Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([C:24]([OH:26])=O)[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:8][C:9]1([C:24]([NH:36][CH:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH3:35])=[O:26])[CH2:10][CH2:11][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:13][CH2:14]1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
4-(tert-Butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (362 mg), 1-(4-chlorophenyl)ethanamine (172 mg), N-(3-dimethylaminopropyl)-3-ethylcarbodiimide (231 mg) and 1-hydroxybenzotriazole (163 mg) were stirred together in DMF (2 mL) under nitrogen for 16 hours. The reaction mixture was partitioned between EtOAc (20 mL) and brine (4×20 mL). The organics were combined, dried over MgSO4 and evaporated in vacuo. The resultant white solid was dissolved in 1,4-dioxane (5 mL) and a 4M solution of HCl in 1,4-dioxane (5 mL) was added. The resulting mixture was stirred for 16 hours, then diluted with diethyl ether (50 mL). The crude product was isolated by filtration as the HCl salt which was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (168 mg, 42%). 1H NMR (d6-dmso, 400 MHz) 1.33-1.49 (m, 5H), 1.84-2.04 (m, 2H), 2.12-2.22 (br s, 2H), 3.54 (t, 2H), 4.39 (t, 2H), 4.81-4.92 (m, 1H), 6.55-6.59 (m, 1H), 7.13-7.18 (m, 1H), 7.31-7.39 (m, 4H), 8.12 (s, 1H), 8.30 (d, 1H), 11.62 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:26])[CH:17]=[C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])[CH:19]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:16]2[CH:17]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[CH3:25])[CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COc1cc(N)cc(N2CCC[C@@H]2C)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(Nc2nc(Cl)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Temperature: 30 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
The mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (200 mg, 0.97 mmol), (S)-3-methoxy-5-(2-methylpyrrolidin-1-yl)benzenamine (220 mg, 1.07 mmol) and DIPEA (150 mg, 1.17 mmol) in DMSO (50 mL) was heated to 30° C. with stirring for 16 h. The mixture was diluted with water, extracted with ethyl acetate (50 mL), combined organics washed with water (10 mL×4) then brine (10 mL×2), dried over Na2SO4 and concentrated to give the residue which was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford (S)-5-chloro-N-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (280 mg, 77%) as yellow oil. LC-MS: 376 [M+H]+, tR=1.825 min.
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].[OH-].[Na+]>O>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:1][OH:2])[C:5]=1[OH:11]
Reactant: Cc1ccc(O)c(C)c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(O)c(CO)c1
Temperature: 50 °C

Procedure:
A 38% solution of formaldehyde (32.0 grams, 0.4 mol) was added to a stirred solution of 2,4-dimethylphenol (36.6 grams, 0.3 mol) in water (100 ml) containing sodium hydroxide (14 gr., 0.35 mol) and heated at 50° C. for 4 to 5 hours. The reaction was cooled and solid sodium hydroxide added to precipitate the salt of the product. The solid was removed by filtration and dissolved in water. This solution was neutralized with carbon dioxide (dry ice) and the resulting mixture was extracted with methylene chloride. The organic layer was removed, dried, and evaporated to yield a light brown solid. This solid was washed in hexane containing a small amount of toluene to afford a tan solid. The NMR1 and FD/MS2 data support the structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:17]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:2][CH2:3]3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc2c(c1)CCc1ccccc1N2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(N2c3ccccc3CCc3ccccc32)CC1
Reaction time: 1 h

