Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:36]1[CH:37]=[CH:38]C2N(O)N=[N:42][C:40]=2[CH:41]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:59][C:60]1[CH:73]=[CH:72][CH:71]=[CH:70][C:61]=1[O:62]NC1CCNCC1>CN(C=O)C.O>[Cl:59][C:60]1[CH:73]=[CH:72][CH:71]=[CH:70][C:61]=1[O:62][CH:36]1[CH2:37][CH2:38][N:42]([C:24](=[O:25])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:19][N:18]=2)=[O:21])[CH2:40][CH2:41]1
Reactant: On1nnc2ccccc21
Reactant: Clc1ccccc1ONC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred solution of {[5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.001736 mol), HOBt (0.065 g, 0.00048 mol) and EDCI.HCl (0.0925 g, 0.000482 mol) at ambient temperature. After 5 minutes (2-chlorophenoxy)-piperidin-4-yl-amine hydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 0.08 g (33%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 544.2 (M+1)+, 99.03%.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:13]([NH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([N:15]([CH2:13][CH3:14])[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCN(CC(=O)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add, in a dropwise manner, 20.4 g. of carbobenzyloxy chloride to a stirred ice-cooled mixture of 16.3 g. of N-ethyl-α-aminoacetophenone hydrochloride and 12.7 g. of sodium carbonate in 125 ml. of water and maintain the reaction temperature at about 20°-25° C. When the addition is complete, stir for one hour at room temperature and extract the product with ether. Wash the ether extract successively with 5% hydrochloric acid, water saturated aqueous sodium bicarbonate and finally with water. Dry over magnesium sulfate and filter. Remove the ether in vacuo and obtain the product of this step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.II.[Mg].[CH:13]([O-])([O-])[O:14]CC.S(=O)(=O)(O)O>C(OCC)C>[F:9][C:5]1[CH:4]=[CH:3][C:2]([CH:13]=[O:14])=[CH:7][C:6]=1[CH3:8]
Reactant: CCOC([O-])[O-]
Reactant: Cc1cc(Br)ccc1F
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cc(C=O)ccc1F
Reaction time: 8 h

Procedure:
A solution of 5-bromo-2-fluorotoluene (6 g) in ethyl ether (10 ml) and a catalytic amount of iodine were added to a suspension of magnesium (960 mg) in ethyl ether (10 ml) under nitrogen atmosphere and the whole was refluxed for 30 minutes. After cooling, a solution of ethyl orthoformate (5.4 g) in ethyl ether (20 ml) was added to the mixture and the whole was stirred overnight. Sulfuric acid (10%, 20 ml) was added to the mixture and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate (10:1) as eluent to give 4-fluoro-3-methylbenzaldehyde as an oil.
Reaction SMILES: [N:1]([C:8](OCC)=O)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH2:2].Cl[CH2:14][CH2:15][CH2:16]CCl.[OH-:19].[K+]>CN1CCN(C)C1=O>[N:1]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:14][CH2:15][CH2:16][N:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:19]
Reactant: CCOC(=O)N(N)C(=O)OCC
Reactant: ClCCCCCl
Reactant: [OH-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)N1CCCCN1C(=O)OCC
Yield: 143.3 %

Procedure:
Into a 500-ml, four-necked flask equipped with a reflux condenser, a stirrer and a thermometer were charged 35.2 g (0.2 mole) of diethyl hydrazinedicarboxylate, 25.9 g (0.204 mole) of 1,4-dichlorobutane, 200 ml of 1,3-dimethylimidazolidinone and 22.4 g (0.4 mole) of potassium hydroxide, gradually warmed up to 50°-60° C. and aged for 3 hours. After completion of the reaction, the reaction mixture was cooled and filtered to remove the solid matters, after which the solvent was removed by distillation under reduced pressure. The residue obtained was distilled under reduced pressure (110° C./1 mmHg) to obtain 33.0 g of diethyl hexahydropyridazine-1,2-dicarboxylate. The yield was 72%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCOc1ncc(C(=O)O)cc1-c1ccc(F)c(F)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: COCCOc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)cc1-c1ccc(F)c(F)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3,4-difluorophenyl)-6-(2-methoxyethoxy)-nicotinic acid (example CE) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 87.6%, 459.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:10][C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
4-Iodoaniline (11.0 g, 50.4 mmol) was dissolved in 60 mL of ethyl acetate and the solution was added with 10 mL of acetic anhydride (10.8 g, 106 mmol) and 7.8 mL of pyridine (7.65 g, 99.4 mmol), and the mixture was stirred at room temperature for 2 hours with an equipment of a CaCl2 tube. A solvent was evaporated under reduced pressure to obtain 4-iodoacetanilide (yield: 13.0 g, percent yield: 99.0%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][CH2:11]2)=[O:5].C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:10]2[CH2:9][CH2:8][C:7]3[C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccncc1
Reactant: COC(=O)c1cccc2c1CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
5-Methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1 g, 4.39 mmol) and triethylamine (666 mg, 6.58 mmol) were mostly dissolved in tetrahydrofuran (30 mL). 4-Pyridinecarboxaldehyde (494 mg, 4.61 mmol) and sodium triacetoxyborohydride (1.3 g, 6.15 mmol) were then added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The tetrahydrofuran was removed under vacuum and the remaining residue was dissolved in ethyl acetate then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to give 1.29 g of methyl 2-(pyridine-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate as a light yellow oil. MS (ESI, pos. ion) m/z: 283.0 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)[C:2]#[CH:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:34]=[CH:35][C:36]([C:3]#[C:2][CH2:1][N:4]3[CH:8]=[CH:7][CH:6]=[N:5]3)=[CH:37][CH:38]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCn1cccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCn3cccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-Propargylpyrazol (500 mg, 4.7 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (680 mg, 1.24 mmol; example 15) in a mixture of tetrahydrofuran (10 mL) and triethylamine (10 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (118 mg, 0.1 mmol) and copper(I) iodide (38 mg, 0.2 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, diluted with benzene (100 mL) and the resulting mixture was washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene-chloroform/ether 2:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[Na].[CH2:19]([N:25]=[C:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(OCC)C>[CH2:19]([NH:25][C:26](=[O:27])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][CH2:10]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccn1
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccn1
Reaction time: 0.03 h
Yield: 68.2 %

