Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@@:5]([CH3:23])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C@@:5]([CH3:23])([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccc(OC)cc1
Product: CCOC(=O)[C@](C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccc(OC)cc1

Procedure:
The title compound was prepared from (S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-methoxyphenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester to produce a colorless oil (32%). 1H NMR (300 MHz, CDCl3): δ 7.57 (d, 1H, J=3.5), 7.36 (d, 1H, J=5.1), 7.15 (d, 2H, J=8.6), 7.07 (dd, 1H, J=5.1, 3.5), 6.81 (d, 2H, J=6.6), 6.78 (d, 2H, J=8.6), 6.71 (d, 2H, J=6.6), 4.21 (q, 2H, J=7.2), 4.20 (t, 2H, J=6.4), 3.74 (s, 3H), 3.21 (d, 1H, J=13.7), 3.08 (d, 1H, J=13.7), 2.95 (t, 2H, J=6.4), 2.35 (s, 3H), 1.28 (s, 3H), 1.25 (t, 3H, J=7.2). MS [EI+] 522 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:42])[CH:25]=[C:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CC(C)=O>[CH2:1]([N:8]([C@H:16]([C:24](=[O:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 50 °C
Reaction time: 9 h
Yield: 83.5 %

Procedure:
An autoclave was charged with (2S)-2-(N,N-dibenzylamino)-5-tert-butoxycarbonylamino-1,6-diphenyl-4-hexen-3-one (0.56 g, 1 mmol), 25 mg of 3%-Pd-alumina and 5 ml of acetone. After introducing hydrogen under a pressure of 10 atm, the contents were stirred at 50° C. for 9 hours. The reaction mixture was filtered through a celite pad to remove the catalyst, and the filtrate was concentrated under reduced pressure to obtain 0.47 g (yield: 83%) of the title compound. 1H-NMR indicated that the purity of the (2S,5S) isomer was 95% or higher.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][O:12][N:13]=[CH:14][C:15]([NH:17][C@H:18]2[C@@H:21]([S:22][CH2:23][CH2:24][OH:25])[NH:20][C:19]2=[O:26])=[O:16])[N:10]=1)=[O:4].[CH2:27]1[O:30][CH:28]1C.C(Cl)(=O)C>CC(N(C)C)=O>[C:28]([O:25][CH2:24][CH2:23][S:22][C@H:21]1[NH:20][C:19](=[O:26])[C@H:18]1[NH:17][C:15](=[O:16])[CH:14]=[N:13][O:12][CH2:11][C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])[S:7][CH:8]=1)(=[O:30])[CH3:27]
Reactant: CC1CO1
Reactant: O=C(C=NOCc1csc(NC(=O)CCl)n1)N[C@@H]1C(=O)N[C@@H]1SCCO
Solvent: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)OCCS[C@H]1NC(=O)[C@H]1NC(=O)C=NOCc1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 0.65 g of (3R,4R)-3-[[[(2-chloroacetylamino-4-thiazolyl)(methoxyimino)]acetyl]amino]-4-[[2-(hydroxy)ethyl]thio]-2-azetidinone in 5 ml of dimethylacetamide are added 1 ml of propylene oxide and 0.36 g of acetyl chloride, and the mixture is stirred at 0° C. for 3 hours. After further addition of 0.36 g of acetyl chloride, the mixture is stirred for additional 3 hours. The solvent is then distilled off under reduced pressure to give crystals, which are collected by filtration and washed with methylene chloride. The above procedure gives 0.558 g of (3R,4R)-4-[[2-(acetoxy)ethyl]thio]-3-[[[(2-chloroacetylamino-4-thiazolyl)(methoxyimino)]acetyl]amino]-2-azetidinone.
Reaction SMILES: C1(S([N:10]2[C:18]3[CH:17]=[C:16]([Cl:19])[CH:15]=[C:14]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:32])[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:12]([C:13]=34)=[C:11]2[C:33]([O:35]C)=[O:34])(=O)=O)C=CC=CC=1.CO.[OH-].[Na+].Cl>C1COCC1>[Cl:19][C:16]1[CH:15]=[C:14]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:32])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]3=[C:11]([C:33]([OH:35])=[O:34])[NH:10][C:18]([CH:17]=1)=[C:13]23
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC1CCc2cc(Cl)cc3[nH]c(C(=O)O)c1c23)Nc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.7 %

