Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[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>[CH3:32][C:22]1[CH:21]=[C:20]([O:19][CH2:18]/[CH:17]=[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)\[C:13]2[CH:14]=[CH:15][C:10]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:11][CH:12]=2)[CH:31]=[CH:30][C:23]=1[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: C#CCN1CCCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-Propargylpyrrolidine (250 mg, 2.29 mmol) was added under nitrogen atmosphere to a degassed solution of the above ester (400 mg, 0.68 mmol) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 96 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: N1CC[O:4]CC1.[Li]CCCC.CCCCCC.Br[C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22].[N+](C1C=CC=CC=1)([O-])=O.Cl>C1COCC1>[OH:4][C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: C1COCCN1
Reactant: COc1cc(C=O)c(Br)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(O)c(OC)c1
Temperature: -50 °C
Reaction time: 0.58 h

Procedure:
Morpholine (2.05 g, 24 mmol) and THF (40 mL) were placed in a three-necked, round bottomed flask equipped with a stirring bar, septum cap, dropping funnel, thermometer, and argon inlet. The flask was cooled in a dry ice-acetone bath to −50° C., and a solution of n-BuLi in hexane (1.6M, 15 mL, 24 mmol) was added all at once. After 10 min a solution of 1 (4.9 g, 20 mmol) in THF (30 mL) was added dropwise via a syringe over a period of 4 min, and the mixture was cooled to ˜−75° C. over 20 min. n-BuLi in hexane (1.6M, 20 mL, 32 mmol) was then added dropwise over 45 min, keeping the temperature at −75° C. After complete addition of n-BuLi the solution was stirred for 35 min. A solution of nitrobenzene (6.90 g, 46 mmol) in 10 mL THF was added from the dropping funnel, keeping the temperature at −75° C. The resulting dark mixture was stirred at −75° C. for 4 h and then allowed to warm to room temperature. It was acidified to pH 1 with 6N HCl and stirred for 15 min. After dilution with brine (100 mL), THF was removed in vacuo. The aqueous solution was extracted with diethyl ether (4×40 mL). The combined organic layers were extracted with 2 N NaOH (3×40 mL). The combined NaOH extracts were washed with diethyl ether (3×20 mL) and then acidified to pH 1 with concentrated HCl. The resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine, dried (MgSO4) and adsorbed on silica gel. The product was purified by flash chromatography, eluting with EtOAc/hexane (1:2). Pure 2 was obtained (2.0 g, 55%) as a yellow solid. m/z=183.06 (M+H). 1H NMR (500 MHz, CDCl3): δ: 10.71 (1H, s, OH), 9.91 (1H, s, CHO), 6.77 (1H, d, J4,6=2.8 Hz, H-6), 6.61 (1H, d, J4,6=2.8 Hz, H-4), 3.92 (3H, s, OMe), 3.84 (3H, s, OMe). 13C NMR CDEPT135 (500 MHz, CDCl3): δ: 196.11 (CHO), 107.93 (C-6), 103.90 (C-4), 56.29 (OMe), 55.83 (OMe).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(OC(C)C)(C)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: C1COCCN1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(I)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 g of 4-iodobenzenesulphonyl chloride (0.165 mol) in 500 ml of CH2Cl2 there are added 46 ml of triethylamine (0.33 mol) and then, dropwise, 17 ml of morpholine (0.198 mol). Because the reaction is exothermic, the flask is placed in an ice bath until it has returned to ambient temperature. The reaction mixture is stirred for 1 hour at ambient temperature. After washing the reaction mixture with about 100 ml of 1N HCl and then 100 ml of water, the organic phase is dried (MgSO4) and evaporated under reduced pressure. The solid residue thereby obtained is re-suspended in a small amount of isopropyl ether to yield the title product after filtration and drying in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl.C(OCC)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107 %

Procedure:
4′-Fluoroacetophenone (13.8 g) was dissolved in chloroform (60 mL) and diethyl ether (60 mL), and a solution of bromine (16.0 g) in chloroform (10 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(4-fluorophenyl)ethanone (23.2 g) as crystals. A solution (20 mL) of ethyl 3-oxobutanoate (11.7 g) in N,N-dimethylformamide was added dropwise to a suspension (50 mL) of sodium hydride (60% in oil, 4.00 g) in N,N-dimethylformamide with stirring under ice-cooling. After stirring at the same temperature for 15 min, a solution (10 mL) of crude 2-bromo-1-(4-fluorophenyl)ethanone (23.2 g) obtained above in N,N-dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 2-acetyl-4-(4-fluorophenyl)-4-oxobutanoate as an oil (yield 23.20 g). Without further purification, the product was stirred with ammonium acetate (11.56 g, 0.15 mol) and acetic acid (100 mL) with heating at 80° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2). The residue was crystallized from hexane to give the title compound as crystals (yield 13.6 g, from ethyl 3-oxobutanoate, 61%).
