Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:26][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: ClCC1CO1
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)cc1-c1ccccc1
Reaction time: 24 h
Yield: 47 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (296 mg, 0.81 mmol) in 2-propanol (2.5 mL) and 3 N aq. NaOH (1 mL) is treated with epichlorohydrine (150 mg, 1.63 mmol) and the mixture is stirred at it for 24 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated and the residue is purified by CC on silica gel eluting with hepaten:EA 4:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (160 mg) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=421.22, 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (m, 2H), 3.99 (dd, J=2.9, 11.1 Hz, 1H), 3.72 (dd, J=5.8, 11.1 Hz, 1H), 3.38-3.31 (m, 1H), 3.19-3.11 (m, 2H), 2.98-2.85 (m, 5H), 2.72-2.67 (m, 1H), 2.26 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: FC(F)(C(F)(F)F)C[O:4][C:5](=[O:26])[C@H:6]([OH:25])[CH2:7][C@H:8]([NH2:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1.[OH:32][N:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[N:35]=[N:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([F:23])=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C@@H:8]([NH:24][C:38]([C:36]3[N:35]=[N:34][N:33]([OH:32])[CH:37]=3)=[O:39])[CH2:7][C@@H:6]([OH:25])[C:5]([OH:4])=[O:26])=[CH:15][CH:14]=2)[CH:21]=1
Reactant: N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F
Reactant: O=C(O)c1cn(O)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
(2R,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 2,2,3,3,3-pentafluoropropyl ester (32.1 mg, 68.3 μmol), 1-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid (10.6 mg, 82 μmol) and HATU (39.0 mg, 102 μmol) were stirred in DMF (1.0 mL, 12.9 mmol) for 10 minutes. DIPEA (35.7 μL, 205 μmol) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated and to yield a clear yellow liquid, which was purified using preparative scale C18 column chromatography (small column; 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (4.9 mg). MS m/z [M+H]+ calc'd for C23H19ClF6N4O5, 581.09. found 581.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:5][CH:4]=1.[C:42]1(=[O:48])[O:47][C:45](=[O:46])[CH2:44][CH2:43]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:12]2[N:13]([C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:14][CH:15]([O:17][C:42](=[O:48])[CH2:43][CH2:44][C:45]([OH:47])=[O:46])[CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(c2ccccc2)C2CC(OC(=O)CCC(=O)O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 25, Compound 94 (1.2 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.476 g, 0.64 mL, 4 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 96.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH2:14][C:15]([CH3:23])([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[CH2:14][C:15]([CH3:23])([N:20]([CH3:21])[CH3:22])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCCCC(C)(CNC)N(C)C
Solvent: c1ccccc1
Product: CCCCC(C)(CN(C)C(=O)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (1.048 g., 5 mmole) in dry benzene (25 ml.) was added to a solution of N-methyl-2-methyl-2-dimethylamino hexylamine (0.754 g., 4.4 mmole) in dry benzene (25 ml.) and the solution heated under reflux for 1 hr.. The cooled solution was washed with 2N sodium hydroxide solution (4 × 100 ml.), water (4 × 100 ml.), dried (Na2SO4) and evaporated to a colourless oil (1.612 g.). The oil was dissolved in benzene, chromatographed on a column of alumina (25 × 3.0 cm.) eluting with benzene/ether 1:1, and fractions (9 × 100 ml.) were collected. Fractions 2-8 were combined and, on evaporation, afforded 3,4-dichloro-N-methyl-N-[2-methyl-2-dimethylamino-hexyl]benzamide as a colourless oil (1.282 g., 84%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].N.[CH3:32]O>>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:11]3[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=3[N:19]=[CH:32]2)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)OCC1CC(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(OC(C)=O)C1OC(C)=O
Agent: N
Product: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)(1R*, 2S*, 3R*, 5R*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (5.00 g, 10.8 mmol) was stirred in ammonia/methanol (ca. 2N, 100 mL) at ambient temperature for 18 hours. Evaporation of volatiles in vacuo left residual orange solid (±)-(1R*, 2S*, 3R*, 5R*)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol having an identical Rf on silica gel TLC plates to that of the chiral sample described in Example 54. This solid was reduced with Raney nickel/hydrogen(45 psi) in isopropanol (200 mL). Catalyst was filtered off with Celite. The filtrate-wash was evaporated to dryness in vacuo. The residue was refluxed in formic acid (96%, 50 mL) for one hour, as described in Example 2. The oil remaining on evaporation of the formic acid was dissolved in methanol. The pH was adjusted to 13 with aqueous 5N sodium hydroxide and the solution was stirred at ambient temperature for one hour to hydrolyze formate esters. The pH was adjusted to 7 with 1N hydrochloric acid and volatiles removed by evaporation in vacuo. Pyridine (100 mL) and acetic anhydride (4 mL) were added to the residue and the mixture stirred at ambient temperature overnight. Evaporation of volatiles in vacuo followed by chromatography on silica gel with 1% methanol-chloroform gave (±)(1R*, 2S*, 3R*, 5R*)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as white crystals from ethanol-water (2.6 g, 53%), 1H-NMR(DMSO-d6) consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:32])[CH2:23][CH2:24][N:25]1[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][C:29]2[N:25]([CH2:24][CH2:23][N:22]([CH3:32])[CH3:21])[N:26]=[C:27]([CH3:31])[CH:28]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(N)n(CCN(C)C)n1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: Cc1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)n(CCN(C)C)n1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-5-amine (17.0 mg, 0.10 mmol). The title compound was obtained as a solid (20.8 mg, 23% yield). MS m/z: 501.02, 503.02 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:12][O-:13].[Na+]>CN(C=O)C>[CH3:12][O:13][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(C(F)(F)F)c1