Procedure:
60.0 mg (0.216 mmol) of 5-(4-piperidinyl)-10,11-dihydro-5H-dibenzo[b,f]azepine, 50.0 mg (0.258 mmol) of N-t-butoxycarbonylglycine, 62.1 mg (0.324 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 3 mg (0.03 mmol) of 4-dimethylaminopyridine were dissolved in 1 ml of dichloromethane. 43.7 mg (0.432 mmol) of triethylamine was added to the obtained solution, and they were stirred for 1 hour. The product was purified by the silica gel chromatography (hexane:ethyl acetate=89:11 to 65:35) to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH-].[K+].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br>CCO.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:4]1[C:5](=[O:6])[CH2:7][NH:1][C:2]1=[O:3]
Reactant: O=C1CNC(=O)N1
Reactant: BrCc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CNC(=O)N1Cc1cccc(Br)c1
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Hydantoin (300 mg, 3.0 mmol) was added to a solution of KOH (202 mg, 3.6 mmol) in 90% EtOH at r.t., and the reaction stirred for 30 min. 3-Bromobenzyl bromide (750 mg, 3.0 mmol) was added, and the reaction was heated at reflux for 18 h. The solution was diluted with EtOAc, washed with H2O and brine, dried (MgSO4) and concentrated in vacuo. Precipitation from 50% EtOAc/hexanes followed by collection by filtration gave 512 mg (63%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 5.81 (s, 1H), 4.63 (s, 2H), 4.00 (s, 2H). [M+H] calc'd for C10H9BrN2O2, 269, 271; found, 269, 271.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][NH:17][CH3:18]>CO>[CH3:16][N:17]([CH2:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:18]
Reactant: CNC
Reactant: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1cccc(CN(C)C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Methyl 3-bromomethyl-2-nitrobenzoate (1.6 g) was dissolved in methanol (5 mL). Methanol solution (6 mL) of 2M dimethylamine was added thereto and stirred overnight. After removing the solvent, the residue was diluted with 1M hydrochloric acid and washed with ethyl acetate. The water layer was alkalized with sodium hydrate aqueous solution and extracted with ethyl acetate. The usual workup procedure was conducted to obtain methyl 3-dimethylaminomethyl-2-nitrobenzoate.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14]1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14]1)#[CH:5]
Reactant: COC(=O)C1(c2ccccc2C#C[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: C#Cc1ccccc1C1(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 1-(2-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (I5) (568 mg, 2.09 mmol) in DCM (20.0 mL) at 0° C. was added TBAF (1.0 M in THF, 3.13 mL, 3.13 mmol). The resulting mixture was stirred at 0° C. for 10 minutes then poured into water (50 mL). The aqueous layer was extracted with DCM (2×50 mL), then the combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-25% EtOAc in petroleum benzine 40-60° C.) to give the title compound K2 as an off-white solid (140 mg, 34%); 1H NMR (400 MHz, d6-DMSO) δ 7.46 (dt, J=7.5, 0.8 Hz, 1H), 7.40-7.25 (m, 3H), 4.32 (s, 1H), 3.52 (s, 3H), 1.54 (q, J=4.1 Hz, 2H), 1.25-1.19 (m, 2H). LCMS-A: rt 5.921 min; m/z 201 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]Cl.[N:13]1([C:19]([S:21][CH3:22])=[S:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][N:16]1[CH2:17][CH2:18][N:13]([C:19]([S:21][CH3:22])=[S:20])[CH2:14][CH2:15]1
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1ccc(OC)c(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OC)c(CN2CCN(C(=S)SC)CC2)c1
Yield: 31.9 %

Procedure:
In a nitrogen atmosphere, 2.20 g (11.8 mmol.) of 2,5-dimethoxybenzyl chloride, 2.19 g (11.8 mmol.) of methyl 1-piperazinecarbodithioate, 1.25 g (11.8 mmol.) of anhydrous sodium carbonate and 15 ml of ethanol were mixed and refluxed under heating for 18 hours. Insolubles were removed by filtration. The solvent of the filtrate was distilled off under reduced pressure. To the residue were added 15 ml of dichloromethane and 15 ml of water. The organic solvent portion was taken out, washed with 15 ml of 1-N hydrochloric acid and 18 ml of 1-N aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by column chromatography to give 1.23 g of methyl 4-(2,5-dimethoxybenzyl)-1-piperazinecarbodithioate, yield 31.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>CN(C)C=O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)=[C:21]=[S:22]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N=C=S)cc2)CC1
Reaction time: 1 h
Yield: 104.2 %