Procedure:
A solution of methyl 1-benzenesulfonyl-7-chloro-3-phenylcarbamoylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (140 mg, 0.268 mmol) in a mixture of THF (3 mL), MeOH (3 mL), and 5N NaOH (3 mL) was stirred for 22 h at room temperature, acidified to pH 1 with 1N HCl, and, extracted with 1:1 THF/ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was rinsed with dichloromethane and dried in vacuo to give 64 mg of the title compound (63%): 1H NMR (DMSO-d6) δ5 12.92 (bs, 1H), 11.44 (s, 1H), 9.86 (s, 1H), 7.60 (d, 2H, J=7.3 Hz), 7.30 (t, 2H, J=7.3 Hz), 7.16 (s, 1H), 7.03 (t, 1H, J=7.3 Hz), 6.85 (s, 1H), 3.89 (m, 1H), 3.06 (mt, 1H, J=12.6 Hz), 2.79 (md, 1H, J=16.8 Hz), 2.68 (dd, 1H, J=14.2, 4.3 Hz), 2.50 (m, 1H), 2.06 (md, 1H, J=12.2 Hz), 1.85 (m, 1H).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:88])[C@@H:65]([NH2:87])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:60][CH2:59]1)=[O:57])[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:51]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:88])[C@@H:65]([NH:87][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:62][CH2:63]1)=[O:57])[CH2:52][CH2:53][CH3:54]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 194 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 195 μl DIPEA, 135 mg EDC, 108 mg HOBt and 255 mg 4-[(S)-2-Amino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester hydrochloride. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent deprotection reaction. Yield: 400 mg.
Reaction SMILES: [C:1]([C:5]1[S:13][C:12]2[C:11](O)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:17])=O>C(Cl)Cl>[C:1]([C:5]1[S:13][C:12]2[C:11]([Cl:17])=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2ncnc(O)c2s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc2ncnc(Cl)c2s1
Yield: 45.9 %

Procedure:
6-tert-Butyl-thieno[3,2-d]pyrimidin-4-ol (500 mg, 2.40 mmol, 1 eq.) and phosphorous oxychloride (4.48 mL, 48.0 mmol, 20 eq.) were refluxed under nitrogen for 1.5 hours. Stripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated NaHCO3, 1× with brine. Dried and stripped in vacuo to give 250 mg of amber solids as product. LCMS detects (M+H)+=227.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:3]([CH2:22][C:23]([OH:25])=[O:24])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 55 °C
Yield: 98.3 %

