Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]I.[C:4]([C:7]1[C:8]([F:47])=[CH:9][C:10]([O:45][CH3:46])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]([CH3:29])[C@@H:27]([C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=3)[O:26][C:25]2=[O:44])[CH:12]=1)(=O)[CH3:5]>C(OCC)C>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([C@H:27]2[O:26][C:25](=[O:44])[N:24]([CH2:23][C:14]3[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=3[C:11]3[CH:12]=[C:7]([C:4]([CH3:5])=[CH2:1])[C:8]([F:47])=[CH:9][C:10]=3[O:45][CH3:46])[C@H:28]2[CH3:29])[CH:31]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:33]=1
Reactant: C[Mg]I
Reactant: COc1cc(F)c(C(C)=O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CCOCC
Product: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(OC)cc1F

Procedure:
Methyl magnesium iodide (29 μL, 0.085 mmol) was added dropwise to a solution of (4S,5R)-3-{[5′-acetyl-4′-fluoro-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (30 mg, 0.047 mmol) in diethyl ether (2 mL) at room temperature. The reaction was carefully heated at reflux 4 h. Additional methyl magnesium iodide (63 μL, 0.19 mmol) and ether (1 mL) was added and the reaction was refluxed for 3 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropenyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a clear glass. LCMS=636.3 (M+1)+. 1H NMR (benzene-d6, 500 MHz, mixture of atropisomers): δ 7.59 (s, 1 H), 7.55 (s, 1 H), 7.35 (d, J=8 Hz, 1 H), 7.30-7.27 (m, 2 H), 6.99-6.96 (m, 2 H), 6.45 (d, J=12.9 Hz, 1 H), 5.32 (d, J=16.9 Hz, 1 H), 5.16-5.15 (m, 1 H), 4.90 (d, J=16.3 Hz, 1 H), 4.48 (d, J=7.7 Hz, 1 H), 3.70 (d, J=6.4 Hz, 1 H), 3.16 (s, 3 H), 2.85-2.79 (m, 1 H), 2.12 (s, 3 H), −0.025 (d, J=6.5 Hz, 3 H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:40]=[CH:39][C:36]([CH2:37][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCNc1ccc(OC)cc1C1CCc2cc(O)ccc2C1
Reactant: O=Cc1ccc(OCCN2CCCCCC2)cc1
Product: COc1ccc(NCCCc2ccc(OCCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)c1

Procedure:
Synthesized from 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol according to an analogous synthetic method to Example 36, 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg) and 4-(2-azepan-1-ylethoxy)benzaldehyde (202 mg) were used according to an analogous synthetic method to Example 38 to provide the title compound (32 mg).
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][S:4][CH:3]1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(Cl)(Cl)(=O)=O>>[OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)C1SC=CC1O
Solvent: O=S(=O)(Cl)Cl
Product: O=C(c1ccccc1)c1sccc1O
Yield: 82 %

Procedure:
The compound is prepared by the method described in Example 14c) from 20.6 parts of 3-hydroxy-2-benzoyldihydrothiophene and 6.75 parts of sulfuryl chloride. 16.7 parts (82% of theory) of 3-hydroxy-2-benzoylthiophene of boiling point 127°-132° C./0.5 mbar and melting point 53°-57° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:17](=[CH:18][CH:19]=2)[N:20]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=[N:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(N)c2)CC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A mixture of tert-butyl-4-(3,4-diaminophenyl)piperazine-1-carboxylate (8 g, 27.6 mmol), Ethyl bromopyruvate (8 g, 41.4 mmol), and NMP (40 ml) was stirred at r.t. overnight. The solution was extracted by EA and purified by gel chromatography (PE:EA=3:1) to afford ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoxaline-2-carboxylate (2 g, yield: 20%) as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=1[CH3:19].N1C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=2[CH3:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(CBr)cc1
Yield: 55 %

