Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 88 %

Procedure:
2-Benzyloxy-3-methylbenzaldehyde prepared by the above 2-(1) 20.0 g (88.4 mmol) was dissolved in methylene chloride 100 ml and thereto was added m-chloroperbenzoic acid 16.8 g (97.2 mmol). The mixture was reacted at 20° C. under stirring for 10 hours. After disappearance of the raw material, the solution was neutralized with a saturated sodium bicarbonate solution and extracted with methylene chloride. To the extract (2-benzyloxy-3-formyloxytoluene) was added a 10% sodium hydroxide solution 38.9 g (97.2 mmol) in the ice bath and the mixture was stirred for 3 hours. The reaction mixture was neutralized with a 5% hydrochloric acid solution and extracted with methylene chloride. The solvent was removed in vacuo and the residue was purified in the same manner as in the above mentioned 3-(1) to give 2-benzyloxy-3-methylphenol 16.7 g (yield: 88%).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[C:5]([F:19])=[CH:4][N:3]=1.[C:20]([O:24][C:25](=[O:27])[NH2:26])([CH3:23])([CH3:22])[CH3:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([O:24][C:25](=[O:27])[NH:26][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[C:5]([F:19])=[CH:4][N:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ncc(F)c2nc(-c3c(F)cccc3Cl)sc12
Temperature: 70 °C
Yield: 72.1 %

Procedure:
A mixture of 4-bromo-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.440 g, 1.22 mmol), carbamic acid tert-butyl ester (0.714 g, 6.1 mmol), XantPhos (0.071 g, 0.122 mmol) and K3PO4 (0.530 g, 2.5 mmol) in toluene (8 mL) and water (1.2 mL) was degassed with a stream of argon. Pd2(dba)3 (0.056 g, 0.061 mmol) was added and the reaction mixture was heated in a sealed vial at 70° C. for 3 hours. After cooling to room temperature, the crude mixture was filtered through Celite® washing with EtOAc. The organic layer was washed with brine, then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in pentane to afford the title compound as a white solid (350 mg, 72% yield). LCMS (Method D): RT=4.08 min, m/z: 398 [M+H+].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1>CN(C=O)C>[CH3:21][C:22]1[CH:23]=[N:24][N:25]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH:26]=1
Reactant: Cc1cn[nH]c1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)c1
Temperature: 110 °C
Yield: 70.2 %

Procedure:
To a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K2CO3 (496 mg, 3.59 mmol) in DMF (3 mL) was added 4-methyl-1H-pyrazole (196 mg, 2.391 mmol) in one portion. Then the mixture stirred under N2 was heated to 110° C. and reacted for 15 h. LCMS analysis showed the starting material disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give crude material which was purified by silica column chromatography (PE/EA=10/1 to 5/1) to afford pure product 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (500 mg, 1.678 mmol, 70.2% yield): 1H NMR (400 MHz, CD3OD): δ 8.83 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 2.18 (s, 3H). ES-LCMS: m/z 272.2 (M+H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:13]([NH2:14])=[CH:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35].[NH4+].[Cl-]>C(Cl)Cl>[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:14][C:13]1[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[N:10][N:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)(=[O:36])=[O:35]
Reactant: Nc1cn(-c2ccccc2)nc1C(=O)N1CCOCC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1nn(-c2ccccc2)cc1NS(=O)(=O)c1ccccc1Br)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.3 %

