Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[S:55]1[CH:56]=[CH:57][N:58]=[C:54]1[NH:53][C:36](=[O:38])/[C:35](/[C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[C:41]([C:49]([F:52])([F:50])[F:51])[CH:40]=1)=[CH:34]/[CH2:33][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A solution of triphenylphosphine (550 mg, 2.1 mmol) in methylene chloride (25 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (374 mg, 2.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-4-cyclopentyl-2-[4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-but-2-enoic acid (395 mg, 1.05 mmol) in methylene chloride (5 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (320 mg, 3.2 mmol), and the resulting suspension was stirred at 25° C. over the weekend. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded the (E)-4-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-but-2-enoic acid thiazol-2-ylamide (77 mg, 16%) as an amorphous solid: EI-HRMS m/e calcd for C20H21F3N2O3S2 (M+) 458.0946, found 458.0946.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].Cl[C:13]1[C:14]2[C:21]([CH3:22])=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:19][C:15]=2[N:16]=[CH:17][N:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([O:4][C:5]1[C:10]([NH:11][C:13]2[C:14]3[C:21]([CH3:22])=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ncccc1N
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)C)c2c1C
Temperature: 90 °C
Yield: 66.5 %

Procedure:
iso-Propoxypyridin-3-amine (1.30 g, 8.60 mmol) was added into a solution of methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (2.295 g, 9.46 mmol), XANTPHOS (0.995 g, 1.72 mmol) and cesium carbonate (3.922 g, 12.04 mmol) in degassed 1,4-dioxane (40 mL). The mixture was degassed under sonnication, tris(dibenzylideneacetone)dipalladium (0.394 g, 0.430 mmol) added and the mixture sonnicated further. The reaction was sealed, heated at 90° C. for 3.0 hours, cooled, filtered and the solid washed with cold 1,4-dioxane. The filtrate was poured into ammonium hydroxide solution and the precipitate collected to yield the title compound as dark yellow solid (2.05 g, 66%).
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.[F:12][C:13]([F:15])=[CH2:14].[CH:16]1([CH2:22][CH:23]=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[NH4+].[Cl-]>C1COCC1.CCOCC.[Cl-].[Na+].O>[F:12][C:13]([F:15])=[CH:14][CH:23]([OH:24])[CH2:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CCC1CCCCC1
Reactant: C=C(F)F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OC(C=C(F)F)CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2,2-Difluorovinyllithium1 was prepared by dropwise addition of sec-butyllithium in cyclohexane (88 mL of 1.4M, 0.123 mol, 1.0 equiv) during 10 minutes to a stirred solution of 1,1-difluoroethylene (15.3 g, 0.230 mol, 1.9 equiv) in THF (140 mL) and ether (20 mL). The reaction mixture was maintained between -100° and -93° C. during this addition and was subsequently stirred 10 minutes at -100° C. Cyclohexylacetaldehyde (15.6 g, 0.123 mol, 1.0 equiv) was added dropwise over 5 minutes (the reaction temperature rose to -89° C.), and the resulting mixture was stirred 1 hour between -110° and -93° C. Saturated aqueous NH4Cl (50 mL) was then added, and the mixture was warmed to 0° C. and treated with ether (500 mL) and brine. After separation the organic layer was washed twice with 1N aqueous HCl, H2O, aqueous saturated NaHCO3, and dried over MgSO4. Concentration at reduced pressure gave a yellow oil which was distilled (a small amount of CaCO3 was added) at reduced pressure (ca. 0.1 Torr) giving 6.7 g of the pure title substance as a colorless liquid (bp 65°-70° C.), together with 25° C.-65° C. (5.2 g) and 70°-80° C. (5.2 g) fractions. Separate distillation of these impure fractions separated less polar (TLC) lower and higher boiling contaminants, respectively, affording additional samples of product (total yield, 12.7 g, 54%): TLC Rf 0.15 ether-hexanes; 1H-NMR (300 mHz, CDCl3) δ 0.97 (m, 2H), 1.07-1.93 (overlapping m, 15H), 4.12 (ddd, 1H, J=22, 10, ca 2 Hz), 4.52 (m, 1H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[CH:7])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:29]([SnH:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH2:38]([Sn:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:34][CH2:35][CH2:36][CH3:37])/[CH:7]=[CH:6]/[CH:5]([O:4][Si:3]([CH2:13][CH3:14])([CH2:1][CH3:2])[CH2:15][CH3:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:39][CH2:40][CH3:41]
Reactant: C#CC(CCCCC)O[Si](CC)(CC)CC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Temperature: 25 °C

Procedure:
A solution of 20 g of 3-triethylsilyloxy-1-octyne, 150 mg of azobisisobutyronitrile, and 30 ml of tri-n-butyltin hydride is magnetically stirred under an argon atmosphere at 140° C. for 2 hours, (EXOTHERMIC), then cooled to ambient temperature. The excess tin hydride is removed by distillation (~70°/1.0 mm). The residue is purified by distillation to provide 36.5 g of the oil (bp 165° C. at 0.05 mm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: NCCCCO
Product: O=S(=O)(NCCCCO)c1ccc(Br)cc1C(F)(F)F

