Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH-].[K+]>C1COCC1.O>[CH:1]([C:4]1[C:12]([C:13]([OH:16])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1nn2ccccc2c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nn2ccccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.2 %

Procedure:
A mixture of 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (1.5 g, 1 equivalent) and potassium permanganate (2.9 g, 2.1 equivalents) in 10 mL of THF was stirred at room temperature for 2 days. A solution of potassium hydroxide (2.2 g, 5 equivalents) in 10 mL of water was added and the resulting solution was stirred at room temperature for 2 hours. The mixture was filtered to remove insoluble solids and the filtrate was extracted to remove unreacted aldehyde. The remaining aqueous solution was acidified with concentrated HCl and the precipitates were collected by filtration and dried under reduced pressure to give 2-isopropylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.98 g, 60% yield) as a solid. Compound 1079.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C([O-])(O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[N:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(F)cn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
To a 0° C. solution of 2-amino-5-fluoropyridine (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89 mmol). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5%→40% EtOAc/hexanes) to give the title compound (1.34 g). MS: m/z=197.3 (M+1).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:23]=3[Br:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Brc1ccc(Br)c(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(Br)ccc3Br)CC2)c(OC)nc1C
Yield: 66 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,5-dibromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:2][CH2:4][CH2:5][O:9][CH3:8])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 55.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethene (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2 -methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMRτ(CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[O:9][C:8](=[O:13])[CH2:7]2.[C:14](OCC)(OCC)([O:16][CH2:17][CH3:18])[CH3:15]>>[CH2:14]([O:16]/[C:17](=[C:7]1/[C:8](=[O:13])[O:9][C:10](=[O:12])[C:11]2[C:6]/1=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])/[CH3:18])[CH3:15]
Reactant: O=C1Cc2cccc(F)c2C(=O)O1
Reactant: CCOC(C)(OCC)OCC
Product: CCO/C(C)=C1/C(=O)OC(=O)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
A suspension of 8-fluoro-isochroman-1,3-dione (7.125 g, 39.55 mmol) and triethyl orthoacetate (50.0 mL, 273 mmol) was heated to a gentle reflux during 5 min and reflux continued for 10 min. It was allowed to cool to r.t. with formation of crystalline product. It was cooled further on dry ice-EtOH bath, filtered, washed with cold ethanol (3×15 ml) and dried in vacuo (50° C., 30 min) to give 4.600 g of the title compound as a pink solid. The supernatant was evaporated and the purple oil residue was quenched with ethanol (20 ml) with formation of crystalline product, separated by filtration to give 693 mg more of the title product, total yield 53.5%. LC-MS (m/z) 251.2 (MH+), tR=1.05. 1H NMR (500 MHz, DMSO-d6): 1.41 (t, J=7.0 Hz, 3H, Me of Et), 2.68 (s, 3H, Me), 4.46 (q, J=7.0 Hz, 2H, CH2 of Et), 7.21 (dd, J=8.5 Hz, 10.7 Hz, 1H, C (7)-H), 7.72 (dt, J (d)=5.9 Hz, J (t)=8.3 Hz, 1H, C (6)-H), 8.08 (d, J=8.3 Hz, 1H, C (5)-H). 19F NMR (470.59 MHz): −110.2 ppm (dd, J=5.9 Hz, 10.7 Hz). 13C APT (125.76 MHz, DMSO-d6=39.89 ppm): 14.8 (CH3 of Et), 17.97 (CH3), 66.79 (CH2), 99.71 (C4), 109.04 (d, J=7.9 Hz, C9), 114.04 (d, J=20.6 Hz, CH, C7), 123.43 (d, J=3.3 Hz, CH, C5), 136.28 (d, J=10.5 Hz, CH, C6), 137.43 (s, C3=O), 157.22 (d, J=4.3 Hz, C1=O), 161.77 (C), 162.19 (d, J=262 Hz, C8), 178.45 (═C—OEt).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[S:11][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])C)=[O:16])=[CH:13][CH:14]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].Cl.OC1C=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34]C=1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[S:11][C:12]([C:15]([O:17][C:18]2[CH:20]=[CH:39][C:35]([C:36](=[NH:37])[NH2:38])=[CH:34][CH:21]=2)=[O:16])=[CH:13][CH:14]=1
Reactant: N=C(N)c1ccc(O)cc1
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCCN1Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To the compound (0.55 g, 1.7 mmol) obtained in step 1 was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, pyridine (10 ml), 4-hydroxybenzamidine hydrochloride (0.35 g, 2.0 mmol), and WSC hydrochloride (0.48 g, 2.5 mmol) were added to the obtained residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (0.30 g, 0.49 mmol, 29%).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:21]([CH3:30])[N:22]=CC1C=CC=CC=1)[NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2OCCO2)[CH:11]=1)#[N:2].Cl.[NH:32]1[CH2:37][CH:36]=[CH:35][CH2:34][CH2:33]1.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:30][N:21]1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:32]3[CH2:33][CH:34]=[CH:35][CH2:36][CH2:37]3)[CH:11]=2)=[N:3][C:1]([NH2:2])=[N:22]1
Reactant: C1=CCNCC1
Reactant: CN(N=Cc1ccccc1)C(=NC#N)NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CC=CCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N'-cyano-N-[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1-methyl-2-(phenylmethylene) hydrazinecarboximidamide (2.62 g) in tetrahydrofuran (40 ml) was stirred at room temperature for 0.5 h with 2 N hydrochloric acid (5 ml). The mixture was treated with 1,2,3,6-tetrahydropyridine (9 ml) and stirred at room temperature for a further 1 h. The mixture was treated with sodium borohydride (1.5 g), stirred at room temperature for 18 h, diluted with ethyl acetate, filtered and the filtrate evaporated in vacuo. The resulting oil was partitioned between ethyl acetate and water. The organic phase was evaporated in vacuo and the residue was purified by column chromatography on silica, using methanol. Evaporation of the eluates gave the title compound which was recrystallised from a mixture of benzene and cyclohexane (1.26 g) m.p. 102°-3°. TLC silica; methanol-ammonia 80:1; Rf 0.6.
Reaction SMILES: [C:1]1([S:10]([NH:13][C:14](=[O:17])[CH2:15][NH2:16])(=[O:12])=[O:11])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].Cl[C:21]([O:23][CH3:24])=[O:22].O>CN(C)C=O>[C:1]1([S:10]([NH:13][C:14](=[O:17])[CH2:15][NH:16][C:21]([O:23][CH3:24])=[O:22])(=[O:11])=[O:12])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: NCC(=O)NS(=O)(=O)c1scc2ccccc12
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)NCC(=O)NS(=O)(=O)c1scc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product obtained in Step 1 (0.45 g) in N,N-dimethylformamide (5 ml) was added slowly 60% sodium hydride (75 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Methyl chloroformate (0.14 ml) was added to the above-mentioned mixture followed by stirring for 20 minutes at room temperature. 60% sodium hydride (75 mg) was added to the solution, and the mixture was stirred for 1.5 hours at room temperature, then 15 minutes at 70° C. After cooling to room temperature, water (20 ml) was added to the resultant mixture and this aqueous solution was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water, then saturated aqueous NaCl solution. After drying over anhydrous magnesium sulfate, ethyl acetate was removed in vacuo and the residue was purified by silica-gel columun chromatography to give 0.18 g of the objective compound.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH3:14])[C:7]2=[O:15].[Cl:16][C:17]1[N:22]=[C:21]([C:23]([CH2:25]Cl)=[CH2:24])[CH:20]=[CH:19][CH:18]=1>CO.[I-].[K+]>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:25][C:23]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[N:22]=1)=[CH2:24])([CH3:14])[C:7]2=[O:15]
Reactant: CC1C(=O)c2ccc(Cl)cc2C1=O
Reactant: C=C(CCl)c1cccc(Cl)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(CC1(C)C(=O)c2ccc(Cl)cc2C1=O)c1cccc(Cl)n1
Yield: 87 %