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-1-phenyl-1H-pyrazol-4-amine (260 mg; 0.95 mmol; 1 eq.) in DCM (10 mL) is added pyridine (151 μL; 1.91 mmol; 2.00 eq.) and 2-bromobenzene-1-sulfonyl chloride (317 mg; 1.24 mmol; 1.30 eq.). The reaction is stirred for 48 h at room temperature. After this time, DCM is added to the reaction mixture which is ished with NH4Cl sat, dried over MgSO4 and purified by flash chromatography (AcOEt/heptane 4:1) to give 440 mg (94%) of the title compound as a white solid. 1H NMR (DMSO) δ 9.93 (s, 1H), 8.43 (s, 1H), 8.11-8.02 (m, 1H), 7.91-7.84 (m, 1H), 7.84-7.76 (m, 2H), 7.59-7.45 (m, 4H), 7.40-7.31 (m, 1H), 3.81-3.69 (m, 2H), 3.67-3.49 (m, 6H) HPLC (max plot) 94.6%; Rt 4.83 min. MS (ESI+): 493.2.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:28]=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH:49]4[CH2:52][O:51][CH2:50]4)[CH2:45][CH2:44]3)=[CH:39][N:38]=2)[C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[CH:32]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:28]=[C:29]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH:49]5[CH2:50][O:51][CH2:52]5)[CH2:47][CH2:48]4)=[CH:39][N:38]=3)[C:30]3[N:31]([N:33]=[CH:34][N:35]=3)[CH:32]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c3ncnn3c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4ncnn4c2)c1CO)CCCC3
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A mixture of 108e (250 mg, 0.35 mmol) and LiOH (300 mg, 10 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (1 mL) was stirred at 50° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with Ethyl acetate (5 mL×2). The combined Ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 108 (110 mg, 25%). LCMS: [M+H]+ 664. 1H NMR (500 MHz, DMSO) δ 9.33 (s, 1H), 8.67 (s, 1H), 8.55-8.54 (m, 2H), 7.95 (d, J=3.0, 1H), 7.44-7.41 (m, 2H), 7.37-7.33 (m, 2H), 6.53 (s, 1H), 4.98 (t, J=5.0, 1H), 4.55-4.54 (m, 2H), 4.45-4.44 (m, 2H), 4.13-4.32 (m, 5H), 3.91 (s, 1H), 3.43-3.41 (m, 1H), 3.10 (s, 4H), 2.60-2.38 (m, 8H), 1.78-1.76 (m, 2H), 1.69-1.67 (m, 2H)
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>ClCCl>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:2])=[O:22]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: OCCCCCCCCCBr
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(O)CCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
Pyridinium chlorochromate (38.7 g, 180 mmol) and silica 60A (39 g, particle size 35-70 micron) suspended in dichloromethane (250 mL) were stirred at RT for 45 minutes. 9-Bromononanol (26.7 g, 120 mmol) was added, in one portion, and the suspension was stirred at RT for 18 hours. The reaction mixture was filtered through a column of celite and the resultant filtrate concentrated under vacuum affording the title compound (28.0 g, >100%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)[CH:9]=2)[CH2:4][CH:3]=1.[C:27]([O:33]CC)(=O)[CH2:28][C:29]([CH3:31])=O.Cl>C(O)C.O>[CH3:31][C:29]1[CH2:28][C:27](=[O:33])[N:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH2:3][CH:2]3[CH3:1])[N:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC1=CCc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1=NN(c2ccc3c(c2)C(C)CC3)C(=O)C1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
Di-tert-butyl 1-(3-methyl-inden-5-yl)hydrazine-1,2-dicarboxylate 38e (1.05 g, 2.9 mmol) was dissolved in 16 mL of a solvent mixture of ethanol and water (V:V=5:3) under stirring, followed by successive addition of ethyl acetoacetate (0.377 mL, 2.9 mmol) and 1.45 mL of 6 N hydrochloric acid. The reaction mixture was heated to reflux and reacted for 1.5 hours under nitrogen atmosphere. The mixture was cooled to room temperature and the mixture was concentrated under reduced pressure to remove ethanol. The aqueous layer was extracted with dichloromethane (15 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-methyl-2-(3-methyl-indan-5-yl)-2,4-dihydro-pyrazol-3-one 38f (103 mg, yield 15.6%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.[CH:12]([CH:15]1[C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][N:16]1[C:24](OCC(Cl)(Cl)Cl)=[O:25])([CH3:14])[CH3:13]>C1COCC1>[CH:12]([CH:15]1[C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][N:16]1[C:24]([O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=1)=[O:25])([CH3:14])[CH3:13]
Reactant: OCc1ccc(Cl)cn1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
