Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A solution of 4-bromo-2-fluorobenzyl bromide (26.8 g, 100 mmol) and sodium cyanide (5.4 g, 110 mmol) in ethanol (40 ml) and water (10 ml) was stirred at 100° C. for 8.5 h. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure, and extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (22.6 g, quant.) as a black oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].CS(C)=O>O>[C:20]([NH:24][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC(C)(C)C)ncc2C(N)=O)C[C@H]1O
Temperature: 68 °C
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carboxamide (4 g), tert-butylamine (14 mL) and DMSO (20 mL) was heated to 68° C. and held for 60 hours. After cooling to room temperature, water (20× vol, 80 mL) was added over 2 hours. The slurry was agitated for 2 hours and the crude product was collected as the DMSO hemi-solvate of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (Form H) by suction filtration.
Reaction SMILES: [Na].[CH3:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.O1CCCC1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>O>[CH3:2][CH:3]1[CH2:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:21]([O:22][CH2:23][CH3:24])=[O:25]
Reactant: CCOC(=O)Cl
Reactant: CC1CN(Cc2ccccc2)CCN1
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
580 parts of a sodium bydroxide solution 1N in water were cooled in an ice bath and then there were added 44 parts of 3-methyl-1-(phenylmethyl)piperazine and 82.8 parts of tetrahydrofuran. A solution of 27.13 parts of ethyl carbonochloridate in 103.5 parts of tetrahydrofuran was added dropwise at a temperature at about 5° C. Upon completion, stirring was continued for 4 hours in an ice bath. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 55 parts (87.8%) of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate as a residue (int. 36).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C(Cl)Cl.[OH-].[Na+]>[C:15]([O:14][C:12]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCc1ccc(F)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-4-fluorobenzylamine (10 g, 41 mmol) and TEA (14 mL, 104 mmol) in CH2Cl2 was added BOC2O (9.1 g, 41 mmol). The resulting solution was stirred for 16 h at RT, then diluted with aq. 1 N NaOH and CH2Cl2. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated to give (tert-butoxy)-N-[(3-bromo-4-fluorophenyl)methyl]carboxamide.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OC(=O)C)C>[N+:1]([C:15]1[CH:14]=[C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]=1[OH:19])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 37 %

Procedure:
Fumic nitric acid (d=1.52, 43.6 g, 0.70 mole) was dropwise added under stirring to 4-benzyloxyphenol (138.0 g, 0.69 mole) in ethylacetate (500 ml) at 0° C. The resulting solution was raised at room temperature and then washed in separatory funnel with sodium hydrogen carbonate in water (saturated solution). The organic layer was separated and evaporated under vacuum and the residual solid was crystallized from methanol (100 ml) to give nitrophenol (Yield of (a): 62.54 g, 36%) as yellow prisms. The product structure was confirmed by NMR and IR spectra.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].BrB(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1ccc(CC(=O)O)c(Br)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1ccc(O)cc1Br
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of (2-bromo-4-methoxyphenyl)acetic acid (0.49 g) in dichloromethane (5 mL) was added a solution of tribromoborane (5 mL) dropwise at room temperature. The mixture was refluxed for 3 hr. After cooling to room temperature, the mixture was poured into iced water. The organic layer was separated, and the water layer was extracted by ethyl acetate (30 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was washed with ether to give the title compound (0.45 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 51.6 %

Procedure:
4-Hydroxybenzaldehyde (15 g, 122 mmol) was dissolved in 150 ml of NMP. 6-Chlorohexanol (20.16 g 146 mmol), anhydrous K2CO3 (20.36 g, 146 mmol) and a catalytic amount of KI were added. The batch was stirred at 90 C for 24 hours. Water was added to the cooled solution, which was subsequently extracted with EtOAc (3×100 mL). The combined extracts were washed with 5% KOH (2×100 mL), brine solution and then dried over MgSO4. The concentrated product was then recrystallized from a 1:1 mixture of EtOAc/hexane to give 14 g of an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 69.1 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g Crude, 3.65 mmol, 1.00 equiv), 2-cyanoacetic acid (0.47 g, 5.48 mmol, 1.50 equiv), HATU (2.08 g, 5.48 mmol, 1.50 equiv), TEA (2.54 ml, 18.25 mmol, 5.00 equiv) in DCM (40 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water, and extracted with DCM. The DCM layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was submitted to flash chromatography (SiO2, PE:EtOAc=2:1 to 1:1) to give 1.28 g (69%) of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[CH:6]=1)=[O:4].Cl>CO.[Fe]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2cc(N)ccc2s1