Procedure:
A solution of 4-(4-aminophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (15 g, 54.1 mmol) (from Step B above) in N,N-dimethyl-formamide (120 mL) was added dropwise to a cooled (−15° C.) solution of 1,1′-thiocarbonyldiimidazole (9.66 g, 54.2 mmol) (Aldrich) in N,N-dimethylformamide (40 mL). After the addition was complete, the cooling bath was removed and the solution was stirred for 1 h. The mixture was poured into ice-water (1 L), stirred for 30 minutes, and extracted with diethyl ether. The combined extracts were dried over Na2SO4, and evaporated in vacuo to provide 4-(4-isothio-cyanatophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (18 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([N:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:26][C:25]([CH:35]=O)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:23]1[C:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:26][C:25]([CH2:35][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Product: Cc1ccc(-c2cc(CNCCN3CCN(c4ccc([N+](=O)[O-])cc4)CC3)nn2C(C)(C)C)cc1
Yield: 69.4 %

Procedure:
Compound 56 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:32])[CH:9]=2)=[N:6][CH:7]=1.[OH-].[Na+].C1COCC1.Cl>CO>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH2:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:10]([CH3:32])[CH:9]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(Cl)cn3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A reaction mixture of methyl 4-((1-(4-(5-chloropyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (9.63 g), 1M aqueous sodium hydroxide solution (83 mL), THF (40 mL) and methanol (40 mL) was stirred at 70° C. for 6 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: C([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]2[N:16]=[C:15]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]3=[N:13]2)[C:6]=1[OH:22])(C)(C)C.C1(C)C=CC=CC=1>>[Cl:21][C:19]1[CH:18]=[CH:17][C:15]2=[N:16][N:12]([C:7]3[CH:8]=[C:9]([CH3:11])[CH:10]=[CH:5][C:6]=3[OH:22])[N:13]=[C:14]2[CH:20]=1
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of 2-tert-Butyl-6-(5-chloro-2H-benzotriazol-2-yl)-4-methyl-phenol (50.0 g, 158 mmol) in toluene (700 ml) aluminium trichloride (42.2 g, 317 mmol) is added at 80° C. and the reaction mixture is stirred for 30 minutes, cooled to room temperature and slowly poured on crushed ice. The aqueous phase is extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 34.9 g of 2-(5-Chloro-2H-benzotriazol-2-yl)-4-methyl-phenol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([C:11]([NH:13][CH3:14])=O)=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1.[H-].[Al+3].[H-].[H-].O>O1CCCC1>[NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:13][CH3:14])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: CNC(=O)c1oc(CSCCN)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CNCc1oc(CSCCN)cc1-c1ccccc1
Reaction time: 6 h
Yield: 33.8 %

