Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl:55][C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([C:64]([N:66]3[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)=[O:65])[CH2:61][C:60]=2[CH:72]=1>ClCCl>[Cl:55][C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([C:64]([N:66]3[CH2:67][CH2:68][N:69]([C:19](=[O:21])[CH2:18][O:17][CH:14]4[CH2:13][CH2:12][CH:11]([NH:10][C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:25])[F:23])[CH:6]=5)[CH2:16][CH2:15]4)[CH2:70][CH2:71]3)=[O:65])[CH2:61][C:60]=2[CH:72]=1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: O=C(C1Cc2cc(Cl)ccc2O1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (80 mg, 0.42 mmol 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (84 mg, 0.83 mmol, 3 eq) and 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine (74 mg, 0.28 mmol, 1 eq). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using 5-20% ethyl acetate in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (34.9 mg, 19%). (ES, m/z): [M+H]+ 611.25; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=9.0 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.63 (dd, J=2.1 Hz, 9.0 Hz, 1H), 5.42 (dd, J=7.5 Hz, 9.0 Hz, 1H), 4.23 (s, 2H), 3.82-3.98 (m, 4H), 3.30-3.70 (m, 8H), 2.10-2.20 (m, 4H), 1.42-1.58 (m, 2H), 1.20-1.40 (m, 2H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2](OC)=[O:3].CCOCC.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.Cl>C1COCC1.CCCCCC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]([C:1]([O:7][CH3:8])=[O:6])=[O:3])=[CH:17][CH:16]=1
Reactant: COC(=O)C(=O)OC
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(F)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Dimethyl oxalate (5.90 g, 50 mmol) was dissolved in THF (50 mL) and ether (50 mL) in a 3-neck round bottom flask fitted with a mechanical stirrer. The solution was stirred vigorously at −65° C. as a 1.0 M THF solution of 4-fluorophenylmagnesium bromide (60 mL, 60 mmol) was added dropwise over 40 min. The mixture was stirred 30 min. at −65° C. and allowed to warm to −20° C. over 30 min. before being poured into 2 N HCl (50 mL) with stirring. The layers were separated and the aq. layer was extracted with ether (3×50 mL). The combined organic layers were washed with saturated aq. NaCl (2×50 mL), dried (Na2SO4), decanted, and evaporated. The residue was dissolved in EtOAc, dried (Na2SO4), filtered, and evaporated to give a yellow solid. The crude product was dissolved in warm hexane (25 mL), filtered, and cooled to −20° C. Filtration followed by washing with cold hexane (15 mL) gave 4.95 g of the title compound as light tan crystals. 1H NMR (500 MHz) δ 8.11 (dd, J=9.0,5.0,2H), 7.21 (t, J=9,22H), 4.00 (s, 3H); HPLC A: 2.59 min.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:13])[C@H:6]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:7].O.O.O.O.O.O.O.O.O.O.O.O.OP([O-])([O-])=O.[Na+].[Na+]>O.[OH-].[Na+]>[NH2:7][C@H:6]([C:5]([OH:13])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: COC(=O)[C@@H](N)CCCCN
Agent: *CCO*
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: Cl
Solvent: O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 110 °C