Procedure:
A flask was charged with ethyl 2-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yl)acetate (1.123 g, 2.516 mmol) and THF (40 mL), and 1M sodium hydroxide (7.548 mL, 7.548 mmol) was added. The mixture was heated at 55° C. for 2 hours, and then diluted with THF and acidified with 1M HCl (8 mL). The reaction mixture was concentrated and the resulting slurry was filtered. The solids were washed with water and dried to give the desired product (1.035 g, 98.38% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH:13]=1)=[O:11].[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CCCCn1cc(C(=O)Cc2ccccc2OC)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1CC(=O)c1cn(CCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Ethyl 5-(3-(2-(2-methoxyphenyl)acetyl)-1H-indol-1-yl)pentanoate [Ethyl N-(carboxybutyrate) JWH-250] 7 (856 mg, 2.18 mmol) was dissolved in tertahydrofuran (15 ml) and water (15 ml) was added followed by potassium hydroxide (287 mg, 4.36 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, the residue was acidified to pH 3 and extracted three times with ethyl acetate (3×50 ml). The organic fractions were combined, dried over sodium sulphate and concentrated under vacuo. The residue was purified by column chromatography (silica gel, 50%-100% ethyl acetate in hexane) and then recrystalised from ethylacetate/hexane to give 565 mg (71%) 5-(3-(2-(2-methoxyphenyl)acetyl)-1H-indol-1-yl)pentanoic acid [N-(carboxybutyric acid) JWH-250] (Hapten 2) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].II.[CH3:13][C:14]([CH3:34])([CH3:33])[CH2:15][C:16]([NH:18][C:19]1[C:20]([CH3:32])=[C:21]([CH3:31])[C:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24](=[O:29])[C:23]=2[CH:30]=1)=[O:17]>C1COCC1>[OH:29][C:24]1([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:23]2[CH:30]=[C:19]([NH:18][C:16](=[O:17])[CH2:15][C:14]([CH3:34])([CH3:33])[CH3:13])[C:20]([CH3:32])=[C:21]([CH3:31])[C:22]=2[O:26][C:25]1([CH3:27])[CH3:28]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Reactant: ClCCc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A solution of 2-chloroethylbenzene (648 mg, 4.6 mmol) in THF (5 mL) was added dropwise under an argon atmosphere to a mixture of magnesium (112 mg, 4.6 mmol) and a catalytic amount of iodine, and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (300 mg, 0.98 mmol) obtained in Reference Example 65 in THF (3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice and the product was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) and recrystallized from ethyl acetate-hexane to obtain 201 mg (yield: 51%) of the title compound. Melting point: 99-100° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[C:24]2[C:29]([CH:30]=[C:31]3[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]3)=[CH:28][CH:27]=[CH:26][CH:25]=2>>[CH:25]1[C:24]2[C:29](=[CH:30][C:31]3[C:36]([C:23]=2[CH2:22][N:8]2[C:9]([S:10][C:11]4[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1c2ccccc2cc2ccccc12
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2c3ccccc3cc3ccccc23)c1
Yield: 44.7 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (215 mg, yield: 44.7%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:9]([O-:11])=[O:10].[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(=S)=S>[C:16]([C:13]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:6])=[CH:15][CH:14]=1)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COc1ccccc1C(=O)[O-]
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A one-liter three-neck flask is fitted with a 250 ml dropping funnel, a mechanical overhead stirrer, and a condenser with a drying tube. A mixture of anhydrous aluminum chloride (120 g., 0.9 moles) and carbon disulfide (250 ml) is placed in the flask and cooled to 0-5 degrees C. with an ice bath. A solution of methylsalicylate (45.6 g., 0.3 mole) and n-hexanoyl chloride (81.4 g., 0.6 mole) in carbon disulfide (50 ml) is then added through the dropping funnel over the course of three hours while maintaining the temperature of the reaction mixture below 10 degrees C. The reaction mixture is then allowed to warm to room temperature and stirring is continued for 24 hours. The mixture is then poured slowly onto cracked ice (500 g.) and the resulting slurry is stirred until the ice melts. The slurry is then extracted with four 50 ml portions of diethyl ether and the combined ether extracts are washed with water and dried over anhydrous sodium sulfate. Any remaining liquid is removed by evaporation in a vacuum. The resulting product is found to be n-hexanoyl methyl salicylate in a yield of 77% with a melting point of 48°-49° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1>C1COCC1>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([O:16][CH2:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)=[N:11][O:12][C:13]=2/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:27][CH:28]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1c(-c2ccc(Cl)cc2)noc1/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a suspension of sodium hydride (2.64 g, 60.5 mmol) in THF (100 mL) was added a solution of [3-(4-chloro-phenyl)-5-([E]-styryl)-isoxazol-4-yl]-methanol (17.2 g, 55.0 mmol) in THF (185 mL) at 0° C. The reaction mixture was stirred for 60 min at room temperature. A solution of methyl 6-chloronicotinate (10.6 g, 60.5 mmol) in THF (185 mL) was added at 0° C. The mixture was stirred at room temperature for 2 h and the product was extracted with ethyl acetate/aqueous ammonium chloride and ethyl acetate/brine. Chromatography (silica, ethyl acetate:heptane 2:8 to 7:3) afforded the title compound (15.6 g, 64%) as a white solid. MS: m/e (%)=446 (0.7, M+), 309 (47), 294 (28), 240 (26), 131 (100), 103 (51).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[NH:9][C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][CH:5]=[CH:6][N:7]=1.CC([O-])(C)C.[K+].O=P(Cl)(Cl)Cl>C1COCC1>[C:11]([C:10]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[C:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-2,2-dimethylpropionamide (264 mg, 0.612 mmol) in THF (3 mL), cooled to 0° C., KOtBu (800 μL, 1 M, 0.796 mmol) was added, the cooling bath was removed, and the reaction mixture stirred at ambient temperature for 30 min, under N2. THF was removed in vacuo, POCl3 (25 mL, 42 g, 0.273 mol) was added to the residue, and the reaction mixture was vortexed at 70° C., under N2, for 5 d. POCl3 was evaporated (min. 2 h on high-vacuum), a cold solution of NH3/i-PrOH (2M, 10 mL) was added, the suspension was filtered, and the solid was washed several times with i-PrOH. The filtrate was concentrated, extracted with CH2Cl2 (3×30 mL), washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was dissolved in CH2Cl2, adsorbed onto Hydromatrix, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with EtOAc:CH2Cl2 2%→5%], yielding the title compound, as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.26 (s, 9H), 7.33 (d, J=4.8 Hz, 1H), 7.44-7.50 (m, 1H), 7.50-7.58 (m, 2H), 7.87-7.94 (m, 4H), 8.17-8.22 (m, 2H), 8.24-8.30 (m, 1H), 8.51 (s, 1H); MS (ES+): m/z 412.9/414.9 (100/38) [MH+]; HPLC: tR=4.3 min (OpenLynx, polar—5 min).
Reaction SMILES: [N:1]1([C:7]([CH3:12])=[CH:8][C:9](=O)[CH3:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:13][C:14]([F:24])([F:23])[C:15](=O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)(=O)C>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[C:15]([C:14]([F:24])([F:23])[F:13])=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:8][C:9]=1[CH3:10])[CH3:21]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)C=C(C)N1CCOCC1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 33 %

