Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:19]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])[CH2:18]S[CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.CC(C)=O.O.[S:36]([O-:41])(O[O-])(=O)=[O:37].[K+].[K+]>CO>[O:37]=[S:36]1(=[O:41])[CH2:18][C@@H:19]([NH:20][C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[C@H:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8]2)=[O:14])[CH2:16]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: C[C@@H](N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 72.1 %

Procedure:
[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-[(3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydro-thiophen-3-yl]-methanone (1.02 g, 2.39 mmol) was dissolved in methanol (10 mL) and acetone (10 mL) and stirred on ice. Water (10 mL) was added, and the resulting heterogeneous mixture was treated with potassium peroxymonosulfate (Oxone®, 3.67 g, 5.98 mmol). After 5 min the cooling bath was removed and the mixture was stirred at room temperature. After 20.5 h, the mixture was concentrated and diluted with water. The pH was adjusted to ca. 11 with 1N sodium hydroxide, and the mixture was extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated, and the residue was purified by flash column chromatography (2.5% 2-propanol/chloroform) to provide the product as a glass (790 mg, 72%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH3:20])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.C(Cl)(Cl)Cl>[CH2:18]([C:15]1[N:14]=[C:13]([CH:12]=[CH:11][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:17][N:16]=1)[CH2:19][CH3:20]
Reactant: CCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-propyl-[1,2,4]oxadiazole (compound of Example 3, Method A, Step 1; 1.28 g, 4.66 mmol) was dissolved in dichloromethane (15 mL) and cooled to −78° C. A solution of boron tribromide (4.42 mL, 4.66 mmol) in dichloromethane (5 mL), which was cooled to 0° C., was added slowly over a period of 25 min. After 2 h, the reaction mixture was allowed to warm to room temperature (25° C.) and stirred for 2 h. At the end of the reaction, the mixture was quenched by dropwise addition of methanol (15 mL) at 0° C. and stirred for 20 min at room temperature. The solvent was evaporated and the residue obtained was redissolved in 10% methanol in chloroform at 0° C. and stirred with solid sodium carbonate to obtain pH ˜8. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH2:17]=O>>[O:14]1[CH2:15][CH2:16][N:11]([CH2:17][N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[O:1][C:2]2=[O:10])[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: C1COCCN1
Reactant: C=O
Product: O=c1oc2cccnc2n1CN1CCOCC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4.1 g (0.03 mol) of 3H-oxazolo[4,5-b]pyridin-2-one are dissolved in 100 ml of alcohol at 95° C. 2.88 g (0.33 mol) of morpholine and then 3 ml of 30% aqueous formaldehyde solution are added. The mixture is stirred on a water bath at a temperature in the region of 50° C. for one hour 30 minutes, stirring being maintained. The mixture is left to stand for one hour at room temperature. The crystals are drained and recrystallized.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[Br-:6].[CH2:24]([N+:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: c1cscn1
Product: CCCCCCCCCCCCCCCCCC[n+]1ccsc1
Product: [Br-]
Temperature: 120 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
In a 100 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 3.8 g of thiazole and 10.0 g of 1-bromoctadecane, and the mixture was stirred at 120° C. for 5 hours. After cooling the reaction mixture to room temperature, precipitated crystals were collected by filtration under reduced pressure. The resulting crystals were recrystallized from a mixed solvent of acetone and methanol to obtain 9.1 g of the title compound. Melting point: 83° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[NH3:12]>>[NH2:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: N
Reactant: NS(=O)(=O)c1cnccc1Cl
Product: Nc1ccncc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
15 g of 4-chloropyridine-3-sulfonamide are dissolved in 150 cm3 of concentrated aqueous ammonia. The clear solution is saturated with a stream of gaseous ammonia for exactly half an hour before being introduced into a sealed tube. The tube is placed at 150° C. for 18 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:39])=[C:20]([C:35]([Cl:38])=[CH:36][CH:37]=2)[CH2:21][O:22][C:23]2[C:31]3[N:30]=[C:29]([O:32][CH3:33])[N:28]([CH3:34])[C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:48][C:49]1[C:54]([C:55](Cl)=[O:56])=[CH:53][CH:52]=[CH:51][N:50]=1>ClCCl>[Cl:39][C:19]1[C:18]([N:16]([CH3:17])[C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[N:7][C:2]([NH:1][C:55]([C:54]3[C:49]([CH3:48])=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:56])=[CH:3][CH:4]=2)=[CH:37][CH:36]=[C:35]([Cl:38])[C:20]=1[CH2:21][O:22][C:23]1[C:31]2[N:30]=[C:29]([O:32][CH3:33])[N:28]([CH3:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ncccc1C(=O)Cl
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(N)nc4)c3Cl)cccc2n1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(=O)c5cccnc5C)nc4)c3Cl)cccc2n1C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-aminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (100 mg) and triethylamine (53.3 mg) in dichloromethane (2 ml) was added 2-methyl-3-pyridinecarbonyl chloride hydrochloride (74.2 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and then for 3 hours at ambient temperature. The reaction mixture was concentrated, and the residue was dissolved in methanol (3 ml). To the solution was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 1 hour. Chloroform was added to the reaction mixture, and the solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-methylpyridin-3-carboxamido)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (99 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CN(C=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[O:22])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1
Reaction time: 24 h
Yield: 87.8 %

