Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1.[F:13][C:14]([F:22])([F:21])[C:15]([C:17]([F:20])([F:19])[F:18])=[O:16]>O1CCCC1>[F:13][C:14]([F:22])([F:21])[C:15]([OH:16])([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)[C:17]([F:20])([F:19])[F:18]
Reactant: C=Cc1ccc(Br)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A 5 L three-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple thermometer, addition funnel with a nitrogen bubbler, and a cooling bath container. The nitrogen-flushed flask was charged with 200 mL anhydrous tetrahydrofuran, 67.5 g (2.77 mol) of magnesium turnings, and a small crystal of iodine. The addition funnel was charged with 500 g (2.73 mol) of freshly distilled 4-bromostyrene. Approximately 10 mL of 4-bromostyrene was added to the flask with vigorous stirring. As soon as the Grignard reaction was started, the flask was charged with an additional 1800 mL of anhydrous tetrahydrofuran. The remainder of the 4-bromostyrene was added dropwise to the stirred reaction at such a rate as to maintain the reaction at a temperature of 40° C. while cooling the flask with an ice/water bath. The addition required 2 hours, after which the cooling bath was removed and the reaction stirred another 1.5 hours. The reaction mixture was then cooled to 0° C. with a dry-ice/acetone bath, and the addition funnel was replaced with a gas inlet tube connected with appropriate back-flow safeguards to a cylinder of hexafluoroacetone. Hexafluoroacetone gas was passed into the reaction mixture over 2 hours while maintaining the reaction temperature below 15° C. with the cooling bath. After the reaction exotherm diminished, the gas addition was stopped. A total of 480 g (2.89 mol) hexafluoroacetone had been added. The cooling bath was removed and the reaction stirred overnight. The reaction was maintained below 10° C. as 500 mL of 6 N hydrochloric acid was added dropwise with stirring over 1 hour. The organic layer was separated and the aqueous layer extracted with three 300 mL portions of diethyl ether. The combined organic layers were washed with three 300 mL portions of brine, dried over sodium sulfate, filtered, and evaporated on the rotary evaporator. The residue was distilled under vacuum collecting fractions 58-78° C. at a vacuum of 800-300 mTorr. A total of 589 g (74%) of product containing approximately 15 mol % complexed tetrahydrofuran (THF) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[C:17]([O-])(=[O:19])[CH3:18].[Na+].O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:12][C:13](=[O:15])[CH2:14]1
Reactant: CC(=O)[O-]
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2Br)C1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC1=CC(=O)CC(c2ccc(F)cc2Br)C1
Temperature: 100 °C

