Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)[CH2:4][CH2:3]1.Cl[C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH3:33])[C:30]([NH2:32])=[O:31])[C:18]([Cl:34])=[CH:17][N:16]=1.O>CO>[Cl:34][C:18]1[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH3:33])[C:30]([NH2:32])=[O:31])=[N:20][C:15]([NH:13][C:11]2[CH:10]=[N:9][N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:12]=2)=[N:16][CH:17]=1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C)CC3)c2)ncc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 2 %

Procedure:
A stirred solution of 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.117 g, 0.648 mmol), 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)propanamide A30 (0.060 g, 0.185 mmol) in MeOH (10 mL) and water (1.0 mL) was stirred at 70° C. for 16 hours. Additional 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.052 g, 0.29 mmol) was added and the reaction was stirred for 16 hours at 70° C. After cooling the solvent was removed to afford an oil which was purified by HPLC (Gradient: 30-100%, acetonitrile 0.1% formic acid in water 0.1% formic acid, 12 min) to give the title compound 44 as a red gum (0.0018 g, 2% yield). LCMS-C: rt 4.28 min; m/z 468 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:15][C@@H:16]([OH:38])[C@@H:17]([NH:26][C:27](=[O:37])[O:28][C@@H:29]3[C@H:36]4[C@H:32]([O:33][CH2:34][CH2:35]4)[O:31][CH2:30]3)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:43]([C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48]Cl)#[N:44].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:43]([C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:17]([NH:26][C:27](=[O:37])[O:28][C@@H:29]2[C@H:36]3[C@H:32]([O:33][CH2:34][CH2:35]3)[O:31][CH2:30]2)[C@H:16]([OH:38])[CH2:15][N:14]([S:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)(=[O:12])=[O:13])[CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:24][CH:23]=1)#[N:44]
Reactant: N#Cc1cccc(CCl)c1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2cccc(C#N)c2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Yield: 44.6 %

Procedure:
49 mg of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxy benzyl)propylcarbamate, 20 mg of m-cyanobenzylchloride, 20 mg of cesium carbonate and 0.5 mL of dimethyl formamide were stirred at rt for 5 h. The mixture was diluted with ethyl acetate and extracted with water. Chromatography on silica gel (1:1 ethylacetate/hexane) gave the title compound as a white solid (26 mg). 1H NMR: 0.87(6H,dd), 1.58(2H,m), 1.8(1H,m), 2.75(2H,m), 2.9(4H,m), 3.1(1H,m), 3.62(3H,m), 3.8(3H,m), 3.95(1H,m), 4.25(4H,m), 4.95(2H,m), 5.0(2H,s), 5.62(1H,d), 6.82(2H,d), 6.92(1H,d), 7.1(2H,d), 7.2(2H,m), 7.45(1H,t), 7.6(2H,m), 7.75(1H,s). MS:722 (M+H)
Reaction SMILES: II.[N+:3]([C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[CH2:8][SH:9])([O-:5])=[O:4]>ClCCl>[N+:3]([C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[CH2:8][S:9][S:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=1[N+:3]([O-:5])=[O:4])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(CS)c([N+](=O)[O-])c1
Agent: II
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CSSCc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Yield: 82 %

Procedure:
A solution of iodine (0.321 g, 1.26 mmol) and 2,4-dinitrobenzyl mercaptan (0.493 g, 2.3 mmol) in dichloromethane (25 cm3) was stirred at room temperature ovemight. More dichloromethane (25 cm3) was added and the products were washed with 0.2 mol dm-3 sodium hydrogen sulfite (20 cm3), water (20 cm3) and saturated aqueous sodium hydrogen carbonate (20 cm3). The dried (MgSO4) organic layer was concentrated under reduced pressure and the residue was crystallized from absolute ethanol to give di-(2,4-dinitrobenzyl) disulfide 19 (0.402 g, 82%) (Found: C, 39.4; H, 2.4; N, 13.0. C14H10N4O8 S2 requires: C, 39.4; H, 2.4; N, 13.1%), m.p. 108°-109° C.; δH [CDCl3 ] 4.22 (4 H, s), 7.66 (2 H, d, J 8.5), 8.46 (2 H, dd, J 2.4 and 8.4), 8.91 (2H, d, J2.4);δC [CDCl3 ] 40.0, 121.1, 127.5, 133.9, 139.4, 147.4, 148.0.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[CH2:5].[C:8]([OH:12])(=[O:11])C=C>[Ru].C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[CH:5][C:8]([OH:12])=[O:11]
Reactant: C=CCC(C)(C)C
Reactant: C=CC(=O)O
Agent: [Ru]
Solvent: ClCCl
Product: CC(C)(C)CC=CC(=O)O
Yield: 98.7 %