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[OH:9])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:10]1[C:15](=[O:16])[N:14]([O:17][C:18](ON2C(=O)CCC2=O)=[O:19])[C:12](=[O:13])[CH2:11]1.C(N(CC)CC)C>C(#N)C>[CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[O:9][C:18]([O:17][N:14]1[C:15](=[O:16])[CH2:10][CH2:11][C:12]1=[O:13])=[O:19])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C=CCCC[C@@H]1C[C@H]1O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCCC[C@@H]1C[C@H]1OC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
To a solution of (1R,2R)-2-(pent-4-en-1-yl)cyclopropanol (see International Patent Application Publication No. WO 08/057209) (17.1 g) in acetonitrile (193 mL) was added N,N′-disuccinimidyl carbonate (49.3 g) then triethylamine (53.7 mL) The mixture was heated to 40° C. for 18 hours. The reaction mixture was cooled to room temperature and the solids were removed by filtration. The solvent was removed in vacuo. The residue was purified by flash chromatography (ISCO, 10 to 70% ethyl acetate in hexanes) to give the desired product (18 g). 1H NMR (500 MHz, CDCl3): δ (ppm) 4.06-4.03 (m, 1H), 2.87 (s, 4H), 2.28-2.25 (m, 2H), 1.98-1.97 (m, 1H), 1.72-1.63 (m, 2H), 1.44-1.39 (m, 2H), 1.30-1.25 (m, 1H), 1.12-1.08 (m, 1H), 0.72-0.68 (m, 1H).
Reaction SMILES: N1N(C2C=CC(C(F)(F)F)=CC=2C(O)=O)N=CC=1.N1(C2C=CC(C(F)(F)F)=CC=2C(O)=O)C=CN=N1.[N:37]1[NH:38][N:39]=[CH:40][CH:41]=1.[F:42][C:43]1[C:51]([F:52])=[CH:50][CH:49]=[C:48](I)[C:44]=1[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[F:42][C:43]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]([N:38]2[N:39]=[CH:40][CH:41]=[N:37]2)[C:44]=1[C:45]([OH:47])=[O:46]
Reactant: O=C(O)c1c(I)ccc(F)c1F
Reactant: c1cn[nH]n1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(-n2nccn2)ccc(F)c1F

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 0.75 g, 10.86 mmol) and 2,3-difluoro-6-iodobenzoic acid (CAS number 333780-75-9; 1.54 g, 5.43 mmol) in 1,4-dioxane (10 ml) and water (0.2 ml). The crude solid was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 39a). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 2,3-difluoro-6-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 39b).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][C:24]#[N:25].C(Cl)Cl.CCOC(C)=O>C(#N)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:23][C:24]#[N:25])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a stirred suspension of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.95 g, 22.6 mmol) and NaHCO3 (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml) was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 22.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with DCM and the combined filtrates were concentrated. The resulting brown oil was dissolved into EtOAc and washed with water. The organic phase was dried (MgSO4), filtered and concentrated to give a brown solid which was re-dissolved into DCM/EtOAc and flushed through alumina with DCM. The eluent was concentrated to give 5.2 g of the desired product as a solid, m.p. 149°-151° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C1COCC1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][C:3]=1[F:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a 12-L, three-neck, round-bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel and thermocouple was charged 4-bromo-3-fluoroaniline (800.0 g, 4.21 mol, Matrix lot #Q13H), THF (6.4 L, 8 vol), and solid sodium bicarbonate (530.5 g, 6.32 mol, 1.5 eq). The addition funnel was charged with benzyl chloroformate (861.9 g, 5.05 mol, 1.2 eq), which was added dropwise to the reactor over 70 minutes. The temperature of the reaction was maintained below 20° C. with an ice water bath. The batch was aged 1 hour at room temperature at which point HPLC analysis indicated that the reaction was complete. The reaction mixture was transferred to a 22-L flask and the mixture was diluted with water (6.4 L, 8 vol). The two-phase mixture