Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:21])[C:10]([NH:12][N:13]1[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=[CH:14]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[CH2:1]([O:8][CH:9]([C:10]1[NH:20][C:18](=[O:19])[C:17]2=[CH:16][N:15]=[CH:14][N:13]2[N:12]=1)[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OCc1ccccc1)C(=O)Nn1cncc1C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(OCc1ccccc1)c1nn2cncc2c(=O)[nH]1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
To a solution of compound 10 (1.5 g, 5.2 mmol) in EtOH (10 mL) was added a solution of KOH (870 mg, 15.6 mmol) in H2O (4 mL). Then the resulting mixture was heated at 100° C. under microwave heating for one hour. After removal of the solvent, the mixture was poured into ice water and pH was adjusted to 7 with 1M aqueous HCl solution. The suspension was filtered and the solid was dried to give compound 11 (1.06 g, 75% yield) as a white solid. LC-MS: m/z 271 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.70 (br. s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.39˜7.32 (m, 5H), 4.60 (m, 2H), 4.46 (q, J=6.4 Hz, 1H), 1.57 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=2)[CH:6]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=2)[NH2:17])[CH:6]=1
Reactant: Cc1cn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reaction time: 5 h
Yield: 45.2 %

Procedure:
A suspension of 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole (800 mg, 2.95 mmol) in MeOH (15 mL) was added to a solution of palladium (5.02 μL, 0.078 mmol) in MeOH (15 mL). The mixture was at 25° C. for 5 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, basic condition) to yield a white solid of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (321.83 mg, 1.334 mmol, 86.0% yield). TLC (PE/EA=1:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.24 (s, 1H), 7.02-6.76 (m, 3H), 2.31-2.17 (m, 3H); ES-LCMS m/z 242.1 (M+H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:42](O)[C:43]([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[CH3:42][C:43]([CH3:46])([CH3:45])[CH2:44][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)(C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCC(C)(C)C)cc1
Temperature: 60 °C

Procedure:
To a solution of p-cresol (526 mg, 4.87 mmol) in THF (50 mL), add with stirring diisopropyl azodicarboxylate (2.16 mL, 10.7 mmol) followed by triphenylphosphine (306 mg, 11.7 mmol) and neopentyl alcohol (5.15 g, 58.4 mmol). Heat at 60° C. for 3 h, cool to ambient temperature and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc to give the desired intermediate as a colorless oil.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]2[C:7]3[CH:14]=[CH:13][N:12]([C@H:15]4[C@@H:19]5[O:20]C(C)(C)[O:22][C@@H:18]5[C@@H:17]([CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]5[N:39](COCC[Si](C)(C)C)[C:38]6[CH:48]=[C:49]([Cl:56])[C:50]([C:52]([F:55])([F:54])[F:53])=[CH:51][C:37]=6[N:36]=5)[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:16]4)[C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:4][CH2:3]1>CO>[ClH:56].[Cl:56][C:49]1[C:50]([C:52]([F:55])([F:53])[F:54])=[CH:51][C:37]2[N:36]=[C:35]([CH2:34][CH2:33][CH2:32][CH2:31][N:26]([CH2:25][C@H:17]3[CH2:16][C@@H:15]([N:12]4[C:8]5[N:9]=[CH:10][N:11]=[C:6]([NH:5][CH:2]6[CH2:4][CH2:3]6)[C:7]=5[CH:14]=[CH:13]4)[C@H:19]([OH:20])[C@@H:18]3[OH:22])[S:27]([CH3:30])(=[O:28])=[O:29])[NH:39][C:38]=2[CH:48]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CN(CCCCc3nc4cc(C(F)(F)F)c(Cl)cc4n3COCC[Si](C)(C)C)S(C)(=O)=O)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)N(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2[nH]1)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of 12M HCl(aq) in MeOH (1:1, 5 ml) was added to N-{[(3aR,4R,6R,6aS)-6-[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]methyl}-N-{4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl}methanesulfonamide (155 mg, 0.19 mmol) and stirred at 40° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 ml), washed with sat. NaHCO3 (2×50 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (5:95-1:9) gave the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>Cl.O1CCOCC1>[CH3:11][CH:10]1[CH2:9][C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]([C:19]2[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[O:12]1
Reactant: COc1cccc(CC(C)O)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Yield: 93.3 %

