Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([B:5]([OH:7])[OH:6])[CH2:2][CH2:3][CH3:4].O[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]O.O1C=CC=CB=NO1.O[C@@H]([C@H](O)C(N(C)C)=O)C(N(C)C)=O>ClCCl.[Cl-].[Na+].O>[CH2:1]([B:5]1[O:7][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCB(O)O
Reactant: OCCNCCO
Agent: CN(C)C(=O)[C@@H](O)[C@H](O)C(=O)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(But-1-yl)-tetrahydro-4H-1,3,6,2-dioxazaborocine [CAS 92527-13-4] was prepared from n-butylboronic acid and 2-(2-hydroxy-ethylamino)-ethanol [CAS 111-42-2] as reported in Organic Synthesis, 1998, 76, 86-96. This dioxazaborocine (3 g, 17.5 mmol) and (2S,3S)-2,3-dihydroxy-N,N,N′,N′-tetramethyl-butanediamide [CAS 63126-52-3] (4.65 g) were dissolved in anhydrous dichloromethane (95 mL) under N2. Brine (30 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The two layers were separated, and the aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as an oil 1H NMR (300 MHz, CDCl3): δ 0.82-0.9 (m, 5H), 1.25-1.45 (m, 4H), 2.98 (s, 6H), 3.2 (s, 6H), 5.52 (s, 2H). MS (DCl—NH3) m/z 271 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH3:20]>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:20]
Reactant: CCBr
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc([N+](=O)[O-])ccc1OC
Temperature: 40 °C

Procedure:
2-methoxy-5-nitro-phenol (508 mg, 3 mmoles) was dissolved in DMF (20 mL) under nitrogen atmosphere. K2CO3 (900 mg, 6.5 mmoles), KI (490 mg, 2.95 mmol) and ethyl bromide (0.250 mL, 3.3 mmoles) were added, and the suspension was heated to 40° C. for 28 hours. The mixture was diluted with AcOEt (60 mL) and extracted with 1N NaOH (40 mL) and water (40 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was employed in the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:22])[CH2:17][C:16]3[C:11](=[C:12]([Cl:20])[C:13]([Cl:19])=[C:14]([OH:18])[CH:15]=3)[C:10]2=[O:21])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33]CC)=[O:32].[OH-].[Na+].Cl>CN(C)C=O.O>[O:21]=[C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH2:30][C:31]([OH:33])=[O:32])=[C:13]([Cl:19])[C:12]=2[Cl:20])[CH2:17][C:9]1([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC1(c2ccc(C#N)cc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccc(C#N)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 100 °C

Procedure:
A stirred mixture of 2-(4-cyanophenyl)-2-methyl-5-hydroxy -6,7-dichloro-1-indanone (1.8 g., 0.0054 mole), potassium carbonate (1.5 g., 0.0109 mole) and ethyl bromoacetate (1.8 g., 0.0109 mole) in dimethylformamide (60 ml.) is warmed at 55°-60° C. for 3 hours, then treated with water (60 ml.)-10 N sodium hydroxide solution (3 ml., 0.03 mole) and heated at 100° C. for 1.5 hours. The reaction mixture is added slowly to ice-water (300 ml.)-12 N hydrochloric acid (5 ml.) to precipitate 160 mg. of [1-oxo-2-(4-cyanophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 184°-5° C. after crystallization from acetic acid:water, 1:1.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N+:16]([O-:18])=[O:17])C(OC)=O>Cl.O>[F:15][C:11]1[C:10]([N+:16]([O-:18])=[O:17])=[C:9]([CH2:4][C:3]([OH:19])=[O:2])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(C(=O)OC)c1cccc(F)c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Yield: 86.7 %

