Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C(Cl)Cl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:16]3[CH:25]=[CH:24][C:19]([C:20]4[O:21][C:32](=[O:33])[NH:23][N:22]=4)=[CH:18][CH:17]=3)=[C:8]([C:12]([F:14])([F:15])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(-c3c(C(F)(F)F)oc4cc(O)ccc4c3=O)cc2)o1

Procedure:
4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzohydrazide (1 equiv.) and CDI (10 equiv.) in DCM is refluxed overnight. An aqueous/EtOAc workup followed by purification by prep-HPLC can give the desired product in Example 23.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NCCCCn1c(CC)nc2c(N)nc3ccccc3c21
Yield: 62.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with butyryl chloride (0.40 mL, 3.9 mmol) to provide 0.77 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]butanamide as a light brown solid, m.p. 147.7-148.8° C. Analysis: Calculated for C20H27N5O.0.4H2O: % C, 66.60; % H, 7.77; % N, 19.42; Found: % C, 66.84; % H, 7.77; % N, 19.36.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:20][N:19]=2)=[CH:13][CH:12]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3cccc(F)c3)cc2)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(3-fluoro-phenoxy)-phenyl)-acetohydroximoyl chloride (290 mg, 1.04 mmol) described in Manufacturing Example 81-1-2 and 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (50.0 mg, 0.423 mmol) was added triethylamine (177 μL, 1.27 mmol) at room temperature, which was stirred for 30 minutes at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (38.7 mg, 25.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[Cl:18][C:19]1[C:25]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][C:22]([NH2:23])=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=1.C(Cl)CCl.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:23][C:22]1[C:21]([N+:32]([O-:34])=[O:33])=[CH:20][C:19]([Cl:18])=[C:25]([N:26]2[CH2:31][CH2:30][N:29]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:28][CH2:27]2)[CH:24]=1
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Reactant: Nc1cc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Yield: 38.9 %

Procedure:
A mixture of 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (363 mg, 1.558 mmol, Preparation A), 4-chloro-2-nitro-5-(piperazin-1-yl)aniline (400 mg, 1.558 mmol, prepared as described in [El-Abadelah, M. M.; Nazer, M. Z.; El-Abadla, N. S.; Awadallah, A. M. Asian Journal of Chemistry 1999, 11(4), 1463-1468.]), EDC (448 mg, 2.337 mmol), and N,N-dimethylpyridin-4-amine (571 mg, 4.67 mmol) in DCM (5 mL)/DMF (3 mL) was stirred overnight. The solution was diluted with DCM, then washed with water for three times. Purification via flash chromatography with 20% EtOAc in DCM provided the title compound (286 mg, 0.606 mmol, 38.9% yield). 1H-NMR (CDCl3, 400 MHz): δ8.11 (1H, s), 7.59 (1H, d, J=7.53 Hz), 7.47 (1H, t, J=8.53 Hz), 7.08 (1H, t, J=7.53 Hz), 6.99 (1H, d, J=7.28 Hz), 6.03 (1H, s), 3.80 (3H, s), 3.8 (2H, s) 3.22 (2H, s), 3.01 (2H, s), 2.57 (3H, s), 2.46 (2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:13](=[O:24])[C@@H:12]1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][C@H:29]2[OH:34])[CH2:27]1.[Cl:35]CCl.CO>>[ClH:35].[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:31]2[CH2:32][CH2:33][C:28]3([CH2:26][CH2:27]3)[C@H:29]([OH:34])[CH2:30]2)=[O:23])[C:13](=[O:24])[C@@H:12]1[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: C[C@H]1C(=O)N(CCCCC(=O)O)CCN1C(=O)OCc1ccccc1
Reactant: ClCCl
Solvent: CO
Product: C[C@H]1C(=O)N(CCCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Product: Cl