Procedure:
4-Bromomethylbenzene sulfonyl chloride (3.72 g, 13.8 mmol) was added portionwise to a solution of 4-amino-1,3,5-trimethyl-1H-pyrazole (1.73 g, 13.8 mmol) and pyridine (1.5 ml) in DCM (100 ml) at rt. Concentration in vacuo gave a solid which was collected by vacuum filtration and washed with water (2×25 ml) then Et2O (100 ml) to give the title compound as a white solid (2.71 g, 7.59 mmol, 55%). δH (D-6 DMSO, 300K) 9.13 (1H, s), 7.64-7.55 (4H, m), 4.77 (2H, s), 3.55 (3H, s), 1.80 (3H, s), 1.54 (3H, s). m/z (ES+, 70V) 358.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:32])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].O>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(N)ccc1S(=O)(=O)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccncc1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.79 g, 11.3 mmol) in N,N-dimethylacetamide (20 mL) was added thionyl chloride (1.34 g, 11.3 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Methoxy-4-(4-pyridylsulfonyl)benzeneamine (2.00 g, 7.6 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered through Celite. The Celite was washed with methylene chloride (100 mL), the methylene chloride solution dried (MgSO4) and concentrated in vacuo to an off-white solid. Trituration with ethyl ether yielded the title propanamide as a white solid (1.65 g, 54%); mp 238°-240° C.
Reaction SMILES: [Si](O[C@H]([C@H]1CC(O)(C2C=CC=CC=2)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.FC1C=C(C[C@H](NC(=O)C2C=C(C3OC=CN=3)C=C(C(N(CCC)CCC)=O)C=2)[C@H](O)[C@H]2C[C@@H](OCCC)CN2)C=C(F)C=1.[Si]([O:102][C@H:103]([C@H:138]1[CH2:142][C@@H:141]([O:143][CH2:144][CH2:145][CH3:146])[CH2:140][N:139]1C(OC(C)(C)C)=O)[C@@H:104]([NH:114][C:115](=[O:137])[C:116]1[CH:121]=[C:120]([C:122]2[O:123][CH:124]=[CH:125][N:126]=2)[CH:119]=[C:118]([C:127]([N:129]2[CH2:133][CH2:132][CH2:131][C@@H:130]2[CH2:134][O:135][CH3:136])=[O:128])[CH:117]=1)[CH2:105][C:106]1[CH:111]=[C:110]([F:112])[CH:109]=[C:108]([F:113])[CH:107]=1)(C(C)(C)C)(C)C>Cl.O>[F:112][C:110]1[CH:111]=[C:106]([CH2:105][C@H:104]([NH:114][C:115](=[O:137])[C:116]2[CH:121]=[C:120]([C:122]3[O:123][CH:124]=[CH:125][N:126]=3)[CH:119]=[C:118]([C:127]([N:129]3[CH2:133][CH2:132][CH2:131][C@@H:130]3[CH2:134][O:135][CH3:136])=[O:128])[CH:117]=2)[C@H:103]([OH:102])[C@H:138]2[CH2:142][C@@H:141]([O:143][CH2:144][CH2:145][CH3:146])[CH2:140][NH:139]2)[CH:107]=[C:108]([F:113])[CH:109]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cccc(C(N)=O)c1
Agent: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N(CCC)CCC)cc(-c3ncco3)c2)C1
Agent: Cl
Solvent: O
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step 12 (B): Preparation of N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-5-(oxazol-2-yl)-N3,N3-dipropylisophthalamide. The solution of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (step 12 (A), 110 mg) in HCl (4.0 M solution in dioxane, 2 mL) was added 4 drops of H2O and the mixture was stirred at rt for 2 h. The solvent was removed and the mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 42-82% methanol/H2O/0.1% TFA) to give the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 0.74 (3H, m), 0.97 (3H, m), 1.03 (3H, m), 1.57 (1H, dd, J=5, 15 Hz), 1.63 (1H, m), 1.76 (2H, dd, J=5, 15 Hz), 2.19 (1H, m), 2.54 (1H, m), 2.90 (1H, dd, J=10, 15 Hz), 3.21 (2H, m), 3.35-3.53 (7H, m), 3.85 (1H, m), 4.08 (1H, dd, J=5, 10 Hz), 4.23-4.30 (2H, m), 6.75 (1H, m), 6.92 (2H, m), 7.37 (1H, s), 7.71 (1H, m), 8.06 (1H, s), 8.13 (1H, m), 8.39 (1H, m). MS (ESI) (M+H)+ 613.27.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2cnn(CCN3CCCC3)c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-nitroindazole (2.00 g, 12.3 mmol) and potassium carbonate (5.10 g 37.0 mmol) in DMF (40 mL) was stirred for 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (3.20 g 18.9 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 4H), 2.47 (m, 4H), 2.90 (t, 2H, J=6.45), 4.68 (t, 2H, J=6.44), 7.94 (m, 1H), 8.00 (m, 1H), 8.31 (s, 1H), 8.77 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([Cl:12])[C:8]([CH2:10]Cl)=[CH:9][C:3]=2[O:2]1.[CH3:13][N:14](C)C=O.[C-]#N.[K+]>O>[Cl:12][C:7]1[C:8]([CH2:10][C:13]#[N:14])=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: CN(C)C=O
Reactant: ClCc1cc2c(cc1Cl)OCO2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1cc2c(cc1Cl)OCO2
Reaction time: 6 h