Procedure:
2.33 Grams (10 mmol) of L-lysine methyl ester dihydrochloride, 1.11 g (3.1 mmol) of disodium phosphate 12 hydrate and 0.1 g of polyoxyethylene lauryl ether (“Newcol 1100”, nonionic surfactant produced by Nippon Nyukazai Co., Ltd.) were dissolved in 5.0 ml of water to prepare a treating agent solution. A cotton cloth (150 mm×170 mm, 4.8 g) was in advance treated to be immersed in 25% aqueous sodium hydroxide solution for an hour at room temperature, washed with water and dried. This treated cotton cloth was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for 3 hours at room temperature. The dried cloth was heat-treated for 20 minutes at 140° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently washed with 10% aqueous succinic acid solution and rinsed three times with water, and finally washed with household washing detergent solution, rinsed with water and air-dried. The identification of L-lysine cellulose ester was conducted by the following method. A part of the cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. Also, a part of the cloth was cut and subjected to an infrared spectroscopic analysis whereby there was confirmed a peak based on ester bond at 1730–1750 cm−1. As a result of determination for the amount of the L-lysine bonded, it was 0.19 mmol based on 1 g of the cloth. The degree of esterfication was 0.031. Also, the amount of succinic acid was 0.39 mmol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.S(=O)(=O)(O)O.C1COCC1.C([O:24][C:25](=O)[CH2:26][C:27]1([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)[CH2:31][C:30](=O)[NH:29][CH2:28]1)C>C1COCC1.ClCCl.C(OCC)(=O)C.CCCCCC>[Cl:40][C:35]1[CH:34]=[C:33]([C:27]2([CH2:26][CH2:25][OH:24])[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cool a solution of lithium aluminum hydride (450 mL, 1M in THF, 450 mmol) to −10° C. in a ice/acetone bath. Add dropwise, a solution of sulfuric acid (12 mL, 99.999%, 225.3 mmol) in THF (35 mL). (Use caution when adding the sulfuric acid to the THF and also when adding the sulfuric acid/THF solution to the lithium aluminum hydride solution). After the addition is complete, stir for 1 hour. Warm to ambient temperature and stir for 2 hours. Add dropwise, a solution of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (23.2 g, 73.4 mmol) in THF (70 mL). Heat to 45-50° C. for 36 hours. Cool in an ice bath. Add dropwise, a solution of THF/water (1/1, 70 mL). Filter and rinse the filter cake with THF and dichloromethane, retain the filtrate. Combine the filter cake with THF/water/15% sodium hydroxide solution (1 L/70 mL/20 mL) and vigorously stir for 2 hours. Filter and combine the filtrate with the filtrate obtained above. Concentrate the combined filtrates in vacuo to obtain a residue. Dissolve the residue in dichloromethane and dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Recrystallize the residue from diethyl ether to give the title compound: Rf=0.27 (silica gel, 9:1:0.2; dichloromethane/methanol/ammonium hydroxide); mp; 91-94° C. Elemental Analysis calculated for C12H15Cl2NO: C 55.40; H 5.81; N 5.38; Found: C 55.64; H 5.88; N 5.20.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:9][C:10]1[CH:36]=[CH:35][C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28](=[O:31])(=[O:30])[NH2:29])=[O:20])=[CH:12][CH:11]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:29][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:31])=[O:30])=[O:20])=[CH:35][CH:36]=1
Reactant: CCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
In a stream of nitrogen and at 0° C., 0.18 ml (1.30 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.2 mmol) of 3-(4-chlorobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 4 and 293 mg (2.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 600 mg (yield: 97%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10](=[O:12])[CH3:11])=[C:8]([CH2:13][CH3:14])[N:7]=[C:6]1[CH2:15][CH2:16][CH3:17].C([N-]C(C)C)(C)C.[Li+].[O:31]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]I)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([CH2:11][CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:12])=[C:8]([CH2:13][CH3:14])[N:7]=[C:6]1[CH2:15][CH2:16][CH3:17]
Reactant: ICc1ccccc1Oc1ccccc1
Reactant: CCCc1nc(CC)c(C(C)=O)n1Cc1ccc(I)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1nc(CC)c(C(=O)CCc2ccccc2Oc2ccccc2)n1Cc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
1-(2-fluoro-4-iodobenzyl)-5-acetyl-4-ethyl-2-propyl- 1H-imidazole (5.52 g, 13.3 mmol) was dissolved in 50 mL of THF. The mixture was cooled at 0° C. under N2 and lithium diisopropylamide (7.3 mL of 2M in THF, 14.6 mmol) was added. After stirred at 0° C. for 15 minutes, a solution of o-phenoxybenzyl iodide (5.22 g, 16.8 mmol) in THF (15 mL) was added. The reaction mixture was warmed up to room temperature and stirred for 2 h. The mixture was partitioned between EtOAc and H2O. The two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine, dried over MgSO4. It was concentrated and chromatographed on silica gel with 10-50% EtOAc/hexane to yield 2.35 g of the desired product. MS m/e 597.2, [M+H]+ ; IR (KBr): 1646 cm-1 for CO; 1H NMR (300 MHz, CDCl3): δ 0.95 (t, 3H, CH3), 1.22 (t, 3H, CH3), 1.65 (m, 2H, CH2), 2.57 (m, 2H, CH2), 2.82 (q, 2H, CH2), 2.98 (m, 2H, CH2), 3.10 (m, 2H, CH2) 5.42 (s, 2H, CH2Ar), 6.22 (t, 1H, ArH), 6.82 (d, 1H, ArH), 6.90 (d, 2H, ArH), 7.02 (m, 2H, ArH), 7.18 (d, 1H, ArH), 7.22 (m, 2H, ArH), 7.30 (m, 2H, ArH), 7.40 (d, 1H, ArH). ##STR66##
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.O.CN(C)[CH:19]=[O:20]>>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:19]=[O:20]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(Cl)cc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
18.5 g (0.12 mole) of phosphorus oxychloride are added to 75 ml of dry dimethylformamide at 5°C. 15.15 g (0.1 mole) of 5-chloroindole dissolved in 30 ml of dry dimethylformamide are then added at 5°C. This is stirred for 30 minutes at 20°C, then for 30 minutes at 40°C. 240 ml of water followed by 72 ml of 40% soda are then quickly added. The yellow solution obtained is maintained at 40°-45°C for one hour. After 11/2 hours stirring at ambient temperature the precipitate formed is filtered off and recrystallised from ethyl alcohol.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 0.83 h
Yield: 92.9 %