Procedure:
To a solution of 3-bromo-5-trifluoromethylpyridin (2.25 g 10 mmol, prepared as described in Eur. J. Org. Chem. 2002, 327-330, in DMF was added sodium methoxide (0.8 g, 15 mmol). The resultant solution is stirred for 20 hours at 40° C. The title compound is obtained after evaporation of the solvent under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+].CCOC(C)=O>C1C=CC=CC=1.OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NCCc2cc(Br)ccc21

Procedure:
To a rapidly stirred solution of 5-bromo-1-indanone (Aldrich) (15.0 g, 71.1 mmol) in benzene (200 mL) and H2SO4 (38 mL) was added NaN3 portionwise over 20 minutes. The mixture was diluted EtOAc, washed with water then brine, dried and evaporated. Chromatography of the residue (silica gel; hexane/EtOAc 1:1) afforded the title compound as a solid.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)=O.S(=O)(=O)(O)O>O>[C:1]1([N:7]2[CH:12]=[N:11][C:9]([OH:10])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)NNc1ccccc1
Reactant: O=CO
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ncn(-c2ccccc2)n1

Procedure:
151 g of 1-phenyl semicarbazide, 135.3 g (2.5 mols) of 85% formic acid (technical) and 25 g (0.25 mol) of concentrated sulfuric acid were stirred for six hours at 95° to 100° C. The viscous mass obtained was diluted with 400 ml of water and cooled. The precipitate consisting of 1-phenyl-1,2,4-triazolone-3 was filtered off and washed neutral with water. Drying at 100° C. and 200 mbar gave 145.5 g=90.3% of the theory, of 1-phenyl-1,2,4-triazolone-3 having a melting point of 285° to 286° C. ##STR2##
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([OH:12])=[O:11].[F-].[K+]>CN(C)C=O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([O:12][CH2:2][C:3]([CH2:5][O:12][C:10](=[O:11])[C:9]1[C:8]([Cl:7])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:17])=[O:4])=[O:11]
Reactant: O=C(CBr)CBr
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COC(=O)c1c(Cl)cccc1Cl)COC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
Thus obtained bromomethyl ketone derivative (X, 4.36 g) and 2,6-dichlorobenzoic acid (2.28 g, 1.1 Eq) were dissolved in dimethylformamide (18 ml), KF (1.58 g, 2.5 Eq) was added, and the mixture was stirred for two hours to give 2,6-dichlorobenzoyloxymethyl ketone derivative (XIa). This compound was dissolved in methanol (20 ml) and reacted by adding NaBH4 (412 mg)-methanol solution (40 ml)(−10□˜room temperature, two hours). The reaction was stopped by acetic acid, and the reaction solution was distilled under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (50 ml×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), concentrated under reduced pressure, and separated-purified by column chromatography (ethyl acetate-hexane, 1:5) to give the title compound (4.80 g, Yield 86%) in a diastereomeric form.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:3]([CH2:2][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:13])=[O:14])#[N:4]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1ccccc1S(N)(=O)=O
Reaction time: 16 h
Yield: 66 %

Procedure:
8 g (0.1 mol) of chloroacetonitrile are added dropwise to a stirred suspension of 18 g (0.1 mol) of 2-hydroxybenzenesulphonamide and 15 g (0.1 mol) of potassium carbonate in 250 ml of acetonitrile, and stirring is continued for a further 16 hours at 55° C. to 60° C. when the addition is complete. The reaction mixture obtained is filtered under suction, and the residue is evaporated down and triturated with water. The solid obtained is dried on clay. 14 g (66% of theory) of 2-cyanomethoxyphenylsulphonamide of melting point 184° to 185° C. are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[CH3:20])=[O:8].[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=2[CH3:20])=[O:8])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34]
Reactant: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)c2cc(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 98.7 %