Procedure:
To a solution of 1-(2-pyridylmethyl)indolin-5-ol (20 mg, 88 μmol) in 0.5 mL of diethyl ether was added a piece of sodium (1 mg to 10 mg) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, n-hexylisocyanate (15 μL, 0.11 mmol, 1.2 equivalent) was added with additional stirring for 5 min to 10 min. After removal of sodium, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 30/70) to obtain the title compound (21.2 mg, 68%) as a slightly brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][CH2:12][CH2:13][Cl:14])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.5 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (183.2 g, 1.5 moles), 1-bromo-3-chloropropane (167 mL, 1.58 moles), potassium carbonate (450 g) and acetonitrile (2.2 L) was heated at reflux temperature with good stirring. After 17 hours, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was dried in vacuo to give 290.4 g (97%) of 1-(3-formylphenoxy)-3-chloropropane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]2[CH2:10][CH2:11][C@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[O:13][C:4]=2[C:3]=1[CH3:31].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CCCCCC>[CH3:31][C:3]1[C:4]2[O:13][C@@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[CH2:11][CH2:10][C:5]=2[C:6]([CH3:9])=[C:7]([O:8][C:32]([CH3:33])=[O:34])[C:2]=1[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude α-tocopherol is treated with 25.0 g of acetic anhydride (corresponding to 244.9 mmol), 25.0 g of pyridine (corresponding to 316.1 mmol) and 1.0 g of 4-dimethyl-aminopyridine (corresponding to 8.2 mmol; catalytic amount) and stirred for one hour at room temperature. The reaction mixture is poured on to 100 g of ice/water (about 1:1), stirred for 30 minutes, treated with 250 ml of n-hexane and washed in succession twice with 150 ml of water each time, twice with 100 ml of 2N sulphuric acid each time, with 150 ml of water, with 150 ml of saturated sodium bicarbonate solution and three times with 150 ml of water each time. Thereafter, the mixture is dried over 3 g of anhydrous magnesium sulphate for 10 minutes while stirring. After filtration, distillation of the solvent at 400 mbar and a bath temperature of 60° C. and subsequent drying for 30 minutes at 15 mbar and a bath temperature of 70° C. there are obtained 29.26 g of α-tocopherol acetate as a yellow oil, α-tocopherol acetate content (GC, internal standard squalane) 87.5%, chemical yield (α-tocopherol acetate) 93.1%. This crude acetate is distilled in a bulb tube oven (250° C./10-1 mbar). There are obtained 26.25 g of α-tocopherol acetate as a slightly yellowish oil which crystallizes slowly upon standing at room temperature. α-Tocopherol acetate content (GC, internal standard squalane) 96.2%, chemical yield 91.8%; stereo-chemical purity: 99.6% R,R,R-α isomer (HPLC of the methyl ether derivative on Chiracel OD, n-hexane); the product is identical with α-tocopheryl acetate according to 1H-NMR, IR, MS and microanalytical data.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10](O)[CH:11]1[C:15](=[O:16])[C:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])=[C:13]([O:26][CH3:27])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CI>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[C:11]1\[CH2:12][C:13]([O:26][CH3:27])=[C:14]([C:17]2[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])[C:15]\1=[O:16]
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)c2cc3ccccc3o2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)/C(=C/c2cc3ccccc3o2)C1
Yield: 31.9 %

