Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[N:5]=[C:4]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:13][C:12]([Cl:15])([Cl:14])[C:4]1[N:5]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[N:7]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: ClC(Cl)(Cl)c1nc(N2CCOCC2)nc(C(Cl)(Cl)Cl)n1
Yield: 44.5 %

Procedure:
Dissolved 2-chloro-4,6-bis(trichloromethyl)-1,3,5-triazine (0.1 g, 0.28 mmol) in THF (1.5 mL). Added morpholine (0.24 mL, 0.29 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.34 mmol) and stirred for 18 h at room temperature. Concentrated and purified by silica gel chromatography eluting with CH2Cl2 to obtain the title compound (0.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: OC1CCNC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: OC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 3-pyrrolidinol (42.3 mg; 0.48 mmol) to give Example 142 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.62-7.59 (2H, m), 7.56-7.47 (4H, m), 4.73 (1H, d, J=4.5 Hz), 4.26-4.20 (1H, m), 3.72-3.61 (2H, m), 2.73 (1H, dd, J=9.7, 6.2 Hz), 2.63 (1H, q, J=7.8 Hz), 2.49-2.46 (1H, m), 2.36 (1H, dd, J=9.5, 3.7 Hz), 2.09-1.99 (1H, m), 1.63-1.55 (1H, m). LC/MS (Method C): 484 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 99.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 4-methoxybenzoyl chloride as a yellow oil (91%). M+ (ESI): 552. HPLC, Rt: 5.65 min (Purity: 98.5%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([S:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:23]3[CH:24]=[CH:25][C:20]([S:26][CH3:27])=[CH:21][CH:22]=3)[C:9]=2[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
A solution of 26.2 g (0.10 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (20(1), Table 2, Example 1a) in 25 ml (0.21 mol) of thioanisole is added dropwise to a solution of 14.7 g (0.11 mol) of aluminium chloride in 15 ml (0.13 mol) of thioanisole at 35°-40° C. The reaction mixture is thereafter stirred for 30 minutes at 30° C. and for 2 hours at 80° C., and then after cooling, c. 50 ml of water and then concentrated hydrochloric acid and methylene chloride are added cautiously in sufficient amount to form a homogeneous two-phase mixture. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 6.7 g (18%) of 5,7-di-tert-butyl-3-(4-methylthiophenyl)-3H-benzofuran-2-one, m.p. 125°-131° C. (compound (108), Table 1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[S:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=[S:10].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH2:6]([N:11]1[C:12](=[O:13])[CH2:14][S:8][C:9]1=[S:10])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccco1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CSC(=S)N1Cc1ccco1

Procedure:
To a solution of 2-furaldehyde (43 mL) in hot glacial acetic acid (340 mL) was added rhodanine (68.4 g) and sodium acetate (128.4 g). The solution was refluxed for 0.5 hour and poured into water (2.6 L). The precipitate was collected by filtration and washed with water (1.4 L), ethanol (500 mL), and diethyl ether (200 mL). Recrystallization from acetone gave furfuryl rhodanine (97.4 g). The structure of the product was confirmed by NMR.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1>C(O)C>[N+:36](=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:6])=[N-:37]
Reactant: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a solution of O-acetoacetyl-N-trifluoroacetyl-L-serine (232 mg) and triethylamine (0.41 ml) in ethanol (7 ml) was added p-toluenesulfonyl azide (193 mg) at 0° C. The mixture was stirred for an hour at 0° C. and for 4 hours at room temperature. The solvent was distilled off in vacuo and the residue was diluted with chloroform and washed successively with aqueous acetic acid, water and brine. After drying over sodium sulfate, the chloroform extract was filtered and concentrated. The residue was flash chromatographed on silica gel (10 g) eluting successively with chloroform and a 1:9 mixture of methanol and chloroform to give O-(2-diazo-1,3-dioxobutyl)-N-trifloroacetyl-L-serine (193 mg).
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:29][O:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[O:30][CH3:29])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1COCCC1=O
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)cc(C)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methoxytetrahydro-4H-pyran-4-one (120 mg, 0.90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of cis/trans isomers. LCMS calculated for C26H40F3N4O3: (M+H) 513.3; found 513.2 for both isomers.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH3:28])=[N:20][C:19]=2[CH:29]([NH2:31])[CH3:30])[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH3:28])=[N:20][C:19]=2[CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1nc(C(C)N)c(-c2cccc(F)c2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c2ccccc12
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-9H-purine (0.31 g, 1.6 mmol), 1-[4-(3-fluorophenyl)-1-methylisoquinolin-3-yl]ethanamine (0.220 g, 0.785 mmol), and N,N-diisopropylethylamine (0.27 mL, 1.57 mmol) in ethanol (3 mL) was heated at 100° C. in a sealed tube overnight. The mixture was filtered and filtrate evaporated to dryness under reduced pressure. The resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product as the free base. LCMS calculated for C23H20FN6 (M+H)+: m/z=399.2; Found: 399.1.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:12][O:11][CH:10]2[CH:5]([C@:6]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][CH:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:26])[CH2:17]5)[C@@H:8]3[CH2:9]2)[CH3:7])[O:4]1.[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31]Br)[CH3:28].O>O1CCCC1>[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31][O:26][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH:10]3[O:11][CH2:12][CH2:3][O:4][CH:5]32)[CH2:17]1)[CH3:28]
Reactant: CCOC(CBr)OCC
Reactant: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CO[C@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1)OCC
Reaction time: 2 h

