Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: O=C(Cl)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 64.8 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 23.3 g of triethylamine in 50 ml of toluene was dropped into the above solution at 0° C. to -5° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of triethylamine hydrochloride was recovered by filtration and the filtrate was distilled to recover toluene, whereby 16.0 g of γ-triethoxysilylpropyl isocyanate was obtained at a fraction having a boiling point of 88° C. to 91° C. under 4.5 mmHg.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)[CH3:2].O=S(Cl)[Cl:14]>CN(C=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Cl)cc1
Yield: 100 %

Procedure:
A mixture of 4-ethylbenzoic acid (0.50 g, 3.33 mmol) in SOCl2 (1 mL) and DMF(1 drop) was refluxed for 2 h. The reaction mixture was concentrated and then stripped with toluene (2×10 mL) to yield 4-ethylbenzoyl chloride (0.59 g, >100%) as a colorless oil. The crude acid chloride (0.59 g, 3.5 mmol) in toluene (minimum amount) was added dropwise to conc. aq. NH4OH (1.4 mL). After stirring for 1 h, the reaction mixture was concentrated, the residue was dissolved in water and extracted with EtOAc (3×25 mL). The combined organic layers were washed with 1 N aq. NaOH (10 mL) and brine and dried over Na2SO4 prior to removal of the volatiles to yield 4-ethylbenzamide (460 mg, 88%) as a white solid. A suspension of this crude amide (430 mg, 2.87 mmol) and LiAlH4 (180 mg, 4.7 mmol) in dry THF (5 mL) was refluxed at 65° C. for 4.5 h. More LiAlH4 (60 mg, 1.58 mmol) was added, and the reaction mixture was heated at 65° C. for 2 h. The reaction mixture was cooled, and 1 N aq. NaOH (0.4 mL) was added. After stirring for 4 h, the mixture was filtered, and the filtrate was concentrated to give 4-ethylbenzylamine (350 mg, 90w) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>P([O-])([O-])([O-])=O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
Ethyl (2R/S) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (5 g) was added to an aqueous 0.1 M phosphate buffer pH 7 (10 ml). 100 mg of the lyophilised esterase preparation from Aspergillus oryzae was added and the mixture was stirred for 18 hours at room temperature. During that time, the pH of the reaction mixture was kept constant at pH=6-8 by addition of NaOH. Most of the water was evaporated in vacuo. Methanol was added to the remaining slurry in order to stop the hydrolysis. The precipitate, which formed was filtered off and the methanol was evaporated in vacuo. The remaining oil was dissolved in water followed by extraction of unreacted ester with tert-butyl methyl ether (TBME) (eeester=87%, determined as in Example 2). The water phase was acidified to pH=3 and the acid extracted with TBME. After drying over Na2SO4 and evaporation of the TBME, 1.8 g (2S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid was obtained as an oil, which crystallized on standing (m.p.=105° C., eeacid=>99%, determined as in Example 2).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S([O-])([O-])(=O)=O.[Pb+2].[NH3:27]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19].[NH3:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N
Agent: O=S(=O)([O-])[O-]
Agent: [Pb+2]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 70 °C