Procedure:
To a solution of 1-(3′-methoxyphenyl)-2-propyl alcohol 2 (0.98 g, 5.8 mmol) in 25 ml of HCl solution in 1,4-dioxane was added 4-nitrobenzaldehyde (0.91 g, 6.0 mmol) in one portion. The solution was refluxed for 4 hours. After removing the solvent under reduced pressure, the residue was washed with cold ethanol three times, affording the product 3 (1.62 g, yield 90%). 1HNMR(CDCl3): 8.20 (d, J=8.7 Hz, 2H), 7.50 (d, J=8,7 Hz, 2H), 6.65-6.48 (m, 3H), 5.78 (s, 1H), 4.01 (m, 1H), 3.76 (s, 3H), 2.80 (m, 2H), 1.40 (d, J=6.1 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[CH3:11][CH2:12]CCCC.C([Li])CCC.Cl[Sn](Cl)(Cl)Cl.FC(F)(F)CO.C[Si](C#C)(C)C.[F-].[K+]>ClC1C=CC=CC=1.O.C1COCC1>[CH2:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:10])[CH3:12]
Reactant: CCCCCC
Reactant: CC(C)c1ccccc1O
Agent: C#C[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [F-]
Solvent: Clc1ccccc1
Solvent: OCC(F)(F)F
Solvent: O
Product: CCc1cccc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of isopropyl phenol (10 g) in 200 mL of chlorobenzene was added butyllithium hexane solution (5.9 mL, 2.5 M in hexane) and SnCl4 (0.88 mL) at 0° C. The mixture was stirred at room temperature for 15 min, followed by addition of 2,2,2-trifluoroethanol (0.53 mL) and trimethylsilylethyne (11.5 mL). The mixture was heated at 110° C. for 3 h, THF (120 mL) and KF (4.7 g) were added, and the mixture was stirred for another 5 h. Water (80 mL) was then added and the mixture was stirred for another hour. After separation of the layers, the organic layer was washed with water (2×100 mL) and dried over Na2SO4 and concentrated to about 20 to 25 mL. The crude product including remaining chlorobenzene was chromatographed. The fraction containing 2-isopropyl-6-vinylphenol was collected and concentrated to about 20 mL (but not completely dried). It was diluted with EtOH (50 mL) and concentrated again to about 20 mL. This process was repeated 3 times to reduce the amount of chlorobenzene. A flask containing the EtOH solution (100 mL) of this vinyl phenol was charged with hydrogen in the presence of Pd/C (300 mg) and hydrogenated using a balloon for 5 h. The solid was removed and the filtrate was concentrated to afford 2-ethyl-6-isopropylphenol as a clear oil (8.5 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][C:15]1[CH:16]([O:21][CH2:22][CH3:23])[O:17][C:18](=[O:20])[CH:19]=1)=[O:7])(C)(C)C.N1C(C)=CC=CC=1C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)(O)[O-].[Na+].[CH2:50]([O:57][C:58]([NH:60][CH:61]([C:65]([CH3:68])([CH3:67])[CH3:66])C(O)=O)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>ClCCl.C(OCC)(=O)C>[CH2:50]([O:57][C:58](=[O:59])[NH:60][CH:61]([C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:24])[NH:14][CH:15]1[CH2:19][C:18](=[O:20])[O:17][CH:16]1[O:21][CH2:22][CH3:23])=[O:7])[C:65]([CH3:67])([CH3:66])[CH3:68])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: ClCCCl
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of (R)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (X, R1=Et) (0.14 g, 0.41 mmol) (1H-NMR shows ˜8:2 syn:anti epimers) and lutidine (0.48 mL, 4.1 mmol) in dichloromethane (5 mL) at room temperature under nitrogen was dropwise added trimethylsilyltrifluoromethane-sulfonate (0.48 mL, 2.46 mmol). The reaction was stirred for 0.5 h, then was treated with saturated sodium bicarbonate, was extracted with three portions of dichloromethane, was dried (sodium sulfate), and was evaporated. To the crude intermediate was added 2-benzyloxycarbonylamino-3,3-dimethylbutyric acid (0.12 g, 0.45 mmol) in dichloromethane (5 mL), EDC (0.10 g, 0.51 mmol) and HOBT (0.07 g, 0.51 mmol). The resulting mixture was stirred at room temperature under nitrogen for 3 days. The reaction was diluted with ethyl acetate, was washed with 10% potassium bisulfate, saturated sodium bicarbonate and brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate hexanes provided {1-[2-(2-ethoxy-5-oxo-tetrahydrofuran-3-yl carbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}carbamic acid benzyl ester (0.12 g, 59% yield) as a white foam. 1H-NMR (500 MHz, CDCl3) δ 7.43 (br d, J=7.7 Hz, 1H), 7.28 (s, 5H), 5.40 (m, 2H), 5.02 (AB q, J=12.1, 31.0 Hz, 2H), 4.55 (m, 2H), 4.29 (d, J=9.6 Hz, 1H), 4.23 (m, 0.2H), 3.85 (m, 0.8H), 3.73 (m, 1H), 3.58 (m, 2H), 2.90 (m, 0.2H), 2.74 (dd, J=17.0, 8.4 Hz, 0.8H), 2.30 (m, 2H), 2.05 (m, 1H), 1.90 (m, 1H), 1.80 (m, 1H), 1.20 (t, J=7.0 Hz, 2.4H), 1.15 (t, J=7.0 Hz, 0.6H), 0.93 (s, 9H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Yield: 81.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.335 g; 0.85 mmol), LHMDS 1N in THF (1.27 mL; 1.27 mmol), 1-iodopropane (0.166 mL; 1.7 mmol) in DMF (4.2 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.302 g (82%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:16])=[C:10]([CH2:14]O)[N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:14][C:10]1[N:11]([CH3:13])[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2ccc(Cl)cc2)nn(C)c1CO
Product: Cc1c(-c2ccc(Cl)cc2)nn(C)c1CCl