Procedure:
To a suspension of 5.5 g of NaH (60% dispersion in mineral oil) in 400 ml of dry tetrahydrofuran 8.5 g of 17-ethylenedioxy-androstan-3β-ol were added at room temperature under nitrogen atmosphere. The mixture was kept at 40° C. for 2 hrs, then 26 ml of bromoacetaldehyde diethylacetal were added and the suspension was kept at the same temperature for 4 hrs; 50 ml of water were added cautiously, and the tetrahydrofuran was distilled under reduced pressure. The residue was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 7.5 g of 3β-(2,2-diethoxyethoxy)-17-ethylenedioxy-androstane as a thick oil.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:32])=[C:27]([CH:29]([OH:31])[CH3:30])[CH:28]=1>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:32])=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=1
Reactant: CC(O)c1cc(Br)ccc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1Cl
Reaction time: 15 h
Yield: 85.7 %

Procedure:
Pyridinium dichromate (2.6 g, 6.94 mmol) was added to a solution of 1-(5-bromo-2-chloro-phenyl)-ethanol (1.09 g, 4.6 mmol) in CH2Cl2 (20 mL). The reaction was stirred for 15 hours and then more pyridinium dichromate (2.6 g, 6.94 mmol) was added. After another 24 hours celite was added and the mixture was stirred for 20 mins. The reaction mixture was filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (0.92 g, 85%). 1H NMR (400 MHz, CDCl3): δ 2.64 (s, 3H), 7.29 (d, J=8.6 Hz, 1 H), 7.51 (dd, J=8.6, 2.3 Hz, 1 H), 7.66 (d, J=2.3 Hz, 1 H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH3:17])[C:9](=[O:18])[C:8]([CH3:20])([CH3:19])[C:7]1=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:17][N:10]1[C:11]2[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:12]=2[N:6]([CH3:5])[C:7](=[O:21])[C:8]([CH3:19])([CH3:20])[C:9]1=[O:18]
Reactant: CN1C(=O)C(C)(C)C(=O)N(C)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)C(=O)N(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 72 h

Procedure:
1.3 ml of nitric acid (65%) were cautiously added dropwise at 0° C. to 5.1 ml of acetic anhydride. The solution was added to a solution of 3.00 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-2,4-dioxo-1H-1,5-benzodiazepine in 6.5 ml of acetic anhydride and 2.1 ml of glacial acetic acid. The reaction mixture was left to stand at room temperature for 3 days, filtered, the residue was washed thoroughly with water, dried and recrystallized from ethanol. There were obtained 2.11 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-7-nitro-2,4-dioxo-1H-1,5-benzodiazepine, m.p. 224°-225° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])[CH:7]=[CH:8][CH:9]=1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:14]=[C:12]([CH:11]=[CH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:16])[F:1])[CH:5]=2)[O:13][CH:20]=1
Reactant: NC(=O)C=Cc1cccc(OC(F)(F)F)c1
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1cccc(C=Cc2nc(CCl)co2)c1
Yield: 58.6 %