Procedure:
2-(3-Fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (12 g, 44 mmol) in 200 mL 6N hydrochloric acid (6N, 200 mL) was heated under reflux for 4 hours. The mixture was cooled, diluted with 250 mL of water and extracted with diethyl ether, dried (MgSO4), and concentrated in vacu., Crystallization from hexane/ethylacetate (95/5), gave (3-fluoro-2-nitro-phenyl)-acetic acid (7.6 g, 54%) which was used without further examination.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]#[N:15])=[C:8]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].Cl.C(C1(C(O)=O)C(C2C=CC=CC=2)=C2C(C=CC=C2)=N1)#N>C(O)C>[C:14]([C:9]1[NH:10][C:11]2[C:7]([C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2)#[N:15]
Reactant: COC(=O)c1ccc2[nH]c(C#N)c(-c3ccccc3)c2c1
Agent: Cl
Agent: N#CC1(C(=O)O)N=c2ccccc2=C1c1ccccc1
Solvent: CCO
Product: N#Cc1[nH]c2ccc(C(=O)O)cc2c1-c1ccccc1
Reaction time: 264 h

Procedure:
A suspension of 1.50 g. (5.4 mmol) of 2-cyano-3-phenylindole-5-carboxylic acid methyl ester in 50 ml. of 6 N hydrochloric acid was heated under reflux, enough ethanol (~ 100 ml.) was added to effect solution, and heating was continued for 11 days. The reaction was concentrated to a small volume under vacuum, diluted with water and made basic with sodium hydroxide. Filtration gave 840 mg. of recovered 2-cyano-3-phenylindole-5-carboxylic acid methyl ester. The basic solution was acidified, the amorphous precipitate was collected by filtration and recrystallized four times from methanol with charcoal to give 111 mg. (19%) of 2-cyano-3-phenylindole-2-carboxylic acid as colorless crystals, m.p. 302°-304°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][Si:8]([CH3:17])([CH3:16])[C:9]1[O:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1>O1CCCC1>[OH:15][CH2:14][C:11]1[CH:10]=[C:9]([Si:8]([CH3:17])([CH3:16])[CH3:7])[O:13][CH:12]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(CO)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of lithium aluminum hydride (0.01 g., 0.263 mmol) in 1 ml dry tetrahydrofuran at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.09 g., 0.535 mmol). This mixture was allowed to warm to room temperature, stirred for 15 minutes, quenched with a 5% ammonium chloride solution, and extracted twice with ethyl ether. The organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol. This material was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][Si:16]([CH2:23]Cl)([CH3:22])[O:17][Si:18]([CH3:21])([CH3:20])[CH3:19].O>C(OCC)(=O)C>[C:3]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:19][Si:18]([CH3:21])([CH3:20])[O:17][Si:16]([CH3:23])([CH3:22])[CH2:15]1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C[Si](C)(C)O[Si](C)(CCl)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)C[Si](C)(C)O[Si](C)(C)C1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Reaction method: To a dry 1 L 3-neck round bottom flask equipped with a reflex condenser, addition funnel and a N2 gas inlet was added di(ethyleneglycol) diethyl ether (diethyl carbitol) (650 mL, 590.85 g). To the solvent was added sodium hydride (28.80 g, 1.20 mol) under a N2 atmosphere, and the suspension was cooled to ˜5° C. in an ice/water bath. To the cooled suspension was added diethyl malonate (192.00 g, 1.20 mol) dropwise through the addition funnel. (CAUTION: A large quantity of H2 gas is evolved.) When the addition of the diethyl malonate was complete, the suspension had turned to a clear solution. The reaction mixture was heated to 50° C. and stirring was continued for 30 minutes at 50° C. To the solution at 50° C. was then added bis(chloromethyl)tetramethyldisiloxane (138.76 g, 0.6 mol) over a 5 minute period through the addition funnel. The reaction mixture was then heated to 112-115° C., and stirring was continued under a N2 atmosphere while the reaction was monitored by GC. After 20 hr, GC showed that a trace amount of bis(chloromethyl)-tetramethyldisiloxane remained (retention time: 11.5 min.). The mixture was cooled to room temperature and the mixture was transferred to a separatory funnel. Water (500 mL) and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (400 mL), and the combined organic layers were washed with water (2×500 mL) and saturated aqueous sodium chloride (500 mL). The organic layer was separated, and the ethyl acetate was removed using a rotary evaporator. The remaining solution was vacuum distilled to remove the di(ethyleneglycol) diethyl ether (b.p. 70° C. @ 8 mm Hg). The solution was concentrated to a final weight of 182 g of crude CDS_E. GC of the crude CDS_E solution was obtained (retention time: 15.2 min.). The solution of the crude product was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15].[H-].[Na+].I[CH3:20]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:20])[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CI
Reactant: CCC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)N(C)c1cc([N+](=O)[O-])ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a stirred solution of 11.2 g (50.0 mmol) of (2) in 150 mL of anhydrous THF at 0° C. under the nitrogen, was added 3.0 g (75 mmol) of NaH (60% in oil). The suspension was stirred for 0.5 h at 0° C. and 10 mL (150 mmol) of iodomethane was added at 0° C. After the mixture warmed to room temperature and stirred for 3 h, the reaction was quenched by ice brine and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, evaporated in vacuo and the solid was washed with hexane/EtOAc (9:1) to give pure product N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) as a light yellow solid (11.3 g, 95% yield).
Reaction SMILES: [CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([CH2:52]Br)=[N:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([CH2:52][CH:19]2[C:18]3[N:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:16][N:17]=3)[C:13]3[CH:28]=[CH:29][CH:30]=[CH:31][C:12]=3[N:11]([CH2:10][C:9](=[O:32])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:33]([CH3:35])[CH3:34])[C:20]2=[O:21])=[N:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 6.1 %