Procedure:
A suspension of 584 (3.52 g, 14.8 mmol) in methanol (100 ml) was treated with Fe powder (6.63 g, 118.7 mmol). The resulting suspension was heated to reflux, and 12M HCl (8.5 ml) was slowly added over 15 min. The resulting green dark suspension was refluxed for an additional 3 h, then cooled and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3, then brine, dried over MgSO4, filtered and concentrated to afford (2.57 g, 84%). 1H NMR: (DMSO) δ (ppm): 7.92 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.88 (dd, J=1.8, 8.4 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H). LRMS: 207.0 (Calc.); 208.1 (found).
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:21]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)CC(c1cccc(O)c1)C1CC1
Agent: O=S(=O)(O)O
Product: COC(=O)CC(c1cccc(O)c1)C1CC1

Procedure:
To a flask containing 3-cyclopropyl-3-(3-hydroxyphenyl)propanoic acid 66.6V (1.2 g, 5.8 mmol) in MeOH (15 mL) was added H2SO4 (0.31 mL, 5.8 mmol). The resulting mixture was stirred at reflux overnight. The reaction was concentrated and purified by combiflash chromatography (0 to 30% EtOAc/Hexanes) to provide methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate 66.6W (1.2 g, 94%). Chiral separation was accomplished on Chiracel-OD (3% IPA in hexane) to provide 66.6X and 66.6Y. Peak 1 was the desired enantiomer. Analytical column (Chiracel-OD (2% IPA in hexane-45 min run) Peak 1-22.5 mins, Peak 2-34.0 mins).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[N:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccncc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cc2ccncc2)cc1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 4-(4-nitrobenzyl)pyridine (7.0 g, 32.68 mmol) in EtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry was shaken under a H2 atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and 1H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a short pad of Celite®. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 90%): 1H-NMR (DMSO-d6) δ 3.74 (s, 2H), 4.91 (br s, 2H), 6.48 (d, J=8.46 Hz, 2H), 6.86 (d, J=8.09 Hz, 2H), 7.16 (d, J=5.88 Hz, 2H), 8.40 (d, J=5.88 Hz, 2H); EI-MS m/z 184 (M+). This material was used in urea formation reactions without further purification. A2. General Method for Substituted Aniline Formation Via Dissolving Metal Reduction of a Nitroarene
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1.O>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CO)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (49.61 mmol) of 2-chloro-3-nitrobenzoic acid are initially charged in 50 ml of THF. With ice cooling, 104 ml of 1M borane/THF complex are added, and the mixture is stirred at RT overnight. At 0° C., the mixture is carefully hydrolyzed using water. After the evolution of gas has ceased, the mixture is diluted with 500 ml of water and the aqueous phase is extracted three times with in total 500 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is then removed under reduced pressure using a rotary evaporator. This gives 9.20 g (98% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[FH:14].F.F.C(N(CC)CC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([OH:11])[C@H:10]([F:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](F)C1

Procedure:
Stir a mixture of 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100 mg, 0.54 mmol) and triethylamine trihydrofluoride (88 μL, 0.54 mmol) at 100° C. for 30 min in a microwave (CEM Discover, 300W). Add saturated aqueous sodium hydrogen carbonate and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give trans-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester which may be used without further purification. 1H NMR (300 MHz, CDCl3) δ 4.85 (1H, d, J=50.86 Hz), 4.29 (1H, dd, J=8.01, 2.92 Hz), 3.38-3.65 (4H, m), 1.39 (9H, s).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14](OCC)=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][OH:15])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)on1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ethyl 5-[4-(trifluoromethyl)phenyl]isoxazole-3-carboxylate (130 mg) was dissolved in ethanol (10 ml), cooled to 0° C., and sodium borohydride (26 mg) was added in portions to the stirred solution. The mixture was stirred at room temperature for 4 hours, then excess water added. Solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography, eluting with 5% methanol/ethyl acetate, to provide {5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methan-1-ol, a compound of formula (24).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1>C1COCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]([O:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(OCc2ccccn2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of NaH (1.44 g, 36 mmol, 60% in mineral oil) in THF (15 mL) was added pyridin-2-ylmethanol (1.16 ml, 12 mmol) and the mixture was stirred for 30 min at rt. Then 3,6-dichloropyridazine (1.79 g, 14 mmol) was added and the mixture was stirred at 55° C. for 4 hours. The reaction was quenched with water and sat. NaHCO3 was added. The product was then extracted with EtOAc, dried over MgSO4 filtered and evaporated. The residue was purified on silica gel(Eluent: 80% EtOAc in hexanes) to give 3-chloro-6-(pyridin-2-ylmethoxy)pyridazine as a white solid (1.64 g, 62%). 1H NMR (300 MHz, dMSO): δ 5.57 (s, 2H), 7.35-7.38 (m, 1H), 7.48-7.54 (m, 2H), 7.82-7.88 (m, 2H), 8.57-8.59 (dd, 1H); MS (M+H, 222).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1
Reactant: BrCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCBr)cc1
Yield: 43.9 %