Procedure:
A mixture of 4-morpholin-4-yl-pent-3-en-2-one (2.50 g, 14.8 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (3.0 g, 16.3 mmol) in acetic acid (40 ml) is heated at 120° C. for 3 h. After completion of the reaction (monitored by TLC), the solvent is distilled off, the residue is taken up in water (20 ml) and the pH of the mixture was adjusted to pH=8 with 25% aqueous ammonia. The aqueous layer is extracted with ethyl acetate (2×20 ml) and the combined organic layers are dried over sodium sulfate, evaporated and the crude product is purified by column chromatography (silica gel, 10% ethyl acetate/cyclohexane) to afford 2-methyl-4-morpholin-4-yl-6-(trifluoromethyl)-benzoic acid ethyl ester (1.55 g, 4.89 mmol, 33%).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH:15]=[O:16].[CH2:17](Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:17][CH3:18])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH:15]=[O:16]
Reactant: CCBr
Reactant: Nc1c(C=O)c(-c2ccccc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccccc2)c(C=O)c(N)c1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 5-amino-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde (Dal Piaz, V., Ciciani, G, Giovannoni, M. P., Heterocycles, 1991, 32, 1173-9) (258 mg, 1.2 mmol), ethyl bromide (294 mg, 2.7 mmol) and anhydrous potassium carbonate (240 mg, 2.4 mmol) in anhydrous DMF (5 mL) was stirred at 85° C. for 2 h. Cold water (25 mL) was added and the precipitate was collected by filtration to yield the title product (90%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][C:12](=[O:17])[C:13]([Cl:16])([Cl:15])[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([NH:25][NH2:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C(OC)(C)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][C:12]([C:13]([Cl:16])([Cl:15])[Cl:14])([OH:17])[N:25]([C:20]2[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C#CCOCc1ccccc1)C(Cl)(Cl)Cl
Reactant: NNc1ncccc1Cl
Solvent: COC(C)(C)C
Product: OC1(C(Cl)(Cl)Cl)CC(COCc2ccccc2)=NN1c1ncccc1Cl
Temperature: 30 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
5-(Benzyloxy)-1,1,1-trichloropent-3-yn-2-one (2.9 g, 0.01 mol) and 3-chloro-2-hydrazinopyridine (1.43 g, 0.01 mol) were initially charged in 20 ml of methyl tert-butyl ether (exothermic), and the mixture was stirred at 30° C. for a further 1 h. The solvent was concentrated by rotary evaporation and the resulting mixture was analysed by means of LC/MS. Only one isomer at m/e 435 was identified. The yield was 94%, the purity 92% (area per cent).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)=[O:4].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>C(O)C.C(O)(=O)C>[C:14]([O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)=[O:4])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COc1cc(C(=O)CCl)ccc1O
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C(=O)COC(C)=O)ccc1O
Yield: 36.1 %

Procedure:
To a slurry of 80.2 g (0.4 mole) of 2-chloro-1-(4-hydroxy-3-methoxyphenyl)ethanone in 576 ml of absolute ethanol and 24 ml of glacial acetic acid was added 73.6 g (0.75 mole) of potassium acetate, and the mixture was heated at reflux temperature for 1 hr. The mixture was cooled, filtered, and the filtrate concentrated to a gummy residue. The residue was triturated with four 200 ml portions of hot benzene. The combined extracts were washed with three 200 ml portions of saturated aqueous sodium bicarbonate solution and once with brine, dried over sodium sulfate, and concentrated to give a solid residue. The solid was recrystallized from benzene (with charcoal treatment) to yield 32.4 g (36% yield) of the title compound as a white solid, mp 115°-117° C.
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.[CH2:16]([NH2:19])[CH2:17][CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:16][CH2:17][CH3:18])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: CCCNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 99.4 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and propylamine (0.32 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-propyl-2-(trifluoromethyl)benzenesulfonamide (0.53 g, 100%) was provided after purification. MS (ESI) m/z 346. HPLC purity 100.0% at 210-370 nm, 9.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.