Procedure:
The title compound was prepared reacting 5-(2-bromo-4-fluoro-phenyl)-cyclohexane-1,3-dione (example 1/f stage 2) (5 g, 17.4 mmol) and sodium acetate (1.42 g, 17.4 mmol) in neat acetic anhydride (30 ml). The reaction mixture was heated for 2 h at 100° C. and allowed to cool to ambient temperature whereupon water (60 ml) was added. The mixture was extracted with EtOAc (2×80 ml) and the combined organic layers washed with sat aq sodium bicarbonate until the pH was neutral. Then the organics were dried over sodium sulphate, filtered, and the solvent removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4Cl)nc23)CC1
Yield: 92.4 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0067 mL (0.053 mMol) 2-chlorobenzoyl chloride, 0.015 gm (91%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][NH:2][C:3](=S)[NH:4][NH2:5].[CH2:7]([O:9][C:10](=[O:16])[CH:11](Cl)[C:12]([CH3:14])=O)[CH3:8]>C1COCC1>[CH2:7]([O:9][C:10]([C:11]1[C:12]([CH3:14])=[N:5][NH:4][C:3]=1[NH:2][CH3:1])=[O:16])[CH3:8]
Reactant: CNC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)n[nH]c1NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A mixture of 1 g of 4-methylthiosemicarbazide (9.51 mmol) and 1.565 g of ethyl-2-chloro-acetoacetate (9.51 mmol) in THF (20 ml) was stirred for 30 min at RT and then heated to reflux for 1 h. The yellow solid that precipitated was filtered off, washed with acetone and then dissolved in hot (95° C.) water. The precipitating sulfur was filtered off, the aqueous solution was cooled to 0° C., vigorously stirred and 5 ml of an aqueous ammonium hydroxide solution (25%) were added. A white precipitate formed and the suspension was stirred for an additional hour at RT. The precipitate was then filtered off and dried to give 1.04 g (60%) of 3-methyl-5-methylamino-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid. MS (ISP) 184.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([C:30]#N)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:32])[CH2:6][CH2:5]2.C[Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[CH2:13][C@@H:12]1[CH3:32])[CH2:6][CH2:5]2
Reactant: C[C@H]1CN(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2cc(Br)ccc21
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of tert-butyl 4-[(3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylate (0.32 g, 0.64 mmol) in THF (2 mL) was added a 3 M solution of methylmagnesium bromide (1.1 mL, 3.3 mmol). After stirring at room temperature overnight, the solution was concentrated. Purification on silica (2:1 hexane/EtOAc) afforded the title compound (0.25 g). MS calculated for C25H37BrN3O2: (M+H)+ 491. found 491.2, 494.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([OH:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[F:13][C:2]([F:1])([F:12])[CH:3]([O:11][C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: OC(CN1CCOCC1)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cc1)OC(CN1CCOCC1)C(F)(F)F
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
In a round bottomed reaction vessel, under argon, was placed 0.239 g (1.2 mmol) of 1,1,1-trifluoro-3-morpholin-4-yl-propan-2-ol and 0.203 g (1.3 mmol) of 4-chlorophenyl isocyanate. The vessel was capped, set in a bath at 85° C. and stirred. After 90 min, the mixture was cooled. The crude material was purified by chromatography on silica gel, eluting with hexanes-ethyl acetate (90:10), to give 0.250 g (59%) of (4-chloro-phenyl)-carbamic acid 2,2,2-trifluoro-1-morpholin-4-ylmethyl-ethyl ester as a white crystalline solid. (M+H)+=353 m/e.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[NH:20][C:14]2[N:15]=[CH:16][N:17]=[C:18](O)[C:13]=2[CH:12]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[C:13]2[CH:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[NH:20][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]c(-c3ccc4ccccc4c3)cc12
Product: Clc1ncnc2[nH]c(-c3ccc4ccccc4c3)cc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Under a protective gas, 198.5 mg (0.76 mmol) of 6-(naphth-2-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ol in 3 ml of phosphorus oxychloride are heated at boiling for 5 hours. The reaction mixture is poured into ice-water and stirred for 1 hour to complete the reaction. The crystals are filtered off and washed with water. Dissolving the crude product in THF/methanol, filtering through active carbon, concentrating the filtrate by evaporation, stirring the residue in isopropanol and washing with hexane yield the title compound; m.p. 268-269° C. (decomposition); FAB-MS: (M+H)+ =280.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][Cl:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:38].[CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:28])[C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:37][C:34]5[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=5)=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)[C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2]
Reactant: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(O)cc4)cc3)ccn2c1=O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(OCc5ccncc5)cc4)cc3)ccn2c1=O
Yield: 83.6 %

Procedure:
A solution of 6-ethyl-1-[4-(4-hydroxybenzoyl)-benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (126 mg), 4-picolyl chloride hydrochloride (154 mg) and potassium carbonate (274 mg) in DMF (7 ml) was stirred at room temperature for 17 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol =19:1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (140 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([NH2:11])=[N:10][C:5]2=[CH:4][CH:3]=1.CCN(CC)CC.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])#[CH:25]>C1(C)C=CC=CC=1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[C:24]#[C:25][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([NH2:11])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: CC(C)(C)Cn1c(N)nc2ccc(Br)nc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)Cn1c(N)nc2ccc(C#Cc3ccc(F)cc3F)nc21
Yield: 40.1 %