Procedure:
In 20 ml of methanol was dissolved 1.32 g of 85% potassium hydroxide, and then 3.89 g of 5-chloro-2-methylindan-1,3-dione, 3.76 g of 6-chloro-2-(1-chloromethylvinyl)pyridine and 0.05 g of potassium iodide were added to the solution. After refluxing under heating for 3 hours, the solvent was evaporated and water was poured. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and with a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the solvent was evaporated, the residue was separated and purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to obtain 6.02 g of the compound No. 115 shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(=O)(=O)(O)[OH:23].O>C(Cl)Cl>[Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:17])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc2c(c1Cl)C(=O)N(C1(C#N)CCCCC1)C2=O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1Cl)C(=O)N(C1(C(N)=O)CCCCC1)C2=O
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of about 4.35 g (14.4 mmol) of 3-chloro-N-(1-cyanocyclohexyl)-4-methylphthalimide in about 50 ml methylene chloride is added to concentrated sulfuric acid and water at less than 10° C. with rapid stirring. The reaction mixture is stirred very vigorously at ambient temperatures for 4 hours (reaction complete by thin layer chromatography), poured over crushed ice and extracted with about 450 ml methylene chloride. The organic extracts are combined and concentrated in vacuo to give a white fluffy precipitate. The precipitate is filtered and air dried to give the title product, 2.86 g (62% yield), mp 192° C.-208° C., identified by infrared and NMR analysis.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C>CO>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:8]1([C:7]2[CH:6]=[CH:5][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:24][CH:23]=2)[C:10]2[C:11](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=2[Cl:19])[C:12](=[O:14])[O:13]1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 90 °C
Yield: 48.2 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (3.61 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X= (CH3)2N, Y2 = H, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = Cl) (5.60 g., m.p. 206°-207.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](N)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[CH2:21]([OH:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:23][CH2:21][CH3:22])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: CCO
Reactant: COc1cc(C(N)=O)ccc1-c1nc2ncncc2[nH]1
Product: CCOC(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
A quantity of 0.42 gm of 8-(2'-methoxy-4'-chlorocarbonyl-phenyl)-purine hydrochloride (see Example 43) was refluxed in 30 ml of ethanol for 45 minutes. The solvent was evaporated off, and the residue was purified over a silica gel column [eluant:methylene chloride/ethanol (50:1 to 19:1)].
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([C:21](OC)=[O:22])[C:8]=2[CH2:25][CH2:26][CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH:10]=[C:9]([CH2:21][OH:22])[C:8]=2[CH2:25][CH2:26][CH3:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCc1c(CO)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 98.2 %