Procedure:
Following the procedure described in Example 3(A), Step A, N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 10) (210 mg, 0.451 mmol) was alkylated with 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (150 mg, 0.473 mmol). The reaction was diluted with a pH 6.8 buffer solution and the aqueous solution was washed with EtOAc. The organic solution was washed with brine (3×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (2×) by preparative chromatography eluting with 5% acetone in CH2Cl2 followed by medium pressure chromatography eluting with a solvent gradient (2% acetone in CH2Cl2 to 14% acetone in CH2Cl2) to provide 19.1 mg of 3-{6-[(benzyl-isopropyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD2Cl2) δ 8.05 (m, 1H), 7.12-7.71 (m, 15H), 7.03 (m, 1H), 6.92 (d, 1H), 5.21 (d) and 4.90 (d, total 1H), 4.61-4.72 (m, 2H), 4.49 (s, 1H), 4.43 (t, 1H), 4.25-4.32 (m, 1H), 3.96-4.15 (m, 2H), 1.61 (d, 9H), 1.16 (dd, 3H), 1.04 (dd, 3H); MS 696.4 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)#[N:2].C(O)C.CC1CCCO1.[O-]CC.[Na+].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>>[C:13]([O:12][C:11]([NH:10][C:7]1[N:8]=[CH:9][C:4]([CH:3]([C:1]#[N:2])[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[N:5][CH:6]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC1CCCO1
Product: CCOC(=O)CCC(C#N)c1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
To tert-butyl 5-(cyanomethyl)pyrazin-2-ylcarbamate (0.32 g, 1.37 mmol) in a mixture solvent of ethanol/2-methyltetrahydrofuran (5 mL/5 mL) was added freshly prepared sodium ethoxide (1 M, 1.366 mL), and the mixture was stirred at 0° C. for 10 min, followed by addition of ethyl acrylate (145 ul, 1.366 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction was quenched at this point by adding sat. NaHCO3 (5 mL), and the reaction mixture was stirred for another 10 min, diluted with EtOAc (20 mL), filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), washed with pH 7.0 sodium phosphate buffer, and EtOAc layer was concentrated, and the light brown residual oil was purified by flash column eluted with gradient EtOAc/heptane (0-50%) to afford ethyl 4-(5-(tert-butoxycarbonylamino)pyrazin-2-yl)-4-cyanobutanoate (100 mg, 22% yield). LCMS (m/z): 279.2 (MH+-tBu), 0.86 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9](O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([I:45])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1CCC(I)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) stirred solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (1.0 g, 5.80 mmol) in 1:2 CH2Cl2/CCl4 (52 ml) is added triphenylphosphine (1.82 g, 6.96 mmol), imidazole (473 mg, 6.96 mmol), and iodine (1.79 g, 7.08 mmol). The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of saturated sodium thiosulphate (c.a. 50 ml) and stirred until the solution becomes clear. The layers are separated and the aqueous layer is extracted with CH2Cl2 (3×30 ml). The combined organic phases are washed with sodium thiosulphate (30 ml), brine (30 ml), dried with anhydrous MgSO4, filtered and evaporated at reduced pressure to an oily solid. Purification by dry flash chromatography, Keiselgel 15-40 grade silica, eluting with 3% ethyl acetate/iso hexane yields the title compound as a clear colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](O)[C:11]3[C:12](=[N:14][N:15]([CH3:17])[CH:16]=3)[N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[C:11]2[C:12](=[N:14][N:15]([CH3:17])[CH:16]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: Cn1cc2c(O)cc(-c3ccc(Cl)cc3)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1cc2c(Cl)cc(-c3ccc(Cl)cc3)nc2n1