Procedure:
In analogy to the procedure described for example 1 b], [5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazol-3-yl]-methanol was reacted with thionyl chloride for 20 min at 0° C. to give 5-chloromethyl-3-(4-chloro-phenyl)-1,4-dimethyl-1H-pyrazole as yellow oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24]>C(Cl)(Cl)Cl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][N:20]([CH2:24][CH2:23][C:25](=[O:26])[CH3:27])[CH2:19][CH2:18]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(c2ccccc2N2CCNCC2)CC1
Reactant: C=CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)CCN1CCN(c2ccccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 81.1 %

Procedure:
A mixture of the 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (30 mg, 0.0998 mmol) produced in Example (10a) and chloroform (0.5 mL) was cooled in an ice bath and stirred. Methyl vinyl ketone (0.017 mL, 0.200 mmol) was added to the mixture, followed by stirring for 2 hours under the same conditions. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 30 mg of the title compound as a colorless oil, as a mixture of diastereomers at the position of t-butylcyclohexyl.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH:6]([CH3:17])[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1I)=[O:4].CC([O-])=O.[K+].[CH:25]1[CH:30]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:26]=1>CN(C)C=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:30][C:25](=[CH2:26])[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH:6]1[CH3:17])=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(I)c(CC(C)NC(=O)C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)C(F)(F)F)C(C)Cc2cc(OC)ccc21
Reaction time: 8 h
Yield: 430 %