Procedure:
A 60-liter capacity vessel equipped with a high-speed stirrer and filled with 40 l of water was charged with 17.532 Kg of powdery lead monoxide (PbO-DP) prepared according to the above-mentioned dry method, and the charges were stirred at a high speed to disperse the lead monoxide sufficiently and homogeneously in water and the dispersion was heated at 65° C. Then, 109 cc of an aqueous solution of acetic acid having a concentration of 2.7 moles per liter was added to the dispersion to convert a part of lead monoxide to lead acetate. Then, 2702.6 cc of an aqueous solution of sulfuric acid having a concentration of 7.0 moles per liter was dropped to the dispersion over a period of 40 minutes. Then, aging was carried out under agitation at 65° C. for 60 minutes to form a slurry of needle crystals of a polybasic lead sulfate. Separately, a 10-liter capacity vessel of stainless steel was charged with 5 l of water maintained at 70° C. and 558 g of stearic acid was dissolved in this water. Then, 24 cc of 7 N aqueous ammonia was added to the solution and sufficiently emulsified under agitation to form an ammonia soap liquid. The so formed ammonia soap liquid was poured into the above-mentioned polybasic lead sulfate slurry over a period of 10 minutes, and aging reaction was carried out under high-speed agitation at 65° C. for 20 minutes to enroll stearic acid into the crystals of the polybasic lead sulfate and form a polybasic sulfuric acid/fatty acid lead salt (TBLSS). The so formed TBLSS slurry was sufficiently dispersed, and after coarse granules had been removed by sieving, the slurry was granulated to spherical particles under drying in a spray-drying device.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=1>CN(C=O)C.O>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=3)=[CH:3][CH:4]=2)=[O:10])[C:12](=[O:24])[N:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a solution of N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.80 g, 5.57 mmol) in DMF (35 mL) was added potassium tert-butoxide (1.87 g, 16.7 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (1.046 g, 6.68 mmol). The reaction was heated at 120° C. for 3 hours, then cocentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (1.8 g, 73%).
Reaction SMILES: Br[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5]Br.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[CH:8]1([N:14]2[CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: OC(CBr)CCBr
Solvent: O
Product: OC1CCN(C2CCCCC2)C1
Temperature: 130 °C

Procedure:
With stirring 1,4-dibromo-2-butanol (696 g, 3 mol) was added dropwise to cyclohexylamine (595 g, 6 mol). The addition was rapid until the reaction temperature reached 130° C. and then slowed so as to maintain the temperature at 130°-135° C. When the addition was completed the mixture was heated at 130° C. for 2 h. The mixture was then poured into 3 L of water with stirring. The aqueous mixture was filtered and the filtrate extracted with 1 L of ether. The aqueous solution was basified with 50% sodium hydroxide solution. The oil which separated from solution was removed. The aqueous layer was extracted with three 400 ml portions of ether and the extract combined with the oil. The ether solution was dried (Na2SO4) and concentrated. The residual oil was distilled and the fraction boiling at 165°-180° C./39 mm was collected. A higher boiling fraction (180°-190° C./39 mm) was collected and redistilled to give some additional material boiling at 165°-180° C./39 mm for a total yield of 329.6 g (77%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>[Pd].Cl.C(O)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(N)cc2)CC1

Procedure:
In a manner similar to Preparation 3, hydrogenate 1-methyl-4-(4-nitrophenyl)piperazine over palladium on carbon in HCl/acetic acid to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
In 80 ml of dimethylformamide was dissolved 12.22 g of p-hydroxybenzaldehyde, and 17.66 g of anhydrous potassium carbonate and 13.0 ml of benzyl bromide were added to the solution and the mixture was stirred at room temperature in a nitrogen current for 1 hour. After the reaction, water was added to the reaction mixture and the formed precipitate was recovered by filtration and recrystallized from a dichloromethane/hexane mixed solvent to obtain 20.07 g (yield=94.6%) of 4-benzyloxybenzaldehyde in the form of a colorless needle.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[OH:12].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[O:12][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 5-formyl-2-hydroxy-benzoic acid methyl ester (1.0 g, 5.6 mmol) in CH2Cl2 (10 mL) at −78° C. was added Et3N (0.85 mL, 6.1 mmol) and DMAP (68 mg, 0.56 mmol) followed by dropwise addition of Tf2O (1.03 mL, 6.1 mmol) over 20 min. The reaction mixture was then warmed to room temperature and poured into saturated aqueous NH4Cl and extracted with CH2Cl2 (3×25 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 15% EtOAc/hexanes) to afford Example 236A (1.3 g, 76%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:10][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(Br)cn1