Procedure:
5,5-Dimethyl-hex-2-enoic acid was prepared using a modified procedure from Chatterjee, A. K. et al. J. Am. Chem. Soc. 2003, 125(37), 11360-11370. 4,4-Dimethyl-1-pentene (5.0 mL, 34.77 mmol, 1.5 eq.) and acrylic acid (1.54 mL, 22.51 mmol, 1.0 eq.) were added to a solution of ruthenium catalyst ([1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro [[2-(1-methylethoxy-)phenyl]methylene-]ruthenium, 282 mg, 0.45 mmol, 2 mol %) in CH2Cl2 and heated to reflux for 12 hours under nitrogen atmosphere. The resulting brown solution was diluted with CH2Cl2 and washed with 1M NaOH (3×15 mL). The organic phase was acidified with 4 M HCl (20 mL) and extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried over MgSO4, filtered and evaporated to provide intermediate 5,5-Dimethyl-hex-2-enoic acid as a light brown oil (3.16 g, 22.21 mmol, 99%): 1H NMR (CDCl3, 400 MHz) δ 0.94 (s, 9H), 2.11 (d, 2H, J=8.0 Hz), 5.82 (d, 1H, J=16.0 Hz), 7.12 (dt, 1H, J=16.0, 8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH:11]=1.[N:18]([Sn:21]([CH3:24])([CH3:23])[CH3:22])=[N+:19]=[N-:20]>>[CH3:16][C:13]1([CH3:17])[CH2:14][CH2:15][C:10]([C:3]2[CH:4]=[C:5]([C:6]3[N:18]([Sn:21]([CH3:24])([CH3:23])[CH3:22])[N:19]=[N:20][N:7]=3)[CH:8]=[CH:9][C:2]=2[NH2:1])=[CH:11][CH2:12]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC1(C)CC=C(c2cc(C#N)ccc2N)CC1
Product: CC1(C)CC=C(c2cc(-c3nnnn3[Sn](C)(C)C)ccc2N)CC1

Procedure:
The title compound was prepared from 4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-benzonitrile (as prepared in the previous step, 245 mg, 1.08 mmol), and azidotrimethylstannane (246 mg, 1.19 mmol) according to the procedure in Example 52, step (c) (363 mg, 78%). Mass spectrum (ESI, m/z): Calcd. for C15H19N5, 270.1 (M-SnMe3+2H), found 270.1.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH:10]=[C:11]([CH2:12][C:13]#[N:14])[C:7]=2[CH:6]=1)#N.[CH2:17](O)COCCOCCO>>[C:11]1([CH2:12][C:13]#[N:14])[C:7]2=[C:6]3[C:5](=[CH:16][CH:15]=[C:8]2[O:9][CH:10]=1)[O:4][CH2:3][CH:1]=[CH:17]3
Reactant: OCCOCCOCCO
Reactant: N#CCOc1ccc2occ(CC#N)c2c1
Product: N#CCc1coc2ccc3c(c12)C=CCO3