Procedure:
A solution of N-allyl, N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine (4.45 g, 10.8 mmol) in dimethylformamide (120 mL) was treated with KOAc (3.17 g, 32.3 mmol), n-Bu4NBr (3.47 g, 10.8 mmol), PPh3 (0.283 g, 1.08 mmol), Pd(OAc)2 (0.242 g, 1.08 mmol) and stirred overnight at 80 C. The product mixture was cooled to 20 C, filtered, diluted with water (200 mL), extracted with ether (3×200 mL), the combined organic phases washed with water (100 mL), brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 1.39 g of a yellow oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1.C(Cl)Cl>[CH3:21][S:22]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C#N)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(C#N)=NOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
20 g (0.114 mol) of α-hydroxyimino-4-methoxybenzylcyanide are dissolved in 100 ml of tetrahydrofuran (THF) and charged with 17.2 g (0.17 mol) of triethylamine. To this mixture are added dropwise and with cooling 14.3 g (0.0.12 mol) of methanesulfonyl chloride dissolved in 50 ml of THF. This mixture is then warmed to room temperature and stirred for 12 hours. Subsequently, the reaction solution is diluted with 300 ml of CH2Cl2, washed with water, dilute hydrochloric acid and again with water and is then dried over magnesium sulfate. After filtration, the solvent is distilled off on a rotary evaporator and the brownish crude product is recrystallised from toluene, giving 23.9 g (83%) of α-(methyl-sulfonyloxy-imino)-4-methoxybenzylcyanide in the form of beige crystals having an m.p. of 124-125° C. The 1H-NMR spectrum of the compound shows the product to be a pure stereoisomer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[N:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:13]1([C:19]([O:1][C:2]2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(C)c1cc(O)cc(C=O)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(C=O)cc(OC(=O)N2CCOCC2)c1
Reaction time: 3 h
Yield: 22.1 %

Procedure:
To a stirring solution of 91.9 mg (0.634 mmol) of 3-hydroxy-5-isopropylbenzaldehyde in 5 mL of CH2Cl2 at r.t. was added 220 μL (1.92 mmol) of 4-morpholinecarbonyl chloride and 0.5 mL (3.59 mmol) of Et3N. After 3 h, sat. NaHCO3 (15 mL) was added, and the aqueous layer was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (20% EtOAc/hexanes) provided 38.8 mg of 3-formyl-5-isopropylphenyl morpholine-4-carboxylate as a yellow oil in 24% yield.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2)C.[Li+].[BH4-].O>C1COCC1>[OH:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Temperature: -10 °C
Reaction time: 19.5 h
Yield: 99.6 %

Procedure:
tert-Butyl 6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.602 g, 1.62 mmol) was dissolved in THF (15 mL), and the resulting solution was cooled to −10° C. under N2. LiBH4 (0.0756 g, 3.47 mmol, 2.14 equiv.) was added and the reaction mixture was allowed to warm to rt. After 19.5 h, the reaction mixture was cooled to 0° C., and LiBH4 (0.0250 g, 1.15 mmol, 0.71 equiv.) was added and the reaction mixture was allowed to warm up for 3.5 h. The reaction mixture was combined with water and was extracted with EtOAc (2×). The combined organic layers was washed with brine, dried over MgSO4, filtered, and concentrated to give tert-butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.533 g) in acceptable purity and essentially quantitative yield. 1H NMR (300 MHz, CD3OD) δ 1.48-1.51, 3.00-3.11, 3.66-3.79, 3.87-3.95, 4.27, 7.12, 7.19, 7.32, 7.50; MS (ESI+) for C19H26N2O3 m/z 331.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH:26]=[CH2:27])=[N:9]2)=[CH:5][CH:4]=1.B1C2CCCC1CCC2.[OH-:39].[Na+].OO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH2:26][CH2:27][OH:39])=[N:9]2)=[CH:28][CH:29]=1
Reactant: [OH-]
Reactant: C=Cc1nn(Cc2ccc(OC)cc2)c2nccc(Oc3ccc(N)cc3F)c12
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(CCO)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a stirred solution of 4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (1.17 g, 3.00 mmol) in THF (5 mL) was added 9-BBN (24.0 ml, 12.0 mmol, 0.5 M in THF). The reaction was stirred for 18 hours at room temperature. The reaction was chilled (submerged in an ice bath) and then quenched by addition of 5N aqueous sodium hydroxide (6.00 mL, 30.0 mmol). After stirring for 30 minutes in the ice bath, 30% aqueous hydrogen peroxide (2.88 mL, 30.0 mmol) was added. After stirring for 5 minutes at 0° C., the reaction was allowed to stir for 30 minutes at room temperature. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified by Biotage Flash 40M, eluting with 2% MeOH in DCM (2 L). The product was obtained as a waxy solid (1.0 g, 78%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Cl.[F:32][C:33]1([F:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[F:32][C:33]1([F:39])[CH2:38][CH2:37][N:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([C:13]4[C:14]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][O:16][C:17]=4[CH3:18])=[N:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:35][CH2:34]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(I)cc2)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCC(F)(F)CC3)cc2)o1
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 2-(4-iodo-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.47 mmol) in toluene (2 mL) were added under an atmosphere of nitrogen 2-(dicyclohexylphosphino)biphenyl (15 mg, 0.04 mmol), tris(dibenzylideneacetone)di-palladium(0) chloroform complex (15 mg, 0.01 mmol), sodium tert-butoxide (107 mg, 1.12 mmol) and 4,4-difluoropiperidine hydrochloride (88 mg, 0.56 mmol). The reaction mixture was stirred for 1 h at 100° C. and was extracted with water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 50:50) afforded the title compound (138 mg, 70%) as a light yellow solid. MS: m/e=423.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:5]([C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH:3][CH3:4]>O1CCOCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH2:18][C:14]1[CH:13]=[C:12]([C:11](=[O:21])[CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:17]=[CH:16][CH:15]=1
Reactant: CC=CCC(C(=O)OCC)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1COCCO1
Product: CCCCC(C(=O)OCC)C(=O)c1cccc(N)c1
Yield: 65.2 %