Procedure:
Combine 5-bromo-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine (30.00 g, 105.94 mmol), Et3N (60 mL), and Pd(OAc)2[P(Ph)3]2 (3.97 g, 5.30 mmol) in toluene (150 mL) and heat the resulting mixture to ˜65° C. under nitrogen. Add 1-ethynyl-2,4-difluoro-benzene (21.95 g, 158.92 mmol) in toluene (30 mL) dropwise to the above mixture, and then heat the resulting reaction mixture at 80° C. for 3 h. Cool the reaction to 25° C. and quench with saturated aqueous NH4Cl (300 mL). Stir the resulting reaction mixture at room temperature for 20 minutes, then filter, washing the solid with H2O and drying under vacuum filtration for 30 minutes. Slurry the solid in MTBE (200 mL), then filter and rinse with MTBE (50 mL). Dry the recovered solid under vacuum filtration to provide 14.47 g of the title compound as a light-yellow solid.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(O)(C)C.ClCCl>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1
Reactant: COc1ccccc1-n1ccnc1OCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Oc1ccccc1-n1ccnc1OCC1CCN(Cc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
2.7 ml of a solution of hydrochloric acid (0.5 N) in isopropanol are slowly added, at 0° C. to a solution of 0.5 g (1.32 mmol) of 1-(2-methoxyphenyl)-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole in 15 ml of dichloromethane. The solvents are removed by evaporation and then the product is taken up in 15 ml of dichloromethane. The solution is cooled to −15° C. and 1.05 ml of boron tribromide is slowly added. The reaction medium is stirred for 3 h 30 min while allowing the temperature to return to 20° C. The reaction mixture is poured over ice and sodium bicarbonate is added until a pH=8 is obtained. After separating upon settling out, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and then with brine. The medium is dried over magnesium sulphate, filtered and concentrated. The expected compound is purified on a silica gel, eluting with a 99:1 to 93:7 CH2Cl2/CH3OH mixture. 0.355 g of product is obtained. (Yield 74%)
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[CH:17][N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>>[C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[C:17]([Br:21])[N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Product: O=[N+]([O-])C(Br)=C1SCCCN1S(=O)(=O)Cc1ccccc1

Procedure:
was prepared, as a yellow solid, m.p.: 143° C. (with decomposition), by treating (5A) with N-bromosuccinimide according to the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C-:18]#[N:19].[Na+]>CN(C=O)C>[C:18]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:19]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1C#N
Temperature: 0 °C
Yield: 66.6 %

Procedure:
A solution of 7.36 g of 5-chloro-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester, 3.2 g of sodium cyanide and 25 ml of DMF was heated at approximately 100° C. for 3 hours. The reaction mixture was cooled and poured into 300 ml of ice water. The precipitated solid was collected by filtration to afford 5.79 of solid. This material was recrystallized from ethanol to provide 4.72 g of 5-cyano-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. mp=112°-114° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:19])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=[O:18].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:19])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][C:6]1=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)CCl)C(=O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)CCl)C(=O)C1
Reaction time: 3 h
Yield: 18.3 %

Procedure:
In a 125 ml round-bottom flask equipped with a magnetic stirrer tert-butyl 4-(3-chloro-2-hydroxypropyl)-3-oxopiperazine-1-carboxylate (3.30 g, 11.3 mmol) was dissolved in acetonitrile (10 ml) and Dess-Martin periodinane (5.26 g, 12.4 mmol) was added. After agitating for 3 hours the mixture was diluted with ethyl acetate (100 ml) and washed with sodium bicarbonate and brine, dried and evaporated. Purified by column chromatography and eluting with 3% MeOH/CH2Cl2 to give the title compound (0.600 g, 18.31% yield).
Reaction SMILES: [O:1]1[CH2:25][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[NH3:26]>CCO>[NH2:26][CH2:25][CH:2]([OH:1])[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:8][CH2:9]1
Reactant: N
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CC3CO3)CC2)cc1
Solvent: CCO
Product: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A solution of 1-[1-(2,3-epoxy)propyl]-4-[bis(4-fluorophenyl)methyl]piperazine (8.9 g, 25.8 mmol) and liquid ammonia (20 mL) in EtOH (40 mL) was heated in a teflon reaction vessel in a bomb at 110° C. for 28 h. The solution was then evaporated to dryness to give about 10 g of a glass which was purified using flash chromatography on silica gel and increasing proportions of methanol in methylene chloride to give the product as an oil which solidified upon vacuum drying, 5.7 g (61%), mp 45°-47° C. IR(neat) 3350 cm-1 ; 300 MHz 1H NMR (CDCl3) δ: 7.4-6.9 (m, 8H), 4.21 (s, 1H), 3.68 (br m, 1H) 2.8-2.2 (m, 12H); MS 362 (MH+).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:17])[N:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[F:29]>C1(C)C=CC=CC=1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:5](=[O:18])[NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([N:14]([CH3:15])[CH3:16])=[O:17])=[CH:11][CH:12]=2)=[CH:24][C:23]=1[F:29]
Reactant: CN(C)C(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(Br)c(F)c1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)c(F)c2)cc1
Temperature: 110 °C
Yield: 44.6 %