Procedure:
A mixture of 0.03 mol (6 g) of compound obtained in stage D in 170 ml of triethyleneglycol is refluxed 5 minutes. The reaction is then cooled at room temperature and hydrolysed by a mixture water/ice. The precipitate thus formed is filtrated and recrystallized in isopropanol to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11](C(OCC)=O)=[N:10]2)=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:19])([F:18])[F:20])[CH:11]=[N:10]2)=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2cc(O)c(Cl)cc2F)c(=O)c(C)c1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 130 °C
Yield: 51.4 %

Procedure:
A half gram (0.5 g) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-ethoxycarbonyl-4-methyl-5-trifluoromethylpyridazin-3-one (the present compound 1-27) and 1.5 ml of a mixture of sulfuric acid and water (v/v=1/1) were mixed and heated for 5 hours on a 130° C. oil bath. The reaction solution was cooled to room temperature, allowed to stand at the same temperature overnight, and further heated for 8 hours on a 130° C. oil bath. The reaction solution was cooled to room temperature and poured into 50 ml of water. The precipitated crystals were filtered off, dissolved with 100 ml of ethyl acetate, dried over anhydrous magnesium sulfate and treated with active charcoal. The solvent was removed under reduced pressure to afford 0.21 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (yield:51%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[F:11][C:12]([F:47])([F:46])[C:13]1[CH:14]=[C:15]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17].O>CN(C)C=O>[F:45][C:42]([F:44])([F:43])[C:40]1[CH:39]=[C:15]([CH:14]=[C:13]([C:12]([F:11])([F:46])[F:47])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:29]=[N:28][N:27]([CH2:8][CH2:9][OH:10])[CH:26]=2)[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17]
Reactant: OCCBr
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CCO)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C

Procedure:
Potassium carbonate (158 mg) and 2-bromoethanol (0.045 ml) were added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (300 mg) in N,N-dimethylformamide (3 ml) at room temperature with stirring. After stirring at 100° C. for 5 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography (30 ml) on silica gel using a mixture of ethyl acetate and hexane (3:7) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazine (255.2 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.[C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][C:24]([C:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:20])=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 96 h

Procedure:
A 135 g. portion of aluminum chloride is dissolved in 500 ml. of nitrobenzene, the solution being held below 10°C. by external cooling. A finely ground mixture of 50 g. of succinic anhydride and 75 g. of biphenyl is added to the stirred solution, the temperature being held below 10°C. It is then held at room temperature for 4 days. After pouring the reaction mixture into a solution of 150 ml. of concentrated hydrochloric acid in one liter of ice water, the nitrobenzene is removed by steam distillation. The solid is collected, dissolved in 4 liters of 3% hot sodium carbonate solution, clarified and reprecipitated by the addition of excess 6N sulfuric acid solution. The crude product is collected, dried, and recrystallized from ethanol to give the pure product, melting point 185°-187°C.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:19](OC)[O:20]C)[C:15]([F:18])=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:3]1.O>C1COCC1.C(OCC)(=O)C>[F:24][C:2]1([F:1])[CH2:3][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:19]=[O:20])[C:15]([F:18])=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:5]1
Reactant: COC(OC)c1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F
Temperature: 25 °C
Yield: 92.2 %

Procedure:
(3,3-Difluoroazetidin-1-yl)(5-(dimethoxymethyl)-6,7-difluorobenzo[d]isoxazol-3-yl)methanone (Intermediate 228, 3.336 g, 9.58 mmol) was dissolved in a 4:1 THF:water mixture (62.5 ml) and heated at 75° C. with tosic acid monohydrate (0.911 g, 4.79 mmol) for three hours. The reaction was allowed to cool to room temperature, diluted with ethyl acetate, washed 3× with saturated NaHCO3, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate. Fractions were combined and concentrated to give the title compound (2.66 g, 8.83 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]([F:16])([F:15])[F:14].[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl.NN>Cl.O>[NH:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]([F:16])([F:14])[F:15])[NH2:17]
Reactant: Nc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: NN
Solvent: O
Product: NNc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Temperature: -1 °C
Reaction time: 1 h