Procedure:
Following the procedure of Example 2, 37.8 g. of 6-(4-chlorophenyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ol (0.146 mol.) and 165 ml. of phosphorus oxychloride yield 35.1 g. (86%) of 4-chloro-6-(4-chlorophenyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine, recrystallized from ethanol; m.p. 177°-179°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](CC1C=CC=CC=1)[CH2:8]2)=[O:4].C([O-])(O)=O.[Na+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:34]([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35])[CH2:8]2)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 30 °C

Procedure:
2-Benzyl-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (3.9 g) and NaHCO3 (12.3 g) are suspended in CH2Cl2 (50 mL) and the mixture is treated with benzylchloroformate (Z—Cl) (10.8 mL). The mixture is warmed to 30° C. and after 10 min the reaction mixture is added to a mixture of water (150 mL) with NaHCO3 (12.3 g), the organic phase is separated, dried and evaporated. To the residue are added MeOH and the crystalline solid is collected and dried. 3.79 g of the title compound are obtained with MP 59-65° C.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].CN.[Cl-].[Li+]>[Pt].[C-]#[W].O1CCCC1>[CH3:16][C@@:15]12[C@H:17]3[CH2:18][CH2:19][C@:2]4([CH3:1])[C@@H:3]([OH:21])[CH2:4][CH2:5][C@H:6]4[C@@H:7]3[CH2:8][CH2:9][C@H:10]1[CH2:11][C:12](=[O:20])[CH2:13][CH2:14]2
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [C-]#[W]
Agent: [Pt]
Agent: CN
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
0.50 g. of androst-4-ene-3,17-dione is dissolved in 10 ml. of tetrahydrofuran and electrolyzed in 100 ml. of methylamine with 0.5 g. of lithium chloride for 1 hour between a platinum cathode and a tungsten carbide anode at 0.5 A. After the reaction mixture has been worked up and recrystallized, 0.38 g. of 5α-androstan-17β-ol-3-one is obtained, m.p. 172.5° - 173.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:2]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:14][C:9]=3[N:8]=[C:7]2[CH2:27][C:28]2([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:3]=1
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccccc3)c2)CCCC1
Temperature: 25 °C