Procedure:
0.340 g of tert-butyl-6-[3-(8-fluoro-quinolin-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylate (0.734 mmol) were dissolved in a mixture of 220 ml of DMF and 125 ml of methanol. After addition of 0.078 g of Pd/C (0.734 mmol) and 0.5 ml of acetic acid (8.73 mmol) hydrogenation was performed for 24 h at room temperature, which led to complete double bond hydrogenation according to HPLC/MSD analysis. The catalyst was filtered off, the solvent removed under reduced pressure and the residue extracted three times with ethyl acetate after adding water and a small amount of NaOH (pH 9). The combined organic phases were washed with a small amount of brine, dried over sodium sulfate and the solvent was removed under reduced pressure. 300 mg of the desired product were obtained as a powder (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[C:19]([O:20][CH3:21])=[CH:18][C:16]([NH2:17])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:17][C:16]2[CH:18]=[C:19]([O:20][CH3:21])[C:13]([O:12][CH3:11])=[CH:14][C:15]=2[N+:22]([O-:24])=[O:23])=[O:7])=[CH:9][CH:10]=1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1cc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])cc1OC

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4,5-dimethoxy-2-nitroaniline as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.84 (s, 1H), 9.04 (d, J=1.8, 1H), 8.66 (s, 1H), 8.25-8.21 (m, 1H), 7.77 (s, 1H), 7.53 (d, J=8.7, 1H), 4.07 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([C:20]=1[CH2:21][OH:22])=[N:18][C:17]1[C:16]([CH2:23][OH:24])=[C:15]([O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:14]=[CH:13][C:12]=1[CH:11]=2)[CH3:2]>CS(C)=O.C(N(CC)CC)C>[CH2:31]([N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][O:25][C:15]1[CH:14]=[CH:13][C:12]2[C:17]([C:16]=1[CH:23]=[O:24])=[N:18][C:19]1[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:33][CH3:34])[CH2:1][CH3:2])[C:20]=1[CH:21]=[O:22])[CH:11]=2)[CH3:32]
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(CO)c3nc2c1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(C=O)c3nc2c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 0.469 g of 3,6-bis[2-(diethylamino)ethoxy]-4,5-acridinedimethanol in a mixture of 5.0 ml of anhydrous dimethyl sulfoxide and 2.8 ml of triethylamine is added a solution of 0.96 g of sulfur trioxide-pyridine complex in 5 ml of anhydrous dimethyl sulfoxide. The reaction mixture is stirred at room temperature for one hour. Most of the dimethyl sulfoxide is removed under reduced pressure without heat. The residue is treated first with 50 ml of saturated sodium bicarbonate solution and then with 50 ml of water, giving 0.35 g of the desired product as a yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[C@H:11]2[CH2:28][CH2:27][C@@:26]3([CH3:29])[C:13](=[CH:14][CH2:15][C@@H:16]4[C@@H:25]3[CH2:24][CH2:23][C@@:21]3([CH3:22])[C@H:17]4[CH2:18][CH2:19][C:20]3=[O:30])[CH2:12]2)(=O)=O)=CC=1.[CH2:32]([OH:36])[CH2:33][CH2:34][OH:35].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[OH:35][CH2:34][CH2:33][CH2:32][O:36][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]43)C2)cc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C[C@]12CC[C@H](OCCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