Procedure:
0.25 mL 2-methoxyethanol (3.17 mmol) are added to a mixture of 80 mg (3.17 mmol) sodium hydride in 5 mL THF. The reaction mixture is stirred at r.t. for 10 min before 500 mg (2.11 mmol) 2,5-dibromopyridine are added. After 5 h at 75° C. the reaction mixture is diluted with half sat.aq. NaHCO3 solution and extracted with EtOAc. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 85/15).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:13][CH2:12][CH2:11][NH:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(NCCO)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A mixture of 4-fluorobenzonitrile (6.06 g), 2-aminoethanol (3.71 g), potassium carbonate (8.29 g) and dimethyl sulfoxide (50 mL) was stirred at 100° C. overnight. Water (200 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (200 mL×4). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=30:70, then 50:50, then 80:20, then ethyl acetate) to give 4-[(2-hydroxyethyl)amino]benzonitrile (5.89 g) as a yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.C1COCC1>[F:10][C:9]([F:12])([F:11])[C:6]1([CH:4]=[O:5])[CH2:8][CH2:7]1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CC1(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.6 %

Procedure:
To a solution of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (0.23 g, 1.162 mmol) in diethyl ether (3 mL, aldrich) at 0° C. under Ar(g) was added lithium aluminium hydride (1.0 M solution in THF; 1.39 mL, 1.39 mmol, aldrich) dropwise. After completed addition the reaction was then stirred at 0° C. for 45 min. The reaction was quenched with a solution of KHSO4 (1M) at −78° C. and gradually warmed to RT and stirred for 30 min. The reaction was extracted with diethyl ether (2×10 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to afford 62 mg of the title compound as a light yellow liquid, which was used in the next step without further purification. 1H NMR (CHLOROFORM-d) δ: 9.69 (s, 1H), 1.43 (m, 2H), 1.21 (t, J=7.0 Hz, 2H)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O.C(O)C>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([N:1]=[N+:2]=[N-:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Yield: 80.3 %

Procedure:
After dissolving 22.5 g (0.35 mole) of sodium azide in a small amount of water, the resulting solution was diluted with 130 ml of 90% hydrous ethanol. An ethanol solution having 60 g (0.32 mole) of p-toluenesulfonyl chloride dissolved therein was added dropwise to the solution at 10 to 25° C. They were reacted at room temperature for 2.5 hours. An oil obtained by concentrating the reaction mixture under reduced pressure was washed with water several times and then, dried over anhydrous magnesium sulfate. The desiccant was then removed, whereby 50.7 g of p-toluenesulfonyl azide was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(Cl)(=O)=O)=[CH:17][CH:16]=1>C(#N)C.Cl.CN(C)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Yield: 116 %

Procedure:
A solution of methyl (R)-(+)-lactate (6.66 g) in acetonitrile (33 ml) was cooled to 5° C. and triethylamine (9.8 ml) added followed by trimethylamine hydrochloride (0.62 g). A separate solution of p-toluenesulfonyl chloride (11.6 g) in acetonitrile (33 ml) was added dropwise over 20 mins maintaining the temperature below 5° C. The reaction mixture was filtered and concentrated. Diethyl ether and water were added and the organic fraction dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a yellow oil (13.71 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:6])=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: BrBr
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A stirred suspension of 2,6-dinitroaniline (5 g, 27.3 mmol) in glacial acetic acid (50 ml) was treated, dropwise, with bromine (1.5 ml, 30 mmol) and heated at 120° C. for 2 h. After cooling to ambient temperature, the resultant mixture was poured into water (500 ml). The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 4-Bromo-2,6-dinitroaniline as a yellow solid (6.5 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][NH2:10].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][NH2:10])[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cc(Br)ccn1
Temperature: 70 °C
Yield: 73.4 %