was warmed to 50° C. and held at temperature for 16 hours to quench the excess benzyl chloroformate. The mixture was transferred hot to a separatory funnel to remove the lower aqueous phase. A rag layer was observed which was taken with the aqueous layer. The THF layer was filtered through Whatman #1 filter paper to remove some particulates, and the mixture was transferred back to a 22-L flask equipped for distillation. Heptane was added in portions and distilled to remove the THF. (Note that it is best to distill some of the THF out first before adding the first amount of heptane.) A total of 26.5 L of heptane was added, and the total distillate collected was 25 L. At this point, the pot temperature had reached 97.7° C. and the distillate coming over contained 0.9% THF by 1H NMR analysis. The mixture was cooled to room temperature and the thick white slurry was filtered. The filter cake was washed with heptane (4 L). The product was dried in a vacuum oven at 40° C. to give 1257.0 g of intermediate 5 (92% yield). The HPLC assay was 98.3% (AUC).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20](=[O:23])[NH:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[N:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 0.15 mole of tert-butylcarbazate in 250 ml of hexane is stirred for 18 h at RT. The precipitate is filtered off and dried under vacuum. M.p. 172-174° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[CH3:17][S:18]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-piperidinol (23.98 g), 168.66 g of toluene and 83.56 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 500-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.7° C. Then, 31.73 g of methanesulfonyl chloride was added dropwise over 4 hours and 30 minutes at a flask inside temperature of 5 to 10° C. Water (33 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of 1-benzyl-4-piperidinol methanesulfonate was thus obtained in a yield of 40.3 mole percent.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>C(N(CC)C(C)C)(C)C.C(O)C>[CH:1]1([NH:8][C:9]2[S:10][C:13]3([C:17](=[O:18])[N:11]=2)[CH2:16][CH2:15][CH2:14]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: NC(=S)NC1CCCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(NC2CCCCCC2)SC12CCC2
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-cycloheptylthiourea (0.255 g, 1.48 mmol) and ethyl 1-bromocyclobutanecarboxylate (0.25 mL, 1.48 mmol, Aldrich) in N,N-diisopropylethylamine (0.5 mL) and ethanol (1.0 mL) was heated in a sealed tube in a microwave oven (Emrys Optimizer from Personal Chemistry) at 155° C. for 2 h, then at 170° C. for 1.5 h. After removing the low-boiling solvents in vacuo, the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine, and conc. in vacuo. The residue was purified by flash column chromatography (0 to 35% of EtOAc in hexanes) to give the title compound as a tan solid. MS m/z: 253.2 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=[C:2]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:33][N:32]=2)(=[O:36])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Yield: 96.4 %

Procedure:
A solution of 1.18 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine and 2.12 g (8.88 mmol) of 5-isopropyl-pyridine-2-sulphonamide potassium salt in 25 ml of dry DMSO was heated to 80° C. for 3 hours until the dichloride had disappeared completely. The DMSO was removed in a high vacuum, the residue was taken up with 60 ml of water and the aqueous solution was washed three times with diethyl ether. The solution was then acidified to pH 3.5 with 1N HCl and the product was extracted three times with ethyl acetate. The organic phases were washed twice with water and finally once with saturated sodium chloride solution, combined, dried with sodium sulphate and evaporated. The crystalline residue was digested twice with absolute diethyl ether in order to completely remove a trace of 5-isopropyl-pyridine-2-sulphonamide. The crystals remaining behind were filtered off and dried. There were obtained 1.66 g (96%) of 5-isopropyl-pyridine-2-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide as white crystals of m.p. 168°-176° C., MS: (M-H)- =518.3.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=O)=O.[Br-:24].[Mg+2].[Br-]>CCOCC>[CH2:6]([Br:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: [Br-]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