Procedure:
(S)-(1-Benzyl-2-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (8.10 g, 15.1 mmol, Example 51) was dissolved in CH2Cl2 (50 mL) under nitrogen at ambient temperature. To this solution was added trifluoroacetic acid (12 mL). The resulting reaction mixture was stirred for 50 minutes, then concentrated in vacuo. The viscous pale-amber oil obtained was mixed with 50 mL of saturated aqueous NaHCO3 solution and stirred for 10 minutes, 50 mL of CH2Cl2 was then added. The resulting mixture was stirred until bubbling ceased. The two layers were separated, organic layer was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording 6.11 g (92%) of the pure titled compound as a off-white foam: mp 44-51° C. APCI-MS m/z 436.3 (MH+).
Reaction SMILES: CC1CCCO1.[Br:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([N+:26]([O-])=O)[C:20]=3[F:29])=[O:18])=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.[Sn](Cl)Cl>>[NH2:26][C:21]1[C:20]([F:29])=[C:19]([C:17]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([Br:7])[CH:9]=3)[NH:14][CH:15]=2)=[O:18])[C:24]([F:25])=[CH:23][CH:22]=1
Reactant: O=C(c1c(F)ccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(Br)cc12
Agent: Cl[Sn]Cl
Solvent: CC1CCCO1
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 60 °C
Yield: 96.6 %

Procedure:
A 50-liter flask was added 2-methyl-tetrahydrofuran (2-methyl-THF) (36 L), compound 3 (2.85 kg, 7.455 mol) and tin(II) chloride (5.03 kg, 22.365 mol). The mixture was heated to 60° C. Upon completion, the reaction was quenched with an aqueous potassium carbonate solution (20%). The resulting mixture was filtered with celite and the solid residue was washed with 2-methyl-THF and tetrahydrofuran (THF). The filtrate was washed with an aqueous NaCl solution (15 L, 10%) and the organic layer was separated. The organic layer was further washed with an aqueous NaCl solution (15 L, 20%) and concentrated on a rotovap to yield compound 4 (2.536 kg, 96.65% yield). MS (ESI): M+H+=353 and 354. 1H NMR (DMSO-d6, δ ppm): 5.22 (2H, s), 6.93 (2H, m), 8.12 (1H, s), 8.47 (1H, d J=2.3 Hz), 8.54 (1H, d J-1.6 Hz), 13.2 (1H, s).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.B.[Na]>C(O)C>[OH:3][CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: B
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(C(C)O)cc1
Temperature: 0 °C
Yield: 98.5 %

Procedure:
71.2 g (0.4 mol) of methyl 4-acetylbenzoate, 300 ml tetrahydrofuran and 100 ml of ethanol were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 7.6 g (0.2 mol) of sodium boron hydride was added at 15°-25° C. over a period of 3 hours. The mixture was maintained at the same temperature for 5 hours and the resulting reaction solution was poured into ice-water and extracted twice with 400 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 71.0 g of methyl 4-(1-hydroxyethyl)benzoate (IIII-1) in a 98.6% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[C:11]([OH:19])(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)(=O)CCCCCC.C([Sn](=O)CCCC)CCC>[C:11]([O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([O:9][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]([CH3:8])[CH3:7])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: CCCCCCC(=O)O
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCC(=O)OCC(C)(C)C(OC(=O)CCCCCC)C(C)C