NaH (80.0 mg, 2.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL), the suspension was cooled to 0° C. and 5-chloropyridine-2-methanol (0.29 g, 2.00 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (0.65 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 5-chloropyridine-2-methanol in THF were added after 2 and 3 d, respectively. After 4 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 20% to 80% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 to give (5-chloropyridin-2-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (7.91 mg, 1.2%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:18][N:19]3[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:30][CH2:29]4)[C:20]3=[O:31])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1.CC([O-])=O.[K+]>CO.[Pd]>[CH:28]1([N:21]2[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:19]([CH2:18][C:9]3[N:10]([CH2:11][CH2:12][CH2:13][C:14]([F:15])([F:17])[F:16])[C:5]4[C:6]([N:8]=3)=[N:7][CH:2]=[CH:3][CH:4]=4)[C:20]2=[O:31])[CH2:30][CH2:29]1
Reactant: O=c1n(Cc2nc3nc(Cl)ccc3n2CCCC(F)(F)F)c2cnccc2n1C1CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: O=c1n(Cc2nc3ncccc3n2CCCC(F)(F)F)c2cnccc2n1C1CC1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Compound 39 (1000 mg, 2.22 mmol) was dissolved in 30 mL MeOH. Pd/C (10%) and KOAc (218 mg, 2.22 mol) were added. The mixture was placed under H2 and hydrogenated overnight. The mixture was filtrated over a plug of dicalite and evaporated. Compound 41 was purified by column chromatography on silicagel using CH2Cl2 to CH2Cl2/MeOH (NH3) 9-1 as the eluent. After evaporation 550 mg (59% yield) of 41 was obtained as a white solid with a purity of 99%. m/z=417 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93-1.05 (m, 2 H), 1.18 (s, 2 H), 1.91 (s, 2 H), 2.12-2.31 (m, 2 H), 2.91 (tt, J=6.93, 3.48 Hz, 1 H), 4.46 (t, J=7.80 Hz, 2 H), 5.42 (s, 2 H), 7.14 (d, J=5.27 Hz, 1 H), 7.25 (dd, J=8.28, 4.77 Hz, 1 H), 7.66 (dd, J=8.16, 1.38 Hz, 1 H), 8.36 (d, J=5.27 Hz, 1 H), 8.59 (dd, J=4.77, 1.51 Hz, 1 H), 8.80 (s, 1 H).
Reaction SMILES: O1CCOCC1.[OH-].[Li+].[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:19][CH:18]([C:32]([O:34]CC)=[O:33])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[CH2:19][CH:18]([C:32]([OH:34])=[O:33])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
99 ml of dioxane, 50 ml of water and 1.37 g (57.0 mmol) of lithium hydroxide were added to 5.9 g (14.3 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylate. The mixture was stirred at RT overnight. For work-up, the dioxane was removed under reduced pressure, water was added to the reaction mixture and the mixture was acidified using aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Yield: 5.3 g (95% of theory)
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C:13]=1[CH:14]=[CH:15][C@@H:16]1[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]1[CH2:18][CH2:19][C@@H:20]2[C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>O1CCCC1.O>[CH:1]([NH:11][C:12]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C:13]=1[CH:14]=[CH:15][C@@H:16]1[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]1[CH2:18][CH2:19][C@@H:20]2[C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:2]
Reactant: O=CO
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(NC=O)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A solution of formic acid (0.22 mL, 5.84 mmole) and acetic anhydride (0.46 mL, 4.76 mmole) was heated at reflux temperature for 2 hours under a nitrogen atmosphere. The cooled solution was diluted with tetrahydrofuran (5 mL) and a solution of 4-amino-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide, (0.35 g, 0.91 mmole) in tetrahydrofuran (10 mL) was added. The reaction was stirred overnight at room temperature and then diluted with water (25 mL). A gummy material separated which was extracted into diethyl ether-dichloromethane and washed with saturated aqueous sodium bicarbonate. The dried solution was concentrated to a yellow foam which was purified by flash chromatography (hexane-50% ethyl acetate, ethyl acetate) to give 4-formamido-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide (0.25 g, 67.6%, diethyl ether). IR 3440, 3304, 3246, 1684, 1670, 1650 cm-1 ; MS (CI) m/z 413 (100%, M+ +1); (EI) m/z 412 (18%, M+), 57 (100%); 1H NMR (CDCl3) δ 0.78 (3H, s, C18 -Me), 1.14 (3H, s, C19 -Me), 1.37 (s, 3× tBu-Me's), 5.11 (1H, s, NHCOBu), 6.15-6.45 (2H, m, C6 -H+C7 -H), 7.07-7.20 (1H, d+s, NHCO), 8.12+8.29 (1H, d+s, CHO).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH2:17][CH2:18][O:9][C:3]=2[CH:4]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)OCCN2
Temperature: 130 °C
Reaction time: 11 h

