystals.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2)(=O)C.[H-].[Na+].[OH:17][C:18]([C:40]([F:43])([F:42])[F:41])([CH2:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33])[CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[OH:17][C:18]([C:40]([F:41])([F:42])[F:43])([CH2:31][CH:32]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH3:33])[CH2:19][NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2
Reactant: Cc1ccc(S(=O)(=O)OCC(O)(CC(C)c2ccccc2)C(F)(F)F)cc1
Reactant: CC(=O)Nc1ccc2c(c1)COC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CC(O)(CNc1ccc2c(c1)COC2=O)C(F)(F)F)c1ccccc1
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
760 mg of 5-acetamido-phthalide in 20 ml of dimethylformamide is mixed at 0° C. with 144 mg of sodium hydride (80% in mineral oil), and, after 20 minutes, with 800 mg of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)-ester. After 16 hours at 60° C., the solvent is concentrated by evaporation in a vacuum, the residue is dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with cyclohexane/ethyl acetate (2:1), 266 mg of 5-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-phthalide, melting point 110° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5](OC2C=CC=CC=2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=2)=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)cc1Oc1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)cc1NCc1cccc(C(F)(F)F)c1

Procedure:
Using a procedure analogous to that described in Example 12, 3 gm (71.2% of theory) of the title compound, m.p. 140°-142° C. (recrystallized from ethanol), were obtained by stirring a mixture of 3.51 gm of 6-chloro-4-nitro-1,3-diphenoxy-benzene, 4 gm of 3-trifluoromethyl-benzylamine and 5 ml of dioxane for 20 hours at 100° C.