Procedure:
1.025 g of 6-chloropiperonyl chloride, 5 ml of dimethylformamide, 330 mg of potassium cyanide are introduced, agitation is carried out at ambient temperature for 6 hours, the reaction medium is poured into 50 ml of water, extracted with 3×30 ml of ethyl acetate, the extracts are washed with 30 ml of sodium chloride and dried. After recrystallization from 5 ml of isopropyl ether under reflux and separating, 740 mg of expected product (white crystals) is obtained. ANALYSIS: IR CHCl3 cm-1CN 2255 Aromatic 1625-1505-1481
Reaction SMILES: O.[OH-].[Li+].[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[C:21]2/[CH:27]=[CH:28]/[C:29]([O:31]C)=[O:30])(=[O:16])=[O:15])(=[O:7])=[O:6].O1CCCC1.[ClH:38]>O.CO>[ClH:38].[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[C:21]2/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])(=[O:15])=[O:16])(=[O:6])=[O:7].[ClH:38].[ClH:38].[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[C:21]2/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])(=[O:15])=[O:16])(=[O:6])=[O:7]
Reactant: COC(=O)/C=C/c1n[nH]c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/C(=O)O)c2c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
(E)-3-[5(2-Methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]acrylic acid can be obtained in the following way: 36 mg of lithium hydroxide monohydrate and 0.5 ml of distilled water are added successively to a suspension of 72 mg of methyl (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]acrylate, of 0.5 ml of tetrahydrofuran and of 0.5 ml of methanol, and the reaction mixture is stirred for 72 hours at a temperature in the region of 20° C. The medium is then diluted with 5 ml of distilled water, and acidified with 1N hydrochloric acid to a pH in the region of 2. The precipitate formed is isolated by filtration, washed with distilled water and then dried under a ventilated hood for 16 hours. 23 mg of (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]acrylic acid sesquihydrochloride are thus obtained in the form of a white solid melting at 170° C. (analysis C17H15N3O6S2.1.5 HCl % calculated C, 42.88; H, 3.49; Cl, 11.17; N, 8.83; O, 20.16; S, 13.47. % found C, 42.41; H, 3.74; N, 8.56; S, 12.83).
Reaction SMILES: [I-].C[S+](C)C.S([O:11][CH3:12])(OC)(=O)=O.[N:13]1([C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=O)([CH3:20])[CH3:19])[CH:17]=[N:16][CH:15]=[N:14]1>O1CCCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2([C:18]([N:13]3[CH:17]=[N:16][CH:15]=[N:14]3)([CH3:20])[CH3:19])[CH2:12][O:11]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)n1cncn1
Reactant: COS(=O)(=O)OC
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(n1cncn1)C1(c2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