Procedure:
A mixture of 1,2-dibromoethane (3.9 mL, 45 mmol), 4-hydroxybenzaldehyde (1.8 g, 15 mmol) and K2CO3 (10.4 g, 75 mmol) in acetone (40 mL) was heated to reflux for 18 hr. The mixture was cooled, diluted with ethyl acetate (200 mL) and washed with brine (200 mL). Then organic layer was dried (MgSO4), filtered and then concentrated. The resulting residue was subjected to flash chromatography (25% ethyl acetate/hexane) to provide 1.51 g (44%) of 4-(2-bromoethoxy)benzaldehyde.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([N:9]([O:10][CH3:11])[CH3:8])=[O:17]
Reactant: CNOC
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCCCl
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Pyridine (101.28 g, 106.6 mL 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:13](=[O:14])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
Methyl-3,4-diaminobenzoate (1.251 g, 7.5 mmol, Lancaster) was reacted with 1,1′-carbonyldiimidazole (2.128 g, 13.1 mmol, Aldrich) under the conditions of Example 1b to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 193 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[S:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1

Procedure:
Using 4.28 g (22.3 mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde, 1.34 g (33.4 mmol) of sodium hydride (60% pure) and 2.6 g (24.5 mmol) of methyl mercaptoacetate, 4.93 g (80.0% of theory) of the title compound are obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1C(OC)=O>C1COCC1>[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
367 ml of NaHMDS (2M in THF) are added to 250 ml of THF and the mixture is cooled to −70° C. 54 g of (4-methoxyphenyl)acetic acid are then added; the mixture is left stirring for 2 hours and then 49 g of methyl 2,4-dichlorobenzoate are added. The reaction mixture is allowed to return to 10° C. and poured onto 2 liters of ice-cold HCl (2N), and the product is extracted with ether. After drying with a saturated sodium bicarbonate solution and then a saturated NaCl solution, drying the organic phase and evaporating, the product crystallizes from heptane; 32 g of the expected compound are obtained.
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1C(OC)=O>C1COCC1>[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 31.2 %

Procedure:
413 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −65° C., under a nitrogen atmosphere, 300 ml of THF are added, followed dropwise by a solution of 55 g of 4-methoxyphenylacetic acid in 70 ml of THF and the mixture is kept stirred for 3 hours at a temperature of less than −45° C. 64.5 g of methyl 2,4-dichlorobenzoate are then added dropwise and the mixture is kept stirred while the temperature is allowed to rise to 0° C. The reaction mixture is poured over an ice/1 liter 2N HCl mixture, extracted with ether, the organic phase is washed with a saturated NaHCO3 solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluted with heptane and then with the heptane/AcOEt mixture to (90/10; v/v). 29 g of the expected compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 50.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (3.38 g, 7.23 mmol) and 1M boron tribromide/CH2Cl2 (15.2 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.66 g (51%) of the title compound. 1H NMR (DMSO-d6) δ 1.39-1.48 (m, 2 H), 1.59-1.65 (m, 2 H), 1.68-1.76 (m, 2 H), 1.79 (s, 3 H), 1.88-1.95 (m, 2 H), 2.18 (s, 3 H), 3.18 (quintet, 1 H), 3.81 (s, 2 H), 6.87 (d, 1 H), 7.04 (d, 2 H), 7.43-7.47 (m, 3 H), 7.53 (s, 1 H), 10.35 (s, 1 H). IR (KBr) 3300, 2950, 1650, 1575 and 1280 cm-1. mass spectrum (+ESI) m/z 453 (M+H). Anal. Calcd. for C25H25BrO3 : C, 66.23; H, 5.56; N, 0.00. Found: C, 66.12; H, 5.49; N, 0.03.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[CH:12](O)=O>>[NH:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=[CH:12]1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=CO
Product: O=C(O)c1ccc2nc[nH]c2c1

Procedure:
3,4-diaminobenzoic acid (5 g, 32 mmol) and formic acid (20 ml) were mixed and refluxed overnight. Formic acid was removed on rotavapour and water added to the residue to obtain the solid. Solid was filtered and dried to obtain the title compound quantitatively.