Procedure:
To a solution of 5-(benzofuran-2-yl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (1.11 g) in methanol (10 ml) is added potassium carbonate (476 mg), followed by methyl iodide (214 μl) and the resulting suspension heated to reflux for 17 hours. The crude reaction mixture is then concentrated in vacuuo and partitioned between ethyl acetate (50 ml) and water (50 ml) and the organic layer purified by automated flash chromatography to give 5-[1-benzofuran-2-yl-meth-(E)-ylidene]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (337 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13]O.[BrH:19].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[Br-:19].[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][P+:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCc1cc(F)ccc1OCc1ccccc1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Solvent: CC#N
Product: Fc1ccc(OCc2ccccc2Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
4.60 g (17 mmol) of [2-(2-chlorobenzyloxy)-5-fluorophenyl]methanol are dissolved in 10 ml of acetonitrile, 5.62 g (16 mmol) of triphenylphosphine hydrobromide are added, and the suspension is stirred under reflux for 12 h. A further 2.80 g (8 mmol) of triphenylphosphine hydrobromide are added, and the mixture is stirred under reflux for a further 3 h. The solvent is mostly distilled out in vacuo, and the crystals which have separated out are stirred with petroleum ether, filtered off with suction and dried on a clay dish. 9.82 g (15.7 mmol, 92% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][C@@H:18]3[C:33]([O:35]C)=O)=[O:16])[N:12]=[C:11]2[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].CC([CH:47]1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CN[C:48]1=[O:49])C.CN1C=CN=C1.CS(Cl)(=O)=O.C[C@@]1(C([O-])=O)NCCN(C(OCC2C=CC=CC=2)=O)C1>ClCCl>[C:48]([O:35][CH2:33][C@H:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[C:15]([C:13]1[N:12]=[C:11]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:14]=1)=[O:16])(=[O:49])[CH3:47]
Reactant: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3C(=O)OC)nc2-c2ccc(C)cc2)c1
Agent: CS(=O)(=O)Cl
Agent: C[C@]1(C(=O)[O-])CN(C(=O)OCc2ccccc2)CCN1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CCOc1cccc(-n2cc(C(=O)N3CCNC[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Temperature: 25 °C

Procedure:
1-Benzyl 3-methyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1,3-dicarboxylate To a solution of 3.18 g (9.88 mmol) of Intermediate 1 in 75 mL of anhydrous dichloromethane at 0° C. was added 1.5 mL (19 mmol) of 1-methylimidazole followed by 0.80 mL (9.9 mmol) of methanesulfonyl chloride. The resulting mixture was stirred with gradual warming to ambient temperature over 20 min, then re-cooled to 0° C. A solution of 2.39 g (8.59 mmol) of 1-benzyl 3-methyl-(3R)-piperazine-1,3-dicarboxylate in 25 mL of anhydrous dichloromethane was then added and the reaction mixture was allowed to warm to ambient temperature over 1 h. The reaction was then quenched with a saturated aqueous ammonium chloride solution (25 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on a Biotage® purification apparatus (silica gel, 40 to 50% ethyl acetate in hexanes gradient) to yield the title compound as a colorless solid. LC/MS 583.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)cc2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a suspension of [4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenyl]-methanol (WO 2011/070368, which is incorporated herein by reference in its entirety; 3.05 g, 12.4 mmol) in aq. NaOH solution (1M, 31 mL, 31 mmol) and EtOAc (30 mL) at RT was added 2,2,2-trichloroethyl chloroformate (1.88 mL, 13.7 mmol) over 3 min (CARE: exotherm to 35° C.) and the mixture stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (20 mL), then the combined organics washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a pale orange solid. Recrystallisation from hot cyclohexane-EtOAc (3:1, 30 mL) and drying in vacuo gave the title compound as a flocculent off-white solid (3.87 g, 74%). LCMS (Method 3): Rt 4.00 min, m/z 420, 422 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[C:19]1[CH2:24]O.P(Br)(Br)[Br:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[C:19]1[CH2:24][Br:28]
Reactant: BrP(Br)Br
Reactant: Cc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Product: Cc1nnc(CBr)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 5, 2'-chloro-5-nitro- 2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is treated with phosphorus tribromide to give 2'-chloro-5-nitro-2-[3-(bromomethyl)-5methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: C1(N=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12]C2)CCCCC1.C(O)(=[O:23])C1C=CC=NC=1.[CH2:25]([O:43][CH2:44][CH2:45][CH2:46][OH:47])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[C:25]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH2:12][C:13]1[CH:14]=[CH:15][CH:10]=[N:9][CH:8]=1)(=[O:23])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C(O)c1cccnc1
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCOCCCO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOCc1cccnc1
Yield: 81 %

Procedure:
1,3-Dicyclohexylcarbodiimide (211 g, 1.02 mol) and 4-(N,N-dimethylaminopyridine (141 g, 1.15 mol) in methylene chloride (2000 ml) were added with stirring to a solution of nicotinic acid (131 g, 1.07 mol) and 1-(z,z,z-octadeca-6,9,12-trienyloxy)-3-hydroxypropane (300 g, 0.89 mol) in methylene chloride (2000 ml). The progress of reaction was monitored by tlc. On completion, the reaction mixture was filtered and the organic layer washed with 2M hydrochloric acid (2000 ml) and water (3×2000 ml), dried with magnesium sulphate and concentrated under reduced pressure. Purification by dry column chromatography using a gradient of ethyl acetate in hexane yielded 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(nicotinyloxy)-propane as a pale yellow oil in 81% yield.