3β-(p-Toluensulfonyloxy)androst-5-en-17-one (12.00 g) was added to a suspension of propane-1,3-diol (61 mL) and PTSA (610 mg) at 95° C. After stirring for 40 minutes, the mixture was cooled to room temperature, and poured in water (800 mL), bringing the pH to 7 with 5% NaHCO3. After 3 hrs the solid was filtered and dissolved in CH2Cl2. The solution was dried over Na2SO4 and evaporated to dryness under reduced pressure to give 3β-(3-hydroxypropoxy)androst-5-en-17-one (9.10 g, 97%), used without further purification. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 5.35 (1H, m), 4.34 (1H, t), 3.43 (4H, m), 3.06 (1H, m), 2.45-0.85 (21H, m), 0.96 (3H, s), 0.79 (3H, s).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a suspension of Mg (1.7 g, 0.07 mol) in dry ether (25 mL) was added a solution of benzyl bromide (10 mL, 1.5 equ.) in dry ether (25 mL) drop-wise and allowed to stir at RT for 1 h. By the time all magnesium was dissolved and the reaction mixture was cooled to 0° C. To this was added a solution of benzophenone (10 g, 0.05 mol) in dry ether (25 mL) and allowed to stir at RT for 5 h. The progress of the reaction was followed by TLC and when it was ready the reaction mixture was quenched with saturated NH4Cl solution, extracted with ether (100 mL), washed with brine, dried and concentrated under vacuum. The crudeproduct was purified by column chromatography on silica gel (10% ethyl acetate in pet. ether) to give the title compound (9.6 g, 65%) as a white solid. TLC: Pet. ether/EtOAc, 9:1, Rf=0.4
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[BH4-].[Na+].O.CCO[C:24]([CH3:26])=O>C1COCC1>[C:1]1([CH:24]([CH3:26])[CH2:10][CH2:11][NH:12][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of amine 14 (1.3 g, 6.2 mmol) in THF (75 mL) was added 5 (1.44 g, 6.22 mmol). The reaction mixture was stirred for 1 hour, NaBH4 (329 mg, 8.71 mmol) was added followed by water (30 mL). The reaction mixture was stirred for 45 minutes then diluted with EtOAc. The mixture was washed with 1N HCl and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:5:1 CH2Cl2:MeOH:NH4OH) gave 6-[trans-4-(3-phenylbutylamino)cyclohexyl]-3H-benzoxazol-2-one (640 mg, 28%), as a white solid: 1H NMR (300 MHz, DMSO-d6): δ 7.31-7.11 (m, 7H), 6.94 (s, 1H), 2,78 (m, 1H), 2.45-2.35 (m, 5H), 1.87 (br d, J=10 Hz, 2H), 1.73 (br d, J=10 Hz, 2H), 1.68 (m, 2H), 1.44 (dddd, J=10, 10, 10, 2 Hz, 2H), 1.19 (d, J=4 Hz, 3H), 1.08 (dddd, J=10, 10, 10, 2 Hz, 2H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH3:19])([OH:3])=[O:2].[CH2:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH:22]=[CH2:23].[OH-].[K+]>C(O)C>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH:19]=[CH:28][C:27]1[CH:30]=[CH:31][C:24]([CH2:21][CH:22]=[CH2:23])=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: C=CCc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(OCC=C(C)C)cc1OCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)O)cc1
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 834 mg of 2'-(1-carboxymethoxy)-4'-(3-methyl-2-butenyloxy)acetophenone and 500 mg of 4-(2-propenyl)benzaldehyde in 10 ml of ethanol was added 842 mg of potassium hydroxide, and the mixture was stirred for 20 minutes. After neutralization with dilute hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate - n-hexane to give 360 mg of the title compound as a pale yellow needles.
Reaction SMILES: [C:1](#N)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Mg].[CH2:11]([Mg]Br)[CH:12]([CH3:14])[CH3:13].Cl.[O:18]1CCCC1>C(OCC)C.O>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[O:18])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: N#Cc1ccccc1N
Reactant: CC(C)C[Mg]Br
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC(C)CC(=O)c1ccccc1N
Yield: 25 %