Procedure:
Into a 3-liter four neck flask equipped with stirrer, thermometer, a nitrogen inlet tube, Dean-Stark trap and condenser was charged 492 grams (3.36 moles) of 2,2,4-trimethyl-1,3-pentanediol; 963 grams n-heptanoic acid (7.40 moles) and 0.1 wt. percent of dibutyl tin oxide as catalyst. The reaction was carried out under reflux conditions at 220° C. to a hydroxyl value <2.0. The excess heptanoic acid was stripped under reduced pressure for a TAN <1.0. The ester was subsequently treated with concentrated caustic, stripped and filtered to yield 1170 grams of 2,2,4-trimethyl-1,3-pentanediol di-n-heptanoate.
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].N1C=CC=CC=1.CC1C=CC(S(OCCCCC#C)(=O)=O)=CC=1.[O:42]=[CH:43][C:44]1[CH:52]=[CH:51][C:49](O)=[C:46]([O:47][CH3:48])[CH:45]=1>C(Cl)Cl>[CH2:12]([O:18][C:49]1[CH:51]=[CH:52][C:44]([CH:43]=[O:42])=[CH:45][C:46]=1[O:47][CH3:48])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: C#CCCCCO
Agent: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCCCCOc1ccc(C=O)cc1OC
Yield: 61.5 %

Procedure:
4-Methylbenzenesulfonyl chloride (2.9 g, 15 mmol), 5-hexyn-1-ol (1.1 mL, 10 mmol) and pyridine (1.6 mL, 20 mmol) in CH2Cl2 (10 mL) were treated according to Procedure 4 giving hex-5-ynyl 4-methylbenzenesulfonate (2.1 g, 83%) as a colourless oil. Vanillin (0.84 g, 5.6 mmol) was alkylated with hex-5-ynyl 4-methylbenzenesulfonate (2.1 g, 8.3 mmol) according to Procedure 4 and the crude product was recystallised from EtOAc/petrol to provide 4-(hex-5-ynyloxy)-3-methoxybenzaldehyde (0.80 g, 62%) as a colourless crystalline solid; mp 67-68° C.; δH (400 MHz, CDCl3) 1.74 (p, J=7.0 Hz, 2H, CH2), 1.97 (t, J=2.8 Hz, 1H, C≡CH), 2.02 (p, J=7.0 Hz, 2H, CH2), 2.30 (td, J=7.0, 2.8 Hz, 2H, CH2C≡CH), 3.92 (s, 3H, OCH3), 4.14 (t, J=7.0 Hz, 2H, OCH2), 6.97 (d, J5,6=8.0 Hz, 1H, H5), 7.41 (s, 1H, H2), 7.43 (d, J5,6=8.0 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 18.1, 24.9, 27.9, 56.0, 68.5, 68.8, 83.9, 109.3, 111.4, 126.7, 130.0, 149.9, 154.0, 190.9; vmax 1029, 1269, 1584, 1681, 2956, 3246 cm−1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=O)(C)(C)C>C(O)=O>[Cl:21][C:18]1[N:17]=[CH:16][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:6])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cl)nc1
Solvent: O=CO
Product: CN1CCC[C@H]1COc1ccc(Cl)nc1

Procedure:
A 625 mg sample of 3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)-6-chloropyridine, prepared as in Example 45a, was treated with 2 mL of 37% parafornaldehyde and 1 mL of formic acid at reflux for 16 hours. The volatiles were removed by evaporation, and the residue was dissolved in 1 mL of 20% NaOH. The solution was extracted with CH2Cl2 (3×), then the organic layer was dried (Na2SO4) and concentrated. The crude product was purified by chromatography over silica gel, eluting with 100:1 chloroform:methanol to afford 439 mg of the title compound. MS (DCI/NH3) m/e: 227/229 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.09 (dd, J=2.1, 2.1 Hz, 1H), 7.24-7.21 (m, 2H), 4.02 (dd, J=11.0, 3.0 Hz, 1H), 3.93 (dd, J=11.0, 5.8 Hz, 1H), 3.21-3.10 (m, 1H), 2.76-2.64 (m, 1H), 2.51 (s, 3H), 2.40-2.28 (m, 1H), 2.12-1.98 (m, 1H), 1.97-1.68 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Yield: 28.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyrazin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.32 g, 29%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:23][CH2:24][CH3:25]>>[C:1]1([CH2:7][CH2:8][N:9]([CH2:23][CH2:24][CH3:25])[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCI
Reactant: N#Cc1ccc(NCCc2ccccc2)cc1C(F)(F)F
Product: CCCN(CCc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized in a manner similar to step B of Example 1 using 4-[(2-phenylethyl)amino]-2-(trifluoromethyl)benzonitrile, Example 122A and iodopropane: MS (ES) m/z 333 (M+1).