Procedure:
In a 250 mL r.b. flask a suspension of 6-amino-4-trifluoromethylquinolin-2(1H)-one (structure 8 of Scheme II, where R1=trifluoromethyl) (2.28 g, 10 mmol) in 10 mL conc. HCl was cooled to −1° C. and a solution of NaNO2 (0.40 g, 12 mmol) in water (5 mL) was added dropwise in 20 min. The dark yellow suspension was stirred at −1° C. for 1 h and then a solution of SnCl2.2H2O (5.2 g, 15 mmol) in conc. HCl (10 mL) was added dropwise in 10 min. The light yellow suspension of the hydrazine was stirred at −1° C. for 2 h and then used directly or kept in a refrigerator at −1° C. until it was used (the crude compound can be stored for at least one month without decomposition).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[C:33]([CH2:34]Br)=[CH:32][CH2:31][CH2:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[C:33]([CH2:34][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2=CCCC2CO)c(=O)[nH]c1=O
Yield: 22.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same with the example 10 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:23][CH:24]([CH3:26])[CH3:25]>O1CCOCC1>[Cl:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)=[O:7])=[CH:4][C:3]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OC)c(Cl)c(OC(C)C)c2)cc1
Solvent: C1COCCO1
Product: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(OC(C)C)c1Cl
Yield: 57.3 %

Procedure:
4-(4-Chloro-3-isopropoxy-5-methoxybenzamido)benzoic acid (AAA-118) (10 mg, 55%) was prepared from methyl 4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5) (20 mg, 48 μmol) using a procedure essentially the same as in step (ii) for AAA-001 except that dioxane (3 mL) was used instead of THF: m/z 362 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.80 (1H, br s), 10.47 (1H, s), 7.99-7.92 (2H, m), 7.90-7.83 (2H, m), 7.31 (2H, dd), 4.79 (1H, sep), 3.94 (3H, s), 1.33 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([N:19]([O:20][CH3:21])[CH3:18])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2,6-dichloroisonicotinic acid (20.0 g, 0.10 mol) and oxalylchloride (11.2 ml, 0.13 mol) in methylenechloride (100 ml) is stirred at room temperature in the presence of a katalytic amount of dimethylformamide for 2 hours to give a clear solution. The solvent is evaporated under reduced pressure and the residue is added to a well stirred solution of N,O-dimethylhydroxylamine (12.0 g, 0.2 mol) and triethylamine (10.2 g, 0.1 mol) at 0–5° C. After stirring for 2 hours at room temperature the reaction mixture is washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 2,6-dichloro-N-methoxy-N-methyl-isonicotinamide in form of colorless crystals, m.p. 69–70° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([I:7])[S:4][C:3]=1[C:8]1[NH:12][CH:11]=[N:10][N:9]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>CCOC(C)=O.O>[Br:1][C:2]1[CH:6]=[C:5]([I:7])[S:4][C:3]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[N:9]=1
Reactant: Brc1cc(I)sc1-c1nnc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(I)cc2Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of 3-(3-bromo-5-iodo-2-thienyl)-4H-1,2,4-triazole (500.0 mg, 1.40 mmol), N,N-dimethylaminopyridine (17.2 mg, 0.140 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.83 mmol) in N,N-dimethylformamide (17.0 mL, 220 mmol) was added [β-(Trimethylsilyl)ethoxy]methyl chloride (0.270 mL, 1.55 mmol) was added and the solution was stirred for 2 h at rt. Water (5.0 mL) and EtOAc (5 mL) were added, the organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 0-30% EtOAc in hexane) to give the title compound as a yellowish oil (653 mg, (87% major isomer, 13% minor isomer) LCMS: (FA) ES+, 486, 488. (major isomer) 1H NMR (400 MHz, d6-DMSO) δ: 8.81 (s, 1H), 7.45 (s, 1H), 5.540-5.545 (s, br, 2H), 3.62-3.66 (m, 2H), 0.840-0.880 (m, 2H), −0.05 (s, 9H). LCMS: (FA) ES+ , 486, 488. (minor isomer) 1H NMR (400 MHz, d6-DMSO) δ: 8.215 (s, 1H), 7.615 (s, 1H), 5.48 (s, br, 2H), 3.44-3.50 (m, 2H), 0.75-0.80 (m, 2H), −0.08 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(Cl)(Cl)Cl>O>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([Cl:11])[C:3]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH2:23][CH2:22]1
Reactant: CC1CCNCC1
Reactant: Fc1cccc(Cl)c1-c1c(Cl)nc2nccn2c1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1CCN(c2c(-c3c(F)cccc3Cl)c(Cl)nc3nccn23)CC1
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
Under ice-cooling, 0.63 g of 5,7-dichloro-6-(2-chloro-6-fluorophenyl)imidazo[1,2-a]pyrimidine and 0.79 g of 4-methylpiperidine were mixed. The reaction mixture was allowed to stand at room temperature for 10 minutes, and chloroform and water were added thereto. The separated organic layer was with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel chromatography to give 0.73 g of 5-(4-methylpiperidin-1-yl)-6-(2-chloro-6-fluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: S(=O)(=O)(O)O.CC(C)(C)C([NH:10][C:11]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][CH:16]3[CH2:15][CH2:14][C:13]=2[C:12]=1[C:24]([O:26][CH3:27])=[O:25])=O>CO>[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][CH:16]3[CH2:15][CH2:14][C:13]=2[C:12]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1CCC1CCCN21
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1CCC1CCCN21
Reaction time: 96 h
Yield: 94.9 %