Procedure:
Using methyl 5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carboxylate (3.0 g), and a 1.5 mol/L solution (16.1 mL) of diisobutylaluminum hydride in toluene, a procedure as in Reference Example 5 was performed to give the title compound as a pale-red oil (yield 2.73 g, 95%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([CH2:18]O)[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][CH2:18][C:15]1[CH:14]=[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[O:17][N:16]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cc(-c2cc(CCl)no2)cc(C(F)(F)F)c1
Temperature: 75 °C

Procedure:
To a solution of {5-[3,5-bis(trifluoromethyl)phenyl]-3-isoxazolyl}methanol (Example 323B) (0.100 g, 0.32 mmol) in dry carbon tetrachloride (15 mL) was added PS-triphenylphosphine (0.292 g, 2.2 mmol/g, 0.64 mmol). The reaction was heated at 75° C. overnight. The resin was filtered and washed with carbon tetrachloride. Concentration in vacuo afforded the title compound, which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25](Br)[CH:26]=[CH2:27].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:27]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[C:3]([O:23][CH3:24])[CH:4]=2)[CH:9]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=CCN1CCc2cc(OC)c(O)cc2C1Cc1ccc(OC)c(OC)c1
Temperature: 80 °C

Procedure:
27.7 g. (84 mmol) (-)-7-Hydroxy-6-methoxy-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline in 430 ml. ethanol are mixed with 9.18 g. (75.9 mmol) allyl bromide and 17.6 g. (209 mmol) sodium bicarbonate. The reaction mixture is heated for 3 hours at 80° C., while stirring. After cooling and evaporating in a vacuum, the residue is partitioned between water and methylene chloride. The usual working up and chromatographic purification (silica gel; chloroform) gives 22.0 g. of a pale yellow foam. By crystallisation from isopropanol-diethyl ether, there is obtained (+)-2-allyl-7-hydroxy-6-methoxy-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline in the form of colourless crystals; m.p. 108°-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].II.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:13][CH3:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)CCCc1ccc(F)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCCc1ccc(F)cc1
Temperature: 70 °C
Yield: 14.8 %