Procedure:
To a 250 mL round bottom flask, 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (30 g, 0.0885 mol), 4-bromo-3-fluoroaniline (20 g, 0.1062 mol), TEA (24.6 mL, 0.177 mol) and toluene (150 mL) was added. The reaction mixture was maintained at 110° C. for 12 h. The reaction mass was cooled to room temperature. The obtained precipitate was collected by filtration and dried under vacuum to get the desired product [15 g, 50%]. 1H NMR (300 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.99 (s, 1H), 7.65-7.53 (m, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 2.93 (s, 6H); LC-MS (ESI): Calculated mass: 379.0; Observed mass: 382.1 (RT: 1.43 min).
Reaction SMILES: C.[N+:2]([C:5]1[CH:10]=[C:9]([O:11]CC2C=CC=CC=2)[C:8]([O:19]CC2C=CC=CC=2)=[CH:7][C:6]=1[CH2:27][C:28]#[N:29])([O-:4])=[O:3].C1CCCCC=1>[Pd].C(O)C>[N+:2]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:19])=[CH:7][C:6]=1[CH2:27][C:28]#[N:29])([O-:4])=[O:3]
Reactant: N#CCc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: N#CCc1cc(O)c(O)cc1[N+](=O)[O-]

Procedure:
0.75 g of palladium at a concentration of 10% on charcoal, to which 3 g of charcoal have been added, followed by 0.02 mole (7.5 g) of 2-nitro-4,5-dibenzyloxyphenylacetonitrile, are added with stirring to 30 ml of 96° C. ethanol containing 15 ml of cyclohexene; the reaction mixture is heated under reflux for 1 hour.
Reaction SMILES: [OH:1][C@H:2]([CH2:9][OH:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C@H:2]([CH2:9][O:10][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[C@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 30.1 %

Procedure:
To (S)-ethyl 3,4-dihydroxybutanoate (1.40 g, 9.45 mmol) in methylene chloride (20 ml) were added triethylamine (1.15 g, 11.36 mmol) and DMAP (17 mg, 0.139 mmol) and the solution was cooled in ice bath. Trityl chloride (2.90 g, 10.4 mol) in methylene chloride (15 ml) was dropped to the solution under stirring and then stirred at room temperature over night. The reaction mixture was washed with saturated ammonium chloride and then saturated brine, dried on magnesium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-ethyl 3-hydroxy-4-trityloxybutanoate (1.11 g, yield 31%).
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]([NH:11][C:3]2[C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=3)=[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br
Product: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1

Procedure:
The product from Example 140A and 4-trifluoromethoxyphenylboronic acid were processed using the method analogous to that described in example 110C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.29-10.76 (bs, 1H), 9.11 (dd, J=6.9, 1.7 Hz, 1H), 8.63 (dd, J=4.1, 1.7 Hz, 1H), 7.75-7.78 (m, 2H), 7.32-7.39 (m, 2H), 7.24-7.29 (m, 2H), 7.14-7.19 (m, 3H), 3.67 (s, 2H); MS (APCI) m/z 431 (M+H)+. Anal. calculated for C21H14F4N4O2: C, 58.61; H, 3.28; N, 13.02. Found C, 58.37; H, 2.91; N, 12.81.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1.Cl[CH2:11][C:12]1[C:13]([CH3:18])=[N:14][O:15][C:16]=1[CH3:17]>CN(C)C=O>[CH3:18][C:13]1[C:12]([CH2:11][N:3]2[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: O=Cc1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(C=O)cn1
Temperature: 0 °C

Procedure:
Add N,N-dimethylformamide (3 mL) to sodium hydride (0.092 g, 2.29 mmol) and stir at 0° C. Add 1-H-pyrazole-4-carboxaldehyde (0.200 g, 2.08 mmol) and stir at 0° C. for 20 min. Dissolve 4-chloromethyl-3,5-dimethylisoxazole (0.318 g, 2.18 mmol) in N,N-dimethylformamide (4 mL) and add to reaction mixture. Stir reaction at room temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution. Add ethyl acetate and separate organic layer. Extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 25:75 to 75:25 ethyl acetate:hexanes), to give the title preparation (387 mg, 91%). GC-MS: m/z=205 [M+].
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:8][C:3]([CH3:9])([CH2:2][O:1][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
To a solution of 25.0 g of methyl 3-hydroxy-2,2-dimethylpropanoate in 100 ml of pyridine, cooled to 0° C., were added 55.7 g of trityl chloride. The mixture was stirred at room temperature for 20 hours, and then the solvent was evaporated in vacuo. The residue was taken up in 200 ml of ethyl acetate, and the solution was washed successively with water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was taken up in 50 ml of methylene chloride, and to the solution were added slowly, at 0° C., 300 ml of hexane. Trityl alcohol crystallized and was filtered off. The filtrate was evaporated in vacuo to yield 53.5 g of raw methyl 2,2-dimethyl-3-trityloxy-propionate.