Procedure:
A mixture of 2.50 g (7.29 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone, 1.53 g (7.29 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 3.30 g (24 mmol) of potassium carbonate in 50 mL of acetone and 5 mL of DMF was stirred and heated at reflux for 26 hours. After workup as in Example 16 the crude product was purified by HPLC using 10% ethyl acetate-hexane to give 3.40 g (98% yield) of 4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl benzoic acid methyl ester as an oil. The nmr spectrum was consistent with the structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].O[CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)N1CCC(O)CC1
Product: CC(=O)N1CCC(Oc2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)CC1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 1-(4-hydroxy-piperidin-1-yl)-ethanone in analogy to Example 9c): MS (ISP): 521.2 and 523.2 (M+H)+; MS (ISN): 519.1 and 521.2 (M−H)−.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C1(C2C=CC=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:34]=[O:35])=[N:30][C:31]=1[O:32][CH3:33]>O1CCCC1.O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:34]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[OH:35])=[N:30][C:31]=1[O:32][CH3:33]
Reactant: Brc1ccc(C2CC2)cc1
Reactant: COc1nc(C=O)ccc1Cl
Agent: [Li]CCCC
Agent: c1ccc(C2CC2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C(O)c2ccc(C3CC3)cc2)ccc1Cl
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.65 M, 3 mL) was added dropwise to a solution of the mixture of 4-bromo-1-cyclopropylbenzene and cyclopropylbenzene (976 mg) in tetrahydrofuran (20 mL) at −78° C. in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (732 mg) in tetrahydrofuran (9 mL) was added to the reaction solution at −78° C., and the mixture was stirred at the same temperature for three hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→1:10) to give (5-chloro-6-methoxypyridin-2-yl)(4-cyclopropylphenyl)methanol (765 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]2)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 570.9 [M+H]+; single peak at tR=3.46 min (System 1); Rf=0.26 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:37])[C:33]2[C:28](=[C:29]([O:34][CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][C:25]1=[O:36]>>[CH3:35][O:34][C:29]1[C:28]2[CH2:27][CH:26]3[C:25](=[O:36])[C:24]([CH3:37])([C:33]=2[CH:32]=[CH:31][CH:30]=1)[CH2:23][CH2:22][CH2:21][CH2:20]3
Reactant: COc1cccc2c1CCC(=O)C2(C)CCCCCl
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Product: COc1cccc2c1CC1CCCCC2(C)C1=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl- 5,10-methano-5H-benzocyclononen-12-one, there is obtained from 40.5 g. of 1-(4-chlorobutyl)-1-methyl-5-methoxy-2-tetralone, 21.5 g. of the title product, b.p. 130° to 135° C. (0.3 mm.).
Reaction SMILES: [C:1]([NH:9][NH:10][C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:24])([CH3:23])[C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[C:32]([N:10]([C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:23])([CH3:24])[C@H:12]1[OH:25])[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:34])[CH3:33]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N(NC(=O)c1ccccc1)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
Trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (320 mg) was dissolved in 1 ml of chloroform, 0.5 ml of pyridine was added, and 0.28 ml of acetyl chloride was added with stirring under ice cooling. After stirring at room temperature for 80 minutes, the solvent was distilled off under reduced pressure and the residue was dissolved in 5 ml of methanol. The solution was treated with 5 ml of 1N-sodium hydroxide at room temperature for 30 minutes. After the methanol had been distilled off, the residue was shaken together with ethyl acetate-water and the organic layer was washed with an aqueous solution of sodium chloride and subsequently concentrated. This was recrystallized from hexane-ethanol (1:1) to give 170 mg of trans-4-(1-acetyl-2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.monohydrate as white crystals, m.p. 212°-213° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:16][CH2:13][C:14]#[CH:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: C#CCO
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CCOC(=O)CP(=O)(OCC)OCC
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
The above 2-(diethoxyphosphoryl)acetic acid chloride and 31.4 g (0.56 mol) of propargyl alcohol were dissolved in 100 mL of toluene and cooled to 5° C. 67.1 g (0.66 mol) of triethylamine was dropwise added to the solution at 15° C. or lower, then stirred at room temperature for 90 minutes, and disappearance of the starting materials was confirmed through gas chromatography. The formed salt was filtered and washed with 30 ml of a saturated saline solution. The organic layer was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution) to give 111.9 g (yield 93%) of the intended 2-propynyl 2-(diethoxyphosphoryl)acetate. The obtained 2-propynyl 2-(diethoxyphosphoryl)acetate was analyzed through 1H-NMR to confirm the structure thereof. The results are shown below.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.[CH2:14]1COC[CH2:15]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:14][CH3:15])[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ccnc1Br
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Product: CCc1nccc(Cl)c1N

Procedure:
Following a modified synthetic procedure reported in J. Org. Chem. 2006, 71, 7322, a to a stirred solution of 2-bromo-4-chloropyridin-3-amine (prepared as described in US2002/0119982) (1.0 eq.), and Pd(Ph3P)4 (0.05 eq.) in dry THF (0.05M) under argon was added dropwise Me3Al (1.0M in hexane, 2.0 eq.) and the reaction mixture was refluxed for O/N. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with 5-100% EtOAc/petroleum ether affording the titled compound as orange oil. 1H NMR (300 MHz, DMSO-d6, 300K) δ 7.67 (1H, d, J=5.2 Hz), 7.11 (1H, d, J=5.2 Hz), 5.26 (2H, br. s), 2.69 (2H, q, J=7.3 Hz), 1.73 (3H, t, J=7.3 Hz). MS (ES) C7H9ClN2 requires: 156, found: 157, 159 (M+H)+.