Procedure:
Sulphuric acid (5 mL) was added carefully to a solution of methyl 7-(2,2-dimethyl-propionylamino)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (Intermediate 34, 0.820 g) in methanol (50 mL) and and the resultant mixture was stirred and heated at reflux for 4 hours then left at room temperature for 4 days. The mixture was then heated at reflux for a further 1.5 hours. After cooling the solution was evaporated in vacuo and the residue was partitioned between ethyl acetate and water and basified with 20% aqueous sodium hydroxide solution. The organic layer was dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give methyl 7-amino-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoline-6-carboxylate (0.580 g) as a yellow gum.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][S:20][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[OH:29][C:7]1[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])=[N:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]2[S:20][N:21]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:8]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)c2snc(-c3ccccc3)c2c1O
Product: COc1ccc(-c2nc(C(=O)NCC(=O)O)c(O)c3c(-c4ccccc4)nsc23)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-(4-methoxy-phenyl)-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 436.2 (M+1).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][N:42]=1>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][N:42]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)nc1
Yield: 61 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (100 mg, 0.106 mmol) and 2-bromo-5-methylpyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (42 mg, 61%): 1H NMR (CDCl3, 400 MHz) δ 7.64 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.47 (d, 1H, J=7.6 Hz), 7.30-7.26 (m, 2H), 7.19-7.16 (m, 3H), 7.08 (d, 1H, J=7.6 Hz), 4.85 (dd, 1H, J=7.3, 5.8 Hz), 2.60 (t, 2H, J=7.6 Hz), 2.59 (s, 3H), 1.93 (m, 2H), 1.65 (m, 2H), 1.36 (m, 4H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.4, 158.8, 150.9, 146.8, 142.8, 137.0, 128.4, 128.2, 125.5, 124.8, 122.5, 116.1, 68.7, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 24.5, 13.6, −5.0, −5.2.
Reaction SMILES: [F:1][C:2]([C:18](OC)=[O:19])=[CH:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[F:17])[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]([CH2:18][OH:19])=[CH:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=2[F:17])[CH2:6][CH2:5]1
Reactant: COC(=O)C(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Yield: 77.2 %

Procedure:
The method of Example 9 was repeated using 1-(2-Fluoro-2-(methoxycarbonyl)ethenyl)-1-(2-fluoro-4-trifluoromethylphenyl)-cyclopropane (Example 5) (0.77 g), diethyl ether (10 ml) and lithium aluminium hydride (0.18 g) to yield the title compound (0.54 g, 77%).