Procedure:
In analogy to the procedure described in Example 15, (S)-4-(4-carboxy-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester and 1.1 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave after flash chromatography (SiO2, dichloromethane/MeOH 100% dichloromethane to 85/15) the titled compound in 61% yield as light yellow amorphous solid. MS: 458.26 (MH+).
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)[Cl:8].[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>C(Cl)Cl>[Cl:8][C:15]1[CH2:16][CH2:17][C:12]([CH3:19])([CH3:11])[CH2:13][C:14]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CCC(=O)CC1
Solvent: ClCCl
Product: CC1(C)CCC(Cl)=C(C=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N,N-dimethylformamide (1.37 eq.) in CH2Cl2 (1.5 vol.) was cooled to 0° C. and then POCl3 (1.25 eq.) was added slowly to the N,N-dimethylformamide solution at below 25° C. The resulting solution was allowed to warm up to room temperature. A solution of 4,4-dimethylcyclohexanone (1.00 eq.) in CH2Cl2 (1.4 vol.) was added slowly to the above solution at below 30° C., and then the reaction mixture was stirred at 45° C. overnight. The reaction mixture was quenched into a cooled 10% sodium acetate solution (30.0 vol.) at below 15° C., followed by a CH2Cl2 rinse (4.6 vol.). The quenched mixture was stirred while allowing it to warm up to room temperature. The organic layer was separated and then aqueous layer was extracted with CH2Cl2 (7.6 vol.×3). The organic layer and CH2Cl2 extracts were combined and concentrated to give a solution and the solution was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 10.1 (1H, s, CHO) 1H NMR (400 MHz, CDCl3) δ 10.1 (1H, s, CHO), 2.61-2.57 (2H, m), 2.09 (2H, s), 1.54-1.51 (2H, m), 0.95 (6H, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39]([OH:41])=[O:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39]([OH:41])=[O:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of oxalyl chloride (0.166 mL, 0.332 mmol) in dichloromethane (2 mL) was added dimethylsulfoxide (0.047 mL, 0.663 mmol) dropwise. After ten minutes, 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (140 mg, 0.301 mmol; Example 185) in dichloromethane (2 mL) was added dropwise. After 15 minutes, triethylamine (0.210 mL, 1.507 mmol) was added dropwise. The mixture was warmed to 0° C. for 10 minutes and then quenched with 10% aq. citric acid. The mixture was diluted with water and extracted with dichloromethane (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:32])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][OH:31])(=[O:27])=[O:26])[N:21]=[C:8]2[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[C:6]=1[CH3:43])=[O:4].[H-].[Na+].[C:46]1(C)[C:47]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:49]=[CH:50][CH:51]=1.[CH2:57]1COCC1>>[CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:32])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][O:31][S:52]([C:47]3[CH:46]=[CH:51][C:50]([CH3:57])=[CH:49][CH:48]=3)(=[O:53])=[O:54])(=[O:26])=[O:27])[N:21]=[C:8]2[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:42])[F:41])[CH:34]=2)[C:6]=1[CH3:43])=[O:4]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: C1CCOC1
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCO)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCOS(=O)(=O)c3ccc(C)cc3)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Intermediate 28 (470 mg, 0.76 mmol) was dissolved in THF (5 ml), and then sodium hydride (48 mg, 1.2 mmol) was added under an atmosphere of N2. The reaction mixture was stirred at RT for 10 mins, then toluenesulfonyl chloride (191 mg, 1 mmol) was added and stirring was continued for 16 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluing with a gradient of 50-80% EtOAc in cyclohexane to give the title compound as a pale yellow glass (132 mg).
Reaction SMILES: Br[CH2:2][C:3]1([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[N+:30]([C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)([O-:32])=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]([CH2:11][C:3]1([CH2:2][N:34]2[CH:35]=[CH:36][N:37]=[C:33]2[N+:30]([O-:32])=[O:31])[CH2:4][O:5][C:6]([CH3:10])([CH3:9])[O:7][CH2:8]1)[Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC1(C)OCC(CBr)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2ccnc2[N+](=O)[O-])CO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
1.70 g (3.56 mmol equivalents) of 5-bromomethyl-5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-1,3-dioxane was dissolved in 36 mL of dimethylformamide, 402 mg (3.56 mmol equivalents) of 2-nitroimidazole and 1.48 g (10.7 mmol equivalents) of potassium carbonate were added thereto, and the mixture was heated in an oil bath to 80° C. and then stirred for 18 hours. After completion of the reaction, water was added dropwise, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=3/1) to give 362 mg (0.71 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[NH:32][N:31]=[N:30][N:29]=1>C(Cl)Cl>[C:22]1([CH3:21])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:32]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:31]=[N:30][N:29]=1
Reactant: Cc1ccccc1-c1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A solution of triphenylmethyl chloride (348 mg, 1.25 mmol, 2 ml DCM) was added dropwise to a mixture of 5-(2-methylphenyl)-1H-tetrazole (200.5 mg, 1.25 mmol) and TEA (174 μl, 1.25 mmol) in 8 ml DCM. The reaction mixture was strirred overnight at RT, then washed with water (10 ml). The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative chromatography (Cyclohexane/EtOAc 95:5) to yield the above-titled compound (159 mg). 1H NMR (CDCl3): 8.1 (1H, d), 7.45–7.1 (18H, m), 2.5 (3H, s).
Reaction SMILES: C(O[BH3-])(=O)C.[Na+].[CH:7](=O)[CH:8]([CH3:10])[CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[N:20]2[CH2:23][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH2:21]2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)[N:20]2[CH2:21][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][N:38]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH2:23]2)=[CH:17][CH:18]=1
Reactant: CC(C)C=O
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)CN1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 4 h
Yield: 105.2 %