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-2-trifluoromethylphenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol. δC (CDCl3, 62.9 MHz): 26.5, 29.4, 43.3, 62.1, 127.3, 131.7, 131.7, 133.1, 135.4 and 137.9.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C@H:11](O)[C:12]([O:14][CH3:15])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C@H:11]([CH3:10])[C:12]([O:14][CH3:15])=[O:13])=[O:6]
Reactant: COC(=O)[C@H](C)O
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
2.50 g of 3-hydroxybenzaldehyde, 2.77 g of methyl L-(−)-lactate, and 6.44 g of triphenylphosphine were dissolved in 25.0 mL of THF, and 22.2 mL of a 2.2 M diethyl azodicarboxylate/toluene solution was added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction liquid was added an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 1:1) to obtain 1.67 g of methyl (2R)-2-(3-formylphenoxy)propionate. The obtained methyl (2R)-2-(3-formylphenoxy)propionate was dissolved in 33.3 mL of methanol, and 394 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 30 minutes. To the reaction liquid were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 1.68 g of methyl (2R)-2-[3-(hydroxymethyl)phenoxy]propionate.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:18]=[C:17]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccccc1F
Product: COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1F
Yield: 83.3 %

Procedure:
The title compound was prepared from 1-fluoro-2-methoxybenzene (10 mL) and 1-bromoadamantane (3.25 g, 15.25 mmol) according to the step 1 of the example 5, which was given 1-(3-fluoro-4-methoxyphenyl)adamantane (5.05 g, 83.3% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][O:6][C:5]2([CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([O:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[CH:20][CH:19]=3)[CH3:17])[C:9]([CH3:29])([CH3:28])[CH2:8]2)[O:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH3:30][C:2]1([CH3:1])[CH2:7][O:6][C:5]2([CH2:8][C:9]([CH3:28])([CH3:29])[N:10]([O:15][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[CH3:17])[C:11]([CH3:14])([CH3:13])[CH2:12]2)[O:4][CH2:3]1
Reactant: CC(=O)Oc1ccc(C(C)ON2C(C)(C)CC3(CC2(C)C)OCC(C)(C)CO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(ON1C(C)(C)CC2(CC1(C)C)OCC(C)(C)CO2)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8 g acetic acid 4-[1-(3,3,8,8,10,10-hexamethyl-1,5-dioxa-9-aza-spiro[5.5]undec-9-yloxy)-ethyl]-phenyl ester and 3.9 g potassium carbonate in 60 ml methanol is stirred for one hour at room temperature. The mixture is cooled to 0° C. and neutralized by adding 60 ml of 0.5 M hydrochloric acid. The white suspension is diluted with water (60 ml) and filtered through a buchner funnel. The residue is washed with water and dried in a vacuum oven at 50° C. A white solid having a melting point of 133-134° C. is obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]([CH:14]=1)=[N:11][Se:12][N:13]=2>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]([C:14]=1[N+:1]([O-:4])=[O:2])=[N:11][Se:12][N:13]=2
Reactant: Clc1ccc2n[se]nc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2n[se]nc12
Reaction time: 2 h
Yield: 98.9 %