9.6 g (0.044 mole) of trimethylsulphonium iodide are dissolved in 9.6 g (0.118 mole) of dimethyl sulphate under a nitrogen atmosphere. 5.2 g (0.044 mole) of potassium tert.-butylate are added at room temperature and the mixture is subsequently stirred at room temperature for 6 hours. A solution of 9.9 g (0.0397 mole) of 4-chlorophenyl 2-(1,2,4-triazol-1-yl)-prop-2-yl ketone in 16 ml of tetrahydrofuran is then added dropwise at room temperature. The reaction mixture is subsequently led at room temperature for 15 hours and under reflux for 4 hours, cooled and filtered. The filtrate is concentrated in vacuo, the residue is discharged onto water and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. 10.4 g (100% of theory) of 2-(4-chlorophenyl-2-[2-(1,2,4-triazol-1-yl)-prop-2-yl]-oxirane of refractive indes nD20 1.5388 are obtained. ##STR18##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:16]3[CH:15]=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC1Cc2cccc(Br)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1Cc2cccc(-c3cc(F)cc(F)c3)c2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
2.25 g (0.01 mol) of 7-bromo-2-methyl-1-indanone (2), 1.74 g (0.011 mol) of 3,5-difluorophenylboronic acid and 2.33 g (0.022 mol) of sodium carbonate were placed in 38 ml of dimethoxyethane and 12 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 45 mg (0.2 mmol) of palladium acetate and 0.1 g (0.4 mmol) of triphenylphosphine (TPP) were added and the reaction mixture was stirred for 2 hours at 80° C. After addition of 50 ml of water, the mixture was extracted 3 times with 30 ml each time of diethyl ether, the ether phase was washed twice with water and dried over magnesium sulfate. Removal of the solvent gave 2.4 g of 2-methyl-7-(3,5-difluorophenyl)-1-indanone as solid.
Reaction SMILES: C([O:8][C:9]1[CH:57]=[CH:56][C:12]([CH2:13][C@H:14]([NH:28][C:29](=[O:55])[C:30]2[CH:53]=[C:52]([CH3:54])[CH:51]=[C:32]([C:33]([N:35]([CH2:39][CH2:40][CH2:41][CH2:42][O:43]CC3C=CC=CC=3)[CH2:36][CH2:37][CH3:38])=[O:34])[CH:31]=2)[C@H:15]([OH:27])[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:35]([CH2:36][CH2:37][CH3:38])[C:33](=[O:34])[C:32]1[CH:51]=[C:52]([CH3:54])[CH:53]=[C:30]([C:29]([NH:28][C@@H:14]([CH2:13][C:12]2[CH:56]=[CH:57][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:15]([OH:27])[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:55])[CH:31]=1
Reactant: CCCN(CCCCOCc1ccccc1)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)[C@H](O)CNCc2cccc(OC)c2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCN(CCCCO)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2ccc(O)cc2)C(O)CNCc2cccc(OC)c2)c1
Reaction time: 5 h