Linoleyl methanesulfonate (27 g, 78 mmoles), anhydrous magnesium bromide (43 g; 238 mmoles), and 1000 ml of dry ether was placed in a 2500 ml three-necked flask equipped with reflux condenser, inlet and outlet tubes for dry nitrogen, and mechanical stirrer. The mixture was stirred vigorously at room temperature for 24 hr. More ether, and cold, degassed water were added after 24 hours. The water layer was extracted twice with ether. The combined ether phases were washed consecutively with water, 1% potassium carbonate solution, and water, and are dried over anhydrous sodium sulfate. Concentration of the ether phase using a rotary evaporator yielded 25 g (97%) of linoleyl bromide; mp −35° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 100.0 grams (0.64 mole) of ethyl piperidin-4-ylcarboxylate and 94 mL (0.67 mole) of triethylamine in 1400 mL of diethyl ether was cooled to 15° C., and a solution of 86 mL (0.68 mole) of chlorotrimethylsilane in 100 mL of diethyl ether was added dropwise during a 30 minute period. Upon completion of the addition, the thick reaction mixture was stirred vigorously for one hour while warming to ambient temperature. The reaction mixture was then filtered, and the collected solid was washed with diethyl ether. The combined wash and filtrate were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 115.0 grams (79% yield) of ethyl N-(trimethylsilyl)piperidin-4-ylcarboxylate, bp 75° C./0.1 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[Br:25][CH2:26][CH2:27][CH2:28]Br>C(#N)C>[Br:25][CH2:26][CH2:27][CH2:28][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(Cc1ccccc1O)OCc1ccccc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Cc1ccccc1OCCCBr)OCc1ccccc1

Procedure:
A solution of 100 g of 2-hydroxyphenylacetic acid, 75 cm3 of benzyl alcohol and 0.5 g of paratoluenesulphonic acid in 1400 cm3 of toluene is refluxed for 2 hours while removing the water formed. After cooling, treating with 3 g of animal black and filtering, the reaction mixture is concentrated to 150 cm3 and supplemented with 300 cm3 of isopropyl oxide. The crystals obtained by cooling to 0° C. are drained, washed and dried to give 82.5 g of benzyl 2-hydroxyphenylacetate. 174 g of potassium carbonate are added to a solution of 153 g of this ester in a mixture of 500 cm3 of 1,3-dibromopropane and 2500 cm3 of acetonitrile and the mixture is refluxed for 17 hours. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of ethyl acetate and the organic phase is washed twice with 400 cm3 of water and twice with 250 cm3 of a saturated solution of sodium chloride and then dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 9 cm, height 55 cm), eluting with a cyclohexane and ethyl acetate mixture (95/5 by volume) and collecting fractions of 500 cm3. Fractions 12 to 18 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 90 g of benzyl 2-(3-bromopropoxy)phenylacetate in the form of a yellow oil. A solution of 40 g of this product in 500 cm3 of acetonitrile is heated in an autoclave with 27 g of sodium iodide and 90 g of dimethylamine for 16 hours at 80° C. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by acid-base treatment to give 29.3 g of benzyl 2-(3-dimethylaminopropoxy)phenylacetate in the form of a yellow oil. Hydrogenation of this ester at atmospheric pressure at 40° C. in ethyl acetate in the presence of palladium hydroxide, followed by crystallization from ethyl acetate, lead to 17.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid in the form of white crystals; melting point 98° C.