Procedure:
At 0-5° C., a 65% aqueous solution of HNO3 (6.5 g, 103.5 mmol, 3.3 equiv) was added to a solution of 5-chloro-benzo[1,2,5]selenadiazole (6.82 g, 31.35 mmol; 1H NMR (400 MHz, d6-DMSO): δ=7.96 (d, J=1.4 Hz, 1H), 7.82 (d, J=10.2 Hz, 1H), 7.52 (dd, J=10.2/1.4 Hz, 1H)) in sulfuric acid (95-97%, 100 ml). After 2 hours at 5° C., the reaction mixture was poured onto ice water, and the precipitate was filtered off. The solid was washed with water and dried under high vacuum to afford the title compound (8.14 g, 99%). 1H NMR (400 MHz, d6-DMSO): δ=8.13 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccc(Cl)c(C2CC(=O)c3c(C)cnnc3C2)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=NNC(=N)N)c3c(C)cnnc3C2)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
To a mixture of 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.4 g) and aminoguanidine hydrochloride (0.164 g) were added ethanol (8 ml) and concentrated hydrochloric acid (0.15 ml), and the mixture was stirred at 110° C. (bath temperature) for 1.5 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2-chloro-5-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 173) (0.261 g) as blue white crystals.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(OC(=O)C)(=O)C.C(N(CC)CC)C>C([O-])(=O)C.[Ni+2].C([O-])(=O)C.O.CN(C)C=O>[CH2:8]([N:20]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1 Mole of maleic anhydride and 300 g of dimethylformamide were charged into a 2-liter three-necked flask and stirred to dissolve the maleic anhydride into the dimethylformamide. To the resulting solution were added, with stirring, 1.02 moles of laurylamine over a period of 30 minutes while cooling the flask in a cold water bath. The exothermic reaction occurred simultaneously with the addition of the laurylamine which was, therefore, so carefully done that the temperature of the reaction mixture could be maintained at around 50° C. Immediately after completion of the addition of the laurylamine, the bath temperature was increased to 50° C. at which the stirring was continued for 1 hour. After completion of the amide-formation reaction, 1.6 moles of acetic anhydride, 0.016 mole of nickel acetate and 0.16 mole of triethylamine were added, with stirring, to the reaction mixture. The resulting mixture was heated to 90°-95° C. at which the stirring was continued for 1.5 hours to effect the dehydration reaction. Subsequently, the reaction mixture was cooled to room temperature and poured into ice and water to yield a precipitate. The precipitate was collected by filtration, washed with water, neutralized with sodium carbonate and recrystallized twice from water-containing ethanol (90%) to obtain white crystals of N-laurylmaleimide having a melting point of 56° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]#[N:16])=[C:10]([Cl:17])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]#[N:16])=[C:10]([Cl:17])[N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Cl)cc(N)nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl(4,6-dichloro-5-cyanopyridin-2-yl)carbamate (2.1 g, 7.2 mmol) in dichloromethane (30.0 mL) was added TFA (3.0 mL) at 0° C. and stirred at the room temperature for 3 h. After confirming the completion of starting material by TLC, the reaction mixture was concentrated and the crude product was purified by column chromatography (dichloromethane:methanol=9:1) to afford titled compound. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 7.81 (bs, 2H), 6.59 (s, 1H), MS ES calc'd. for C6H3C12N3 [M+H]+ 188. Found 188.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.Cl>C(N(C(C)C)CC)(C)C>[CH3:1][O:2][CH2:3][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
4 ml of chloromethyl methyl ether was added dropwise to a solution of 4′-hydroxyacetophenone (5.44 g) and diisopropylethylamine (10 ml) in 40 ml dinethylformamide at room temperature and stirred at room temperature for 3 hours. After addition of 2 mol/l hydrochloric acid, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give a residue, which was then purified via column chromatography on silica gel (hexane:ethyl acetate=7:1) to provide 4′-(methoxymethoxy)acetophenone (6.73 g, 93%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2CO2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2cccc(F)c2)cc1
Temperature: 78 °C
Yield: 16.9 %

Procedure:
To a stirring solution of 2-(3-fluorophenyl)oxirane (5.60 g, 40.5 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction mixture was allowed to cool to RT and then extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed eluting with 30-40% EtOAc/hexanes to give 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.78 g (17%) of the title compound as a white solid. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) of the regioisomer as a nearly colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@H:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH:20]([CH3:22])[CH3:21]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)[C@@H](N)CO
Product: CC(C)[C@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-3-methyl-1-butanol (CAN 4276-09-9) as starting materials and isolated (51 mg, 54%) as colorless oil; MS (ESI, m/z): 313.1 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14](=O)[C:15]([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound is synthesized by reductive amination of 1-Boc-piperazine and Pivalaldehyde analogously to the preparation of Example 233 as a colorless oil; ES-MS: M+H=257.3; TLC: Rf=0.82 (DCM/EtOAc=4:1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][O:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: Oc1cccc2c1OCCO2
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cccc2c1OCCO2)OCC
Temperature: 140 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of 2,3-dihydro-5-hydroxy-1,4-benzodioxin (0.13 mol), 2-bromo-1,1-diethoxyethane (0.13 mol) and potassium carbonate (0.13 mol) in N,N-dimethylacetamide (250 ml) was stirred overnight at 140° C. The solvent was evaporated. The residue was partitioned between 1,1'-oxybisethane and water. The organic layer was separated, washed with a saturated NaCl solution, dried (MgSO4), filtered and the solvent was evaporated. The residual oil was crystallized from 2,2'-oxybispropane. The precipitate was filtered off and dried, yielding 21 g (60.2%) 5-(2,2-diethoxyethoxy)-2,3-dihydro-1,4-benzodioxin; mp. 73.1° C. (interm. 11).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(CC)(=O)=O)=CC=1C(O)=O.N1CCCC1>>[CH2:1]([S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH3:20]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CCS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 73 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(ethane-2-sulfonyl)-benzoic acid and pyrrolidine and obtained in 73% yield. MS (m/e): 282.2 (MH−, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([O:7][C:6]2[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of the product from step 4 (3.47 g, 10.2 mmol) in DMF (46.0 mL) was added potassium carbonate (2.85 g, 20.6 mmol) and methyl 4-bromobutyrate (1.48 mL, 12.9 mmol). The resulting suspension was stirred at ambient temperature overnight. The reaction mixture was diluted with water and ethyl acetate. The crude residue was extracted into ethyl acetate. The organic portion was washed with water, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (2.30 g, 63%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[CH3:9][N:8]1[C:13](=[O:14])[C:12](=[O:16])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2
Reactant: CNc1ncccc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2cccnc21

Procedure:
3-amino-2-(N-methylamino)-pyridine (0.1 mol) and oxalic acid dihydrate (0,12 mol) was dissolved in 4N HCl (400 ml). The solution was refluxed for 8 hours and then cooled to room temperature whereby the title compound precipitated as crystals. The crystals were separated by filtration and then washed with water. m.p. 271°-272° C.