Procedure:
32 mg of sodium acetoxyborohydride and then 22 mg of isobutyraldehyde are successively added, at a temperature close to 20° C., to a solution of 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine in 2 cm3 of 1,2-dichloroethane. After stirring for 4 hours at a temperature close to 20° C., 3 cm3 of dichloromethane and 2 cm3 of a saturated aqueous sodium bicarbonate solution are added to the reaction medium. After separating after settling out, the organic [lacuna] is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 63 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 0.92 (d, J=7 Hz, 6H), 1.82 (mt, 1H) 2.14 (d, J=8 Hz, 2H), 2.54 (t, J=5.5 Hz, 4H), 2.75 (s, 3H), 3.18 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.89 (dd, J=8 and 2.5 Hz, 1H), 6.97 (broad s, 1H), from 7.15 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH:13]([OH:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:32])C=CC=CC=1.C([N:44]([CH2:47]C)CC)C>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=3)[O:24][C:47](=[O:32])[NH:44]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(Cc2ccc(F)cc2)C(c2ccc(C(F)(F)F)cc2)O1
Yield: 92.4 %

Procedure:
To a solution of (2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionic acid (21.0 g, 61.35 mmol) in tetrahydrofuran (500 ml) were added diphenylphosphoryl azide (14.5 ml, 67.5 mmol) and triethylamine (12.9 ml, 92 mmol), and the mixture was heated under reflux for 3 hrs. The reaction solution was diluted with water (500 ml), and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave (4RS,5SR)-4-((4-fluorophenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3-oxazolidin-2-one (19.24 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11]C)=[O:10])=[N:7][CH:8]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1ccc(OC)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The obtained ester compound was dissolved in 0.5 ml of methanol and 0.5 ml of tetrahydrofuran, and 0.52 ml of aqueous 1 N sodium hydroxide solution was added to it, and stirred at room temperature for 2 hours. This was neutralized with aqueous 10% citric acid solution, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure to obtain 17.2 mg of the entitled compound as a white crystal.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[O:14][C:15]3[C:35]([O:36]CC4C=CC=CC=4)=[C:34]([O:44][CH3:45])[CH:33]=[CH:32][C:16]=3[C:17]=2[C:18]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[O:19])[CH:10]=[N:9]1)C1C=CC=CC=1>[Pd].Cl.C(OCC)(=O)C.CO>[OH:36][C:35]1[C:15]2[O:14][C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)=[C:17]([C:18]([C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)=[O:19])[C:16]=2[CH:32]=[CH:33][C:34]=1[O:44][CH3:45]
Reactant: COc1cc(C(=O)c2c(-c3cnn(Cc4ccccc4)c3)oc3c(OCc4ccccc4)c(OC)ccc23)cc(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)c2c(-c3cn[nH]c3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of crude [2-(1-benzyl-1H-pyrazol-4-yl)-7-benzyloxy-6-methoxy-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (29 mg), 10% palladium on carbon (20 mg) and 6M HCl(aq) (2 drops) in ethyl acetate (2 mL) and methanol (1 mL) was stirred at room temperature overnight. After this time the reaction mixture was filtered through celite and the solvent removed under vacuum. The crude residue was purified by preparative thin layer chromatography to afford the product as a pale yellow resin that was solidified by freeze-drying with t-butanol (5 mg, 2% over two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[SH:12])[NH:5][C:6](=[O:8])[CH3:7].[CH2:13](OC=C(C#N)C#N)C>CC(O)=O>[C:6]([NH:5][C:4]1[CH:9]=[CH:10][C:11]2[S:12][CH:13]=[N:1][C:2]=2[CH:3]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccc(S)c(N)c1
Reactant: CCOC=C(C#N)C#N
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2scnc2c1
Temperature: 125 °C
Yield: 17 %

Procedure:
To a solution of intermediate 3′-amino-4′-mercaptoacetanilide in HOAc (50 mL) was added ethoxymethylene malononitrile (1.95 g, 16 mmol) and the resulting mixture was refluxed at 125° C. for 5 h. After cooling, the product mixture was concentrated under reduced pressure, and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel, eluting with EtOAc-Hex (0:100 to 50:50) to give the title compound (508 mg, 17%) as a yellow solid. 1H-NMR (DMSO-d6): δ 9.35 (1H, s), 8.53 (1H, s), 8.10 (1H, d), 7.63 (1H, d), 2.15 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][C:22]([CH3:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]2[CH:17]([CH2:18][N:19]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:20]2)[C:16]1=[O:38])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:31]([N:19]1[CH2:18][CH:17]2[CH:21]([C:22]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:38])[CH2:20]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)OC1CC(C)(c2ccccc2)C2CN(Cc3ccccc3)CC2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1(O)C(O)CC(C)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
37 cm3 of 1.38 molar 2-methoxyphenylmagnesium bromide solution in tetrahydrofuran are added to a solution containing 2.4 g of (3aRS,5RS,7SR,7aRS)-5-acetoxy-2-benzyl-7-methyl-7-phenyl-4-perhydroisoindolone in 50 cm3 of tetrahydrofuran at 4° C. The reaction mixture is stirred at room temperature for 18 hours, treated with 150 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of water and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 27 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 35 cm3 fractions. Fractions 8 to 15 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1.65 g of (3aRS,4RS,5RS,7SR,7aRS)-2-benzyl-7-methyl-7-phenyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained in the form of a yellow foam.