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-N-methyl-3-phenyl-2-furancarboxamide (1.4 g) in dry tetrahydrofuran (100 ml) at 0° was mixed with a 0.5 molar solution of aluminium hydride in tetrahydrofuran (50 ml). After 6 hours boiling at reflux, water (6 ml) was added and the filtered solution was evaporated in vacuo. The residue was purified by column chromatography (silica/methanol) affording the title compound (0.45 g) as an oil,
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[O:28]=[C:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>>[O:28]=[C:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:36]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCC2=O)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCC2=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(2-oxo-pyrrolidin-1-yl-methyl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=20:1) C28H25N3O4
Reaction SMILES: C(O[CH:5]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=3)[N:11]=[CH:10][C:9]=2[O:8][CH:7]([O:21][C:22](=[O:24])[CH3:23])[CH:6]1[C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)C>[Pd].CO>[C:35]([O:34][C:32]([NH:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([CH:6]2[CH2:5][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=4)[N:11]=[CH:10][C:9]=3[O:8][CH:7]2[O:21][C:22](=[O:24])[CH3:23])[CH2:30][CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COc1ccc2ncc3c(c2c1)C(OC(C)=O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(OC(C)=O)O3
Agent: [Pd]
Solvent: CO
Product: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(OC(C)=O)O3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
10% Palladium on activated carbon (500 mg, 4.70 mmol, 1.09 eq) is added at room temperature to a stirred solution of acetic acid 4-acetoxy-3-(trans-4-tert-butoxycarbonylamino-cyclo hexyl)-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-2-yl ester (2.3 g, 4.29 mmol, 1.0 eq) in methanol (60 mL). The reaction mixture is stirred at room temperature under hydrogen flow (10 bars) for 72 hours. The catalyst is then removed by filtration and the solution is concentrated to afford acetic acid 3-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-2-yl ester as a yellow semisolid (1.45 g, 71% yield) which is directly engaged in the next step.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:6]([O:5][P:4]([C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(N)cc1
Yield: 88.5 %

Procedure:
(4-Nitro-phenyl)-phosphonic acid diethyl ester (7.6 g, 29.1 mmol) and SnCl2 (29.6 g, 0.13 mmol) were heated at reflux for 1 h. The mixture was poured in CH2Cl2 (500 mL) and adjusted to pH 8 with sat'd Na2CO3. The resulting mixture was filtered through Celite (CH2Cl2 wash) and the layers separated. The aqueous layer was extracted with CH2Cl2 and the combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. Concentration yielded a light yellow solid (5.9 g, 88%): MS [M+H]+ 230; m.p. 117–118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:16][CH3:17])=[CH:11][C:12]([CH3:15])=[C:13]([Br:18])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C)c(Br)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
4-benzyloxy-3-methoxytoluene (8.0 g) was dissolved in dimethylformamide (30 ml and a dimethylformamide (15 ml) solution of N-bromosuccinimide (6.36 g) was dropwise added thereto, followed by stirring at room temperature for one night. The reaction solution was poured into ice water (400 ml), and crystals thus deposited were collected by filtration, adequately washed with water, and dried for one night to obtain 10.64 g of 4-benzyloxy-2-bromo-5-methoxytoluene (m.p. 110-111° C.) substantially quantitatively, and its structure was confirmed by nuclear magnetic resonance spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH:32]2[CH2:34][O:33]2)=[CH:13][CH:12]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH:46][S:47]([C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1)(=[O:49])=[O:48].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.Cl>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]([S:47]([C:50]1[CH:51]=[CH:52][C:53]([CH3:56])=[CH:54][CH:55]=1)(=[O:48])=[O:49])[CH2:34][CH:32]([OH:33])[CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:35]=[CH:36][CH:37]=[CH:38][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CO2)cc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2F)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(O)CN(c2ccccc2F)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
A suspension of 2.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-oxiranylmethoxypiperidine-1-carboxylate, 1.23 g of N-(2-fluorophenyl)-4-methylbenzenesulphonamide, 0.29 g of potassium carbonate, 0.35 g of benzyltriethylammonium bromide and 0.053 g of lithium chloride in 30 ml of dioxane is stirred at 90° C. over 17 hours. After 18 hours, another 0.20 g of lithium chloride, 0.50 g of potassium carbonate and 0.30 g of benzyltriethylammonium bromide are added. After a total of 40 hours, the reaction mixture is cooled to room temperature, diluted with 1N HCl and extracted with tert-butyl methyl ether (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.14 (1:2 EtOAc-heptane); Rt=5.96.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][O:37][CH2:38][CH2:39][N:34]2[CH2:33][C@H:32]([CH2:40]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:40][C@@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][O:37][CH2:38][CH2:39][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OC[C@H]1CN2CCOC[C@H]2CO1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CN2CCOC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.