Procedure:
A mixture of 4-bromo-2-fluoropyridine (8.67 g, 49.3 mmol) and anhydrous hydrazine (16.00 ml, 501 mmol) was heated at 70° C. for 2.5 h. The reaction was cooled to RT, basified with 5N NaOH and diluted with 60 mL of water. The precipitate was filtered, washed with water and dried in vacuo at 50° C. to give 6.80 g of the title compound as a white amorphous solid.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1>ClCCl>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 86.3 %

Procedure:
Bromine (80 g, 500 mmol) was added dropwise to a solution of 1-(4-bromo-phenyl)-ethanone (100 g, 500 mmol) in dichloromethane (1500 mL) at ambient temperature. The reaction mixture was stirred for 3 h and then concentrated. The residue was washed with dichloromethane (100 mL) to give the crude title compound (120 g, 86% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.78 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 4.32 (s, 2H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[CH:1](=[C:17]1[C:18]2[N:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cnc2c(c1)CCCC2
Reactant: O=Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C(=C1CCCc2cccnc21)c1ccccc1
Yield: 57.6 %

Procedure:
Benzaldehyde (3.59 mL, 35.30 mmole) was added to a solution of 5,6,7,8-tetrahydro-quinoline (4.70 g, 35.30 mmole) in acetic anhydride (25 mL), and the solution was heated to reflux under a nitrogen atmosphere. After overnight at reflux, the reaction was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (33% EtOAc/hexanes) to give the title compound (4.50 g, 58%) as a waxy yellow solid after drying in vacuo: MS (ES) m/e 222 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:11][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:7](=[O:12])[CH:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n2ccsc2n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a stirred solution of 2-aminothiazole (5.0 g, 49.930 mmol) in acetic acid (40 ml) was added ethyl acetoacetate (9.746 g, 74.90 mmol) at room temperature. The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was allowed to cool to room temperature. The residue obtained after concentration of the reaction mixture was basified with saturated solution of sodium bicarbonate and diluted with ethyl acetate (500 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 4.20 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH3:18].[Al+3].[Cl-].[Cl-].[Cl-].CCCCCC>C(=S)=S>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([Cl:9])[C:15]=2[Cl:16])=[O:7])=[CH:2]1
Reactant: O=C(Cl)c1ccoc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccoc2)c(Cl)c1Cl

Procedure:
3-Furoyl chloride (18.0 g) and 2,3-dichloro anisole (24.7 g) are dissolved in 125 ml of CS2 and treated with AlCl3 (18.7 g), first at 5° C. and then at room temperature. After five hours the reaction is quenched with ice/HCl an extracted with CH2Cl2. Drying and evaporation gives a crystalline product that is titurated with hexane to yield 4-(3-furoyl)-2,3-dichloroanisole, mp 118°-122° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].[OH-].[Na+].CCOC(C)=O>CCO>[N+:1]([C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p. 107) (3.6 g) was dissolved in EtOH and heated to 105° C. prior to the addition of 1N NaOH (60 ml) and 50% NaOH (10 ml). After 2.5 h, the reaction was cooled to rt and EtOAc was added. The organic layer was washed with water and brine. Then it was dried and concentrated to give a crude 2-nitro-3-trifluoromethyl-phenylamine (2.79 g): 1H NMR (CDCl3, δppm, 300 mHz) 5.0 (s, 2H), 7.02 (d, 1H), 7.10 (d, 1H), 7.38 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C)[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:23]1([O:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC>C1(C)C=CC=CC=1>[O:29]([C:30]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[CH2:7][CH2:8]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1F)C1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 57.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine and 68.7 g of potassium carbonate in 750 ml of toluene was added with stirring 47 g of phenylchloroformate. The reaction mixture was heated under reflux for 5 hrs, cooled to room temperature, filtered, and the solvent removed under reduced pressure to give an oil. Trituration of the oil with hexane gave 48.6 g (46%) of product. Recrystallization of 1.0 g of product from ethanol-water (2x) and from ethanol gave the analytical sample, mp 95°-96° C.