Procedure:
At reflux, a solution of 29.5 g (0.25 mol) of anthranilonitrile in 150 ml of tetrahydrofuran is added dropwise to a suspension comprising 18.2 g (0.75 mmol) of magnesium, 375 ml of a 2 M solution of isobutylmagnesium bromide in tetrahydrofuran and 15 ml of diethyl ether. After 5 h of heating under reflux, 100 ml of water are, at 0° C., added to the reaction mixture, and the pH is adjusted to 6 using hydrochloric acid. The organic phase is washed with water and dried over magnesium sulphate. Concentration under reduced pressure and purification on silica gel (mobile phase: petroleum ether/acetonitrile 95:5) gives 11.0 g (25% of theory) of 1-(2-aminophenyl)-3-methylbutan-1-one of logP (pH 2.3)=2.89.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].N1C=CC=CC=1>>[C:34]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCO)cc2)CCSC1(C)C
Solvent: c1ccncc1
Product: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
A mixture of 0.452 g (0.908 mmol) of tert-butyl (3S)-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxylate, 2.6 mL (27 mmol) of acetic anhydride and 0.22 mL (2.7 mmol) of pyridine was stirred at room temperature for 6 h and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:5) to provide 0.476 g (97%) of tert-butyl (3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate as a colorless oil. Electrospray Mass Spec: 540.0 (M+H)+
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.NC(N)=O.[OH:13]O.O.[CH3:16][CH2:17]OC(C)=O>>[N+:3]1([O-:13])[C:4]2[CH2:17][CH2:16][CH2:8][C:5]=2[CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(C)=O
Reactant: OO
Reactant: Cc1ccc(C)nc1
Agent: NC(N)=O
Solvent: O
Product: [O-][n+]1cccc2c1CCC2
Temperature: 85 °C
Reaction time: 18 h

Procedure:
N-Oxide Formation. 5 g of 2,5-dimethyl-pyridine and 8.8 g urea-hydrogen peroxide adduct were heated together to 85° C. The mixture melted and was stirred for 18 h at 85° C. It was then cooled to rt and taken up in water-EtOAc and layers separated. The product containing aqueous layer was treated with solid NaCl and concentrated under reduced pressure and back-extracted several times with EtOAc. The back-extracted organic solution was concentrated and the product crystallized. Three crops were collected by filtration for a total of 3.73 g 2,5-dimethyl-pyridine 1-oxide. LCMS (m/z) 124. N-oxide formation also was performed under the following conditions. To a 6,7-dihydro-5H-[1]pyrindine solution in DCM at 0° C. was added peracetic acid (3 mL, 32% in AcOH), and the reaction was slowly allowed to come to rt and stirred for 12 h. The reaction mixture was diluted with DCM (5 mL) and washed with water, aq NaHCO3, brine, then dried over Na2SO4, filtered and concentrated to afford desired 6,7-dihydro-5H-[1]pyrindine 1-oxide (0.6 g). LCMS (m/z): 136.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[N:13]=2.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)(=O)=O>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:38][CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[N:13]=2
Reactant: COc1nc2c(N)nc(OCC3CCCO3)nc2[nH]1
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCC3CCCO3)nc2n1CC1CCOCC1
Temperature: 60 °C
Yield: 54.3 %

Procedure:
8-(Methoxy)-2-[(tetrahydro-2-furanylmethyl)oxy]-9H-purin-6-amine trifluoroacetate salt (0.30 g) was dissolved in dry DMF (5 mL). To this solution was added anhydrous potassium carbonate (0.4376 g) and then the reaction mixture was heated to 60° C. under nitrogen for 1 hour. The reaction mixture was then cooled to room temperature before adding tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.1690 g) and then the resultant reaction mixture was heated to 90° C. for 2.5 hours. The reaction mixture was cooled and then quenched with water (50 mL), followed by extraction into ethyl acetate (50 mL, 3 times). After separating, the organic layers were combined and dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave mobile oil which was then purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1560 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:10]([C:18]([F:21])([F:20])[F:19])=[N:11][NH:12][C:13]=2[NH:14]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[OH-].[Na+]>[C:1]1([C:7]#[C:8][C:9]2[C:10]([C:18]([F:20])([F:21])[F:19])=[N:11][NH:12][C:13]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1[nH]nc(C(F)(F)F)c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1[nH]nc(C(F)(F)F)c1C#Cc1ccccc1

Procedure:
A solution of N-[4-(2-phenylethynyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]acetamide (900 mg, 3.07 mmol) in ethanol (12 mL) and 25% NaOH (9 mL) was heated to 70° C. for 1.5 h. The organic layer was separated and the aqueous extracted with EtOAc (×2).