Procedure:
3-(3-Trifluoromethoxy-phenyl)-acrylamide (0.99 g, 4.27 mmol), dichloro acetone (1.90 g, 14.95 mmol) and toluene (8 ml) were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 2:1) yielding 0.76 g (71%) 4-chloromethyl-2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-oxazole as tan solid.
Reaction SMILES: [ClH:1].O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(O)(C)C>[ClH:1].[CH2:15]([NH:33][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.45 g of D-glucosamine hydrochloride are dissolved in 30 ml of isopropanol and 10 ml of water at 60° C., and 12.1 g of stearylamine are added. The resulting clear solution is stirred for a further 10 min and then cooled to room temperature. The product which has crystallized out is filtered off with suction and washed first with ethanol/water (5:2, v/v), then with ethanol and finally with ether. The residue is dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])[O:3]1.[Cl-].[NH4+].CCO>[Zn].C1COCC1>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[B:4]1[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3]1)[NH2:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Intermediate 26A (1 g, 3.80 mmol), ammonium chloride (1.432 g, 26.6 mmol), and zinc (1.491 g, 22.81 mmol) were added to a flask, followed by the addition of EtOH (10.0 mL) and THF (10.0 mL). The reaction mixture was stirred at room temperature for 2 hours and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure to yield Intermediate 26 (885 mg, 100% yield). MS (ES): m/z=234.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[C:10]3[C:11]=2[C:6](=[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]2=[CH:9]3)[C:5]1=[O:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][CH2:3][N:4]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[C:10]4[C:11]=3[C:6](=[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]3=[CH:9]4)[C:5]2=[O:22])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCO
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2C(=O)c3cccc4cc5ccccc5c(c34)C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A mixture of 1.01 g (3.5 mmol) of 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione in 10 ml of pyridine is treated with 0.69 g (3.6 mmol) of p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 24 hours and poured into 50 ml of cold water. The solid is collected, washed with water, dried in vacuo, and crystallized from dimethylformamide water to give 1.2 g (77%) of 2-[2-(p-toluenesulfonyloxy)ethyl]-1,2-dihydro-3H-dibenz-[de,h]isoquinoline-1,3-dione. M.p. 240° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]>ClCCl.Cl>[O:26]=[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][CH:12]=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCCO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
To a 250-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added a solution of oxalic dichloride (2.52 g, 19.85 mmol, 1.98 equiv) in 40 mL of anhydrous dichloromethane. This solution was cooled to −78° C. under nitrogen. A solution of DMSO (1.56 g, 19.97 mmol, 1.99 equiv) in dichloromethane (10 mL) was added dropwise with stirring at −78° C. and the resulting solution was stirred for 20 min at −78° C. A solution of 2-(4-hydroxybutyl)-2,3-dihydro-1H-isoindole-1,3-dione (2.2 g, 10.03 mmol, 1.00 equiv) in 20 mL of dichloromethane was added dropwise with stirring. Stirring was continued for 20 min at −78° C., and then TEA (8.1 g, 80.20 mmol, 7.99 equiv) was added via syringe at the same temperature. The resulting solution was allowed to react, with stirring, for an additional 60 min at 0° C. After completion, the resulting mixture was diluted with 1 M aqueous hydrochloric acid, extracted with DCM, washed with 3×100 mL of brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:1) to provide the desired 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)butanal (1.9 g, 87%) as a white solid. MS (ES): m/z 218 (M+H)+.
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C:8]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([CH2:16][O:17]C(=O)C)=[C:10]([Br:21])[C:9]=1[Br:22])(=O)C>O.O1CCOCC1>[Br:14][C:13]1[C:12]([Br:15])=[C:11]([CH2:16][OH:17])[C:10]([Br:21])=[C:9]([Br:22])[C:8]=1[CH2:7][OH:6]
Reactant: CC(=O)OCc1c(Br)c(Br)c(COC(C)=O)c(Br)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OCc1c(Br)c(Br)c(CO)c(Br)c1Br
Yield: 96 %

Procedure:
A solution of potassium hydroxide, 20 parts, in water, 50 parts, was added dropwise to a refluxing solution of 20 parts 2,3,5,6-tetrabromo-p-xylene-α,α'-diol diacetate, prepared as in Example III above, in p-dioxane, 200 parts. After 2 hours at reflux the mixture was cooled somewhat and the bulk of the dioxane-water removed by a rotary evaporator. Water was added to the semi-solid residue, the precipitate filtered, washed with water and air dried to give crude diol, 16.7 parts. Recrystalization from dioxane-water gave 12.2 parts 2,3,5,6-tetrabromo-p-xylene-α,α'-diol, melting at 262°-263.5° C. A second crop, 3.95 parts, melted at 260-262° C. A third crop, 0.4 parts, melted at 225°-245° C. Combining the first two crops gives a yield of 96 percent. Analysis showed the following results: Percent bromine calculated -- 70.5; found -- 71.5.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=[S:34])[CH2:28][CH2:27]1.O>CC(C)=O>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH2:14][S:34][C:33](=[O:35])[CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH2:3]1
Reactant: OC(=S)CN1CCOCC1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCSC(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Yield: 66.8 %

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) was dissolved in acetone (20 ml) and the solution treated with morpholinothioacetic acid (300mg), at reflux for 3 hours. The mixture was poured into water and the emulsion extracted with either. The extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to a foam (540 mg) which was purified by preparative t.l.c. in ethyl acetate/petrol (1:1). The main band gave title compound (490mg.) as a white foam. [α]D + 48° (c = 1.03).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C(Cl)Cl>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 22.5 l of methylene chloride and 3030 ml of tert-butylamine is cooled to 0° C. Then a solution of 3 kg of 4-bromo-benzoyl chloride in 15 l of methylene chloride is added in portions. The mixture is cooled to 0°-5° C. and then stirred over night at room temperature. The reaction mixture is filtered and the filtrate washed with 5 l of methylene chloride, three times with 5 l of 3 N HCl, twice with 4 l of NaHCO3 and twice with 2 l of brine. The organic layer is dried over Na2SO4 and evaporated. The crude crystals are stirred with 8 l of ether for 30 minutes and the mixture is cooled to 0° C. and filtered. Thus 4-bromo-N-tert-butyl-benzamide is obtained in form of white crystals, m.p.133°-134° C.