Procedure:
To a 5 mL microwave vial were added methyl 1-{[1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]methyl}cyclopentanecarboxylate (62 mg, 0.1 mmol), Pd(dppf)Cl2 (8.3 mg, 0.01 mmol), phenylboronic acid (45 mg, 0.35 mmol), K3PO4 (78 mg, 0.37 mmol) and 1,4-dioxane (1.5 mL). The vial was flushed with N2 then capped and placed in a heating block at 100° C. After 6 h the mixture was cooled to RT, transferred to a round-bottomed flask, and concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C38H35N3O3, 581.71; m/z found 582.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[N:10]=[C:9]([O:11][C:12]2[C:18]([CH3:19])=[CH:17][C:15]([NH2:16])=[C:14]([CH3:20])[CH:13]=2)[S:8][N:7]=1.CO[CH:26](OC)[N:27]([CH2:29][CH3:30])[CH3:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[N:10]=[C:9]([O:11][C:12]2[C:18]([CH3:19])=[CH:17][C:15]([N:16]=[CH:26][N:27]([CH2:29][CH3:30])[CH3:28])=[C:14]([CH3:20])[CH:13]=2)[S:8][N:7]=1
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(Oc2nc(Cc3cccc(Cl)c3)ns2)c(C)cc1N
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(Cc3cccc(Cl)c3)ns2)cc1C
Yield: 27.6 %

Procedure:
1.85 g (5.15 mmol) of 4-{[3-(3-chlorobenzyl)-1,2,4-thiadiazol-5-yl]oxy}-2,5-dimethylaniline are dissolved in 10 ml of toluene and treated with 1.37 g (10.31 mmol) of N-ethyl-N-methylformamide dimethylacetal. The reaction mixture is refluxed for 12 h, subsequently cooled, freed of solvent under vacuum and purified by column chromatography. 0.59 g of product is obtained (99.0% purity, 27.3% yield; log P (pH2.3)=2.31).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH3:8][C:9](=[O:30])[C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C:19](=O)[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1.[BH4-].[Na+].[OH-].[Na+].Cl>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)(Cl)Cl.CO.C1(C)C=CC=CC=1.C(N(CC)CC)C>[ClH:1].[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C@@H:19]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:17]([CH2:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C:9](=[O:30])[CH3:8])[CH2:18]1
Reactant: COC(=O)CN
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CN[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reaction time: 3 h

Procedure:
Glycine methyl ester hydrochloride (89 mg, 0708 mmol) with triethylamine (0.072 mL) and 5β-pregnane-3,20-dione (200 mg, 0.632 mmol) were mixed in neat titanium (IV) isopropoxide (302 mg, 1.06 mmol) and dry toluene (0.4 mL). The mixture was stirred under nitrogen for 3 h. Methanol (2.8 mL) was added. Then NaBH4 (38 mg, 1.01 mmol) was carefully added. After 5 min the reaction was finished by adding 0.1 N NaOH. The resulting mixture was filtered through Celite, and the residue was washed with ether (2×30 mL) and ethyl acetate (2×30 mL). The organic layer was separated, dried (MgSO4) and the solvents were removed under reduced pressure. The residue was purified on preparative TLC (5 plates, 200×200×0.3 mm) in a mixture of toluene-ethyl acetate (1:1) to afford 43 mg (17%). 1H NMR (400 MHz, CDCl3): δ 0.59 (s, 3H, H-18); 0.92 (s, 3H, H-19); 2.11 (s, 3H, H-21); 2.45-2.53 (m, 1H, H-3); 2.52 (t, 1H, J=8.8, H-17); 3.46 (s, 2H, H-2′); 3.74 (s, 3H, OMe). 13C NMR (100 MHz, CDCl3): δ 13.34 (C-18); 20.77; 22.86; 23.45; 24.40; 26.37; 27.15; 27.87; 31.45; 34.00; 35.08; 35.69; 35.83; 39.22; 40.29; 42.09; 44.27; 48.09; 51.74; 56.70; 57.24; 63.86; 173.13 (C-1′); 209.51 (C-20). The product was subsequently characterised as hydrochloride. [α]D=+61.9 (c 0.24, CHCl3).IR (CHCl3): 2708 (N+H2), 1758 (C═O, ester), 1698 (C═O, COCH3). 1235 (C—O, ester). MS-ESI: 390.2 [100%, M+H]+; (HR) for [C24H40NO3+H]+ m/z calculated: 390.3003. found: 390.3002.