Procedure:
A solution of ethyl α-(2-butenyl)-3-nitro-β-oxobenzenepropanoate (411 mg, 1.41 mmol) in 1,4-dioxane (12 mL) was stirred at 25° for 8.5 h under a hydrogen atmosphere (1 atm) in presence of Pd/BaSO4 (225 mg+150 mg added after 5.5 h). The suspension was filtered (50μ filter) and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40-63μ silica gel, hexane:EtOAc, 3:1) to give ethyl 3-amino-α-butyl-β-oxobenzenepropionate (242 mg, 65% yield):
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:19]=[C:18]2[C:9]([C:10](=[O:21])[C:11]3[C:16]([C:17]2=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH2:22][CH2:23][CH2:24][C:7]=12)(=O)C.O.C(N(CC)CC)C>CO>[OH:4][CH2:5][C:6]1[CH:19]=[C:18]2[C:9]([C:10](=[O:21])[C:11]3[C:16]([C:17]2=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH2:22][CH2:23][CH2:24][C:7]=12
Reactant: CC(=O)OCc1cc2c(c3c1CCC3)C(=O)c1ccccc1C2=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(=O)c2c1cc(CO)c1c2CCC1
Temperature: 55 °C

Procedure:
A mixture of 2,3-dihydro-4-acetoxymethyl-1H-cyclopent[a]anthracene-6,11-dione (74 mg, 0.23 mmol) in MeOH (12 mL) containing H2O (3mL) and triethylamine (2mL) is heated at 55° C. for 3 hours. The mixture is evaporated in vacuo, and the residue is coevaporated twice with EtOH (10 mL) to dryness. The residue is recrystallized from CHCl3 to give2,3-dihydro-4-hydroxymethyl-1H-cyclopent[a]anthracene-6,11-dione, 48 mg (75%), mp 191°-192° C. 1H NMR (DMSO-d6): δ2.14 (2H, q, J=7.6 Hz, CH2 -2), 2.88 (2H, t, J=7.6 Hz, CH2 -3), 3.40 (2H, t, J=7.6 Hz, CH2 -1), 4.61 (2H, d, J=5.5 Hz, CH2 --OH), 5.53 (1 H, t, J=5.5 Hz, OH), 7.90-8.18 (5H, m, Ar--H). Anal. Calc'd for C18H14O3 : C, 77.68; H, 5.07. Found: C, 77.70; H, 5.06.