Procedure:
At 0° C., a solution of 4-(4-fluorophenyl)-N-methylbutyramide (1.30 g, 6.70 mmol) in THF (15 ml) was added dropwise to a suspension of sodium borohydride (604 mg, 16.0 mmol) in THF (15 ml). Successively, a solution of iodine (1.70 g, 6.70 mmol) in THF (20 ml) was added dropwise. The reaction mixture was heated to 70° C. for 16 hours. It was cooled to 0° C. Methanol (50 ml) was added carefully. The solvents were removed in vacuo. The residue was dissolved in a mixture of a 32% aqueous solution of sodium hydroxide (100 ml), water (50 ml), and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using a mixture of DCM/methanol/25% aqueous ammonia (first 100:10:1, then 100:20:2) as eluent, to give 180 mg of N-[4-(4-fluorophenyl)butyl]-N-methylamine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>>[CH3:29][O:30][C:31]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:32]=1[C:33]([N:23]1[CH2:24][CH2:25][CH:20]([N:18]2[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]3[C:8]4[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[N:19]2)[CH2:21][CH2:22]1)=[O:34]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c5c4CC(C)(C)O5)C(C)(C)C3=O)CC2)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B5) and 2,4-dimethoxybenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:16])[CH:7]=[C:8]([C:13](O)=O)[CH:9]=2)[N:4]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:16])[CH:7]=[C:8]([C:13]3[NH:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:24]=3)[CH:9]=2)[N:4]=1
Reactant: COc1ccc2cc(C(=O)O)cc(C)c2n1
Reactant: Nc1ccccc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(-c3nc4ccccc4[nH]3)cc(C)c2n1

Procedure:
2-Methoxy-8-methylquinoline-6-carboxylic acid (1.09 g) was added in portions to a stirred mixture of o-phenylene diamine (0.54 g) and phosphorus oxychloride (20 cm3) at room temperature (20° ). The mixture was heated under reflux for 4 hours and then solvent was evaporated in vacuo. Ice (20 g) was added to the residue which was then basified to pH 9 with aqueous 2.5M sodium hydroxide and filtered to yield a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:100 by volume. Combination and evaporation of appropriate fractions gave the title compound which was characterised spectroscopically and used directly in Example 2 without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Br:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Br:29][C:27]1[CH:26]=[CH:25][C:5]2[N:6]([C@@H:7]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]3[OH:9])[C:2]([Cl:1])=[N:3][C:4]=2[CH:28]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)ccc32)[C@H](O)[C@@H]1O
Yield: 85 %

Procedure:
A solution of 0.304 g (0.621 mmole) of 86 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 h. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature<40° C.). The residue was recrystallized from MeOH to give 0.192 g (85%) of 87 as white crystals. MP 154°-155° C. MS (CI) m/e 362.9735 (40%, MH+ =362.9747). 1H NMR (DMSO-d6): d 8.01 (d, 1, 7-H, J7-6 =8.5 Hz), 7.87 (d, 1, 4-H, J4-6 =2.0 Hz), 7.41 (dd, 1, 6-H), 5.89 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6-5 Hz), 5.28 (d, 1, 3'-OH, J3'-3'OH =4 5 Hz), 5.25 (t, 1, 5'-OH, J5'-5'OH =5.0 Hz), 4.44 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.13 (m, 1, 3'-H, J3'-4' =2.5 Hz), 3.98 (m, 1, 4'-H, J4'-5' =J4'-5" =3.5 Hz), 3.68 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): d 142.81 (C3a), 141.23 (C2), 132.20 (C7a), 125.92 (C6), 121.32 (C4), 115.27 (C5), 114.89 (C7), 89.08 (C1'), 86.21 (C4'), 71.47 (C2'), 69.73 (C3'), 61.22 (C5').