Procedure:
A mixture of N1-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N3-[4-(benzyloxy)butyl]-5-methyl-N3-propylisophthalamide (X, 100 mg, 0.130 mmol) and palladium on carbon (10%, 100 mg) in absolute glacial acetic acid (5 mL) is shaken under an atmosphere of hydrogen at 35 psi for 5 hours. The resulting mixture is filtered through diatomaceous earth and washed with methanol. The combined filtrates are concentrated under reduced pressure. The concentrate is purified by flash column chromatography (silica; gradent of dichloromethane/methanol/ammonium hydroxide 97/3/0.05 to 93/7/0.05) to give the title compound: NMR (300 MHz, CD3OD): δ 7.55–6.64, 4.19, 3.99–3.72, 3.63–3.36, 3.21–3.09, 2.79–2.69, 2.39, 1.90–1.40, 1.29 and 1.02–0.6; ESI-MS (m/z) [M+H]+=592.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=[O:7])=[O:6]>C1CCCCC1.C(OCC)(=O)C>[N:8]1([S:5]([CH2:4][C:3]([OH:14])=[O:2])(=[O:7])=[O:6])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: COC(=O)CS(=O)(=O)N1CCOCC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CS(=O)(=O)N1CCOCC1

Procedure:
(Morpholine-4-sulfonyl)acetic acid methyl ester (0.5 g, 2.24 mmol) is dissolved in 0.66 N KOH aqueous ethanol solution (1/1, 150 mL) and the mixture is heated at reflux during 16 h. The solvent is evaporated and residue is extracted with dichloromethane/methanol 4:1 to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][C@H:14]([NH2:16])[CH3:15]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:16][C@H:14]([CH3:15])[CH2:13][O:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: COC[C@@H](C)N
Reactant: N#Cc1cnc(N)cc1F
Product: COC[C@@H](C)Nc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and (R)-1-methoxy-2-propylamine, reacted in an analogous manner to the preparation of intermediate 112. (UPLC-MS 7) tR 0.42; ESI-MS 207.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[NH2:13])=[CH:5][CH:4]=1.[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>O1CCOCC1>[N:13]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)=[C:15]=[O:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2cccc(N)c2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2cccc(N=C=O)c2c1

Procedure:
To a solution of the title compound of Step B (5.0 g) in p-dioxane (115 mL) at room temperature was added via syringe diphosgene (4.2 mL) followed by the addition of triethylamine (4.8 mL). The mixture was heated at reflux overnight while stirring. The reaction was monitored by IR (2267 cm-1). The reaction mixture was filtered and the residue was washed with diethyl ether. The filtrate was concentrated under reduced pressure to give 5.8 g of the title compound of Step C as a beige solid which was used without further purification.
Reaction SMILES: BrC1C=C(O)C=CC=1.BrCC(OC)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[O:19][CH2:20][C:21]([O:23]C)=[O:22]>>[Br:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[O:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)COc1cccc(Br)c1
Agent: COC(=O)CBr
Agent: Oc1cccc(Br)c1
Product: O=C(O)COc1cccc(Br)c1

Procedure:
6-bromo-3-coumarone is prepared in four steps from commercial 3-bromophenol. The first step consists of an O-alkylation of the 3-bromophenol by methyl bromoacetate. The saponification of the methyl 3-bromophenoxyacetate allows one to obtain 3-bromophenoxyacetic acid, which is converted into the acid chloride by the action of thionyl chloride. This is subjected to an intramolecular Friedel Craft acylation to yield 6-bromo-3-coumarone.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:20])[CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1.O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[CH3:20][N:7]([CH3:6])[CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: CN(C)CCCc1c[nH]c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Yield: 50 %

Procedure:
Phosphorus oxychloride (9.2 g, 0.06 mol) was slowly added to 12 ml of dimethylformamid at 0° C. with stirring and the mixture stirred for 30 minutes. Dimethyl-[3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-amine ( 6.2 g, 0.03 mol) was dissolved in 10 ml of dimethylformamide and added to the mixture. The reaction was stirred for 2 hours at room temperature. The stirred mixture was cooled in an ice bath and water was slowly added followed by 10 N sodium hydroxide solution until pH was 10. The mixture was stirred at room temperature for 45 minutes and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (3.5 g, 50% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[CH:6][C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].Br[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[N+:1]([C:4]1[C:5]([NH:14][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)=[CH:6][C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCCO2
Reactant: OCCc1ccc(Br)cc1
Product: O=[N+]([O-])c1cc2c(cc1Nc1ccc(CCO)cc1)OCCO2

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 7-nitro-2,3-dihydro-1,4-benzodioxin-6-amine (step 1) and 4-bromophenylethyl alcohol.