Procedure:
To a solution of 2-amino-5-methylphenol (5.0 g) in N,N-dimethylformamide (50 ml), potassium carbonate (28.3 g) and 1,2-dibromoethane (10.6 ml) were added and stirred at 130° C. for 11 hours. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 9:1) to give the titled compound, i.e., 7-methyl-3,4-dihydro-2H-1,4-benzoxazine (980 mg) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.Cl[CH2:41][CH2:42][OH:43]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:41][CH2:42][OH:43])[CH2:9][CH2:8]1)=[O:5]
Reactant: OCCCl
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCO)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).
Reaction SMILES: C([Li])(CC)C.C(O[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=1)(C)(C)C.[O:19]1CC[CH2:21][CH2:20]1>>[CH3:21][C:20]([C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[CH2:16])=[CH:17][CH:18]=1)=[O:19]
Reactant: C1CCOC1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: [Li]C(C)CC
Product: C=Cc1ccc(C(C)=O)cc1
Reaction time: 0.5 h

Procedure:
A 1-liter flask was charged with 500 ml of tetrahydrofuran as a solvent and 0.01 mol of sec-butyl lithium as an initiator. To the solution at −78° C. was added 30 g of p-tert-butoxystyrene. With stirring, polymerization reaction was effected for 30 minutes. The reaction solution turned red. For producing a branched polymer, 0.005 mol of p-methylcarbonylstyrene was added to the reaction solution whereupon reaction was effected for 5 minutes. Further 15 g of p-tert-butoxystyrene was added. With stirring, polymerization reaction was effected for 30 minutes. Polymerization was stopped by adding 0.1 mol of methanol to the reaction solution.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11](O)=[O:12])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].CSC.B.CO>C1COCC1>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][OH:12])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S*,4S*)-pyrrolidine-1,3,4-tricarboxylic acid 1-tert-butyl ester 3-ethyl ester (10 g, 34.8 mmol) in THF (180 mL), a solution of borane dimethylsulfide complex (2N in THF, 24.4 mL, 48.7 mmol) is added slowly at −10° C. The mixture is stirred at −10° C. for 20 min, then allowed to reach RT and further stirred for 4 h. MeOH is carefully added (exothermic!), and the mixture is concentrated under reduced pressure. MeOH is again added, and the mixture is concentrated. This operation is repeated 3 times, then the mixture is finally taken up into a saturated aqueous solution of NaHCO3 and extracted 3 times with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH from 100:0 to 95:5) to give the title compound as product. TLC, Rf (AcOEt)=0.52. MS (LC-MS): 174.1 [M+H-Boc]+.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7]3[C:6]=2[C:5]([C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]=23)=[CH:4][CH:3]=1
Reactant: O=C1CCCCCC1
Reactant: CN1CCc2c(Cl)cccc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCCCC4
Temperature: 25 °C
Yield: 34.1 %

Procedure:
To a solution of 7-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.20 g, 5.32 mmole) in 1-propanol (100 mL) was added cycloheptanone (6.65 g, 59.3 mmole) followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmol) and the resulting reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.55 g of the title compound as a white solid, mp 132-134° C. MS (ESI) m/z 303 ([M+H]+).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[Na+]>S(=O)(=O)(O)O>[C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]([NH2:9])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)c1ccccn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(c1ccccc1)c1ccccn1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of (RS)-phenyl-pyridin-2-yl-acetonitrile (0.928 g, 4.80 mmol) in 5 ml of conc. sulfuric acid was stirred overnight at room temperature. The mixture is poured on 100 g of ice, the pH is adjusted to 8-9 by addition of 28% sodium hydroxide solution and the product is extracted with ethyl acetate/water. After drying (MgSO4) and concentration, the crude material is purified by flash chromatography on silicagel using ethyl acetate as eluant to yield 0.878 g (4.14 mmol, 86%) of (RS)-phenyl-pyridin-2-yl-acetamide as a white solid, m.p. 134° C. and MS: m/e=213.2 (M+H+).