Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].[Li+].[Cl-].C(=O)C1C=CC=CC=1>C1COCC1>[CH2:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:10]=[CH2:11]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCc1ccc(C#N)cc1
Yield: 81 %

Procedure:
Highly substituted chloro and methoxy aryl bromides can readily be converted into the desired Grignard reagents 3i, j. After the reaction with ClPPh2 and oxidative work-up, the phosphine oxides 2ia, ja are obtained in good yields (entry 15, 16). This type of compound is of interest in relation with P-ligands for asymmetric catalysis.[5] Also functions like a cyano group are tolerated. Thus, the reaction of 4-bromobenzonitrile in THF at −7° C. leads to the desired arylmagnesium reagent (3d) in only 50% conversion using i-PrMgCl whereas over 90% is observed with i-PrMgCl.LiCl (Scheme 3). The addition of benzaldehyde provides the alcohol 2da in 81% yield whereas allylation of arylmagnesium reagent (3d) with allyl bromide leads to the corresponding 4-allylbenzonitrile in 92% yield (entry 5,6 of Table 1). See FIG. 3 for additional information.
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:4]=1[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18]2>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:4]=1[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH:20]([OH:24])[CH2:19][CH2:18]2
Reactant: O=C1CCc2cc(-c3ncccc3-c3ccncc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2cc(-c3ncccc3-c3ccncc3)ccc21
Yield: 104.2 %

Procedure:
Sodium borohydride (21 mg) was added to a stirring solution of 5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one (162 mg) in MeOH (4 mL). The reaction mixture was concentrated and quenched with aq. NH4Cl. The resultant solid was extracted into CH2Cl2 (2×20 mL). Combined organic layers were stirred over MgSO4, filtered and concentrated. Flash chromatographic purification (Combiflash® companion System® with RediSep® silica gel column 12 g, 50-75% EtOAc/hexanes as eluting solvent) provided rac-5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-ol (170 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.69 (dd, J=4.8, 1.6 Hz, 1H), 8.48 (d, J=6.0 Hz, 2H), 7.85 (dd, J=7.8, 1.7 Hz, 1H), 7.48 (dd, J=7.8, 4.7 Hz, 1H), 7.25-7.11 (m, 4H), 7.00 (dd, J=7.8, 1.5 Hz, 1H), 5.29-5.20 (m, 1H), 5.00 (q, J=6.4 Hz, 1H), 2.81 (ddd, J=16.0, 8.7, 3.9 Hz, 1H), 2.61 (dt, J=15.9, 8.0 Hz, 1H), 2.36-2.21 (m, 1H), 1.74 (dtd, J=12.8, 8.2, 6.3 Hz, 1H). LCMS: rt 2.81 min (A), purity 99%, MS (m/e) 289 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:9]([O-])=O)=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cccnc1N
Reaction time: 4 h
Yield: 91 %

Procedure:
A suspension of 3-methoxy-2-nitropyridin (30 g, 194.8 mmol) and 10% Pd/C (10 g) in ethanol (1 L) was hydrogenated in a par hydrogenator (H2, 40 psi pressure) at RT for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to afford the title compound (22 g, 91%, brown solid). 1H NMR (400 MHz, CDCl3): δ=7.66 (d, J=5.2 Hz; 1H), 6.91 (d, J=7.6 Hz, 1H), 6.63-6.60 (m, 1H), 4.65 (br, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.FC1C=C(C(=O)C)C=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([NH:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=2[Cl:75])[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[Cl:75][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=1[NH:68][CH:65]1[CH2:64][CH2:63][N:62]([C:60](=[O:61])[CH2:59][NH:58][C:22]([C:19]2[CH:18]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)[NH:21][N:20]=2)=[O:24])[CH2:67][CH2:66]1
Reactant: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)[nH]n1
Agent: CC(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2cccc(F)c2)[nH]n1
Reaction time: 8 h
Yield: 46.3 %

Procedure:
DIPEA (165 mg, 1.3 mmol) was added to a stirred solution of 5-(3-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (75 mg, 0.36 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 3′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (51 mg, 0.38 mmol) and EDCI.HCl (73 mg, 0.38 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone hydrochloride (120 mg, 0.36 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. Washing with methanol afforded 76 mg (43.1% Yield) of 5-(3-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 456, 100%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.06 (t, 1H), 7.44 (m, 4H), 7.12 (m, 4H), 6.84 (d, 1H), 6.58 (m, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.2 (m, 2H), 3.7 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 1.9 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][CH:40]=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]CC)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1COCC1.[Li+].[OH-].Cl>C(Cl)Cl.O.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][CH:40]=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]([OH:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 20 mL vial were added ethyl 1-{[1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]methyl}cyclopentanecarboxylate (57 mg, 0.09 mmol), THF (1 mL) and MeOH (1 mL) followed by LiOH (1 mL, 1 M). The reaction mixture was capped and heated to 80° C. for 3 h. The mixture was then cooled to RT, water (5 mL) was added to the mixture and the pH was adjusted to 4 using 1 M HCl. To this mixture was added DCM (5 mL) and stirred for 1 h at RT. The organic layer was separated and the aqueouse layer was further extracted with DCM. The combined organics were dried, filtered and concentrated to dryness. The residue was then purified by FCC to provide the title compound. MS (ESI): mass calcd. for C31H28BrN3O3, 569.13; m/z found, 570.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.6, 1H), 8.11 (d, J=8.3, 1H), 7.83 (d, J=8.3, 1H), 7.77-7.72 (m, 1H), 7.69 (d, J=8.6, 1H) 7.58-7.53 (m, 1H), 7.45 (d, J=7.8, 1H), 7.36-7.34 (m, 1H), 7.23 (s, 1H), 7.21-7.15 (m, 2H), 7.11-7.06 (m, 1H), 6.90 (d, J=7.6, 1H), 5.44 (s, 2H), 5.28 (s, 2H), 3.04 (s, 2H), 2.44-2.34 (m, 2H), 1.77-1.66 (m, 2H), 1.50-1.41 (m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH:17]1(O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCC1
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.85 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 3.14 mmol cyclopentanol and 3.28 mmol triphenylphosphine in 10 ml THF was added 3.14 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant:ethyl acetate/heptane 2:3) to afford the title compound as a colourless oil. MS (m/e): 312.1 ([M−H]−, 100%)
Reaction SMILES: [CH:1]1([N:4]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:33])=[O:32])[C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[N:12](C(OC(C)(C)C)=O)[CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:3][CH2:2]1>C(OCC)(=O)C.Cl>[CH:1]1([N:4]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:33])=[O:32])[C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[NH:12][CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
1-tert-Butyl 2-ethyl 7-[cyclopropyl(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)indoline-1,2-dicarboxylate (1.70 g) was added to 4N hydrogen chloride-ethyl acetate solution (50 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.34 g, yield 96%) as a pale-yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.[CH3:25][N:26]([CH3:36])[C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:25][N:26]([CH3:36])[C:27]1[N:32]=[CH:31][C:30]([C:2]2[CH:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=4)=[N:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)c1ccc(-c2ccc(C(=O)NCc3ccc(-c4ccnc(F)c4)nc3)nc2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a tube was added 5-bromo-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)picolinamide 38-4 (38 mg, 0.10 mmol), 6-(dimethylamino)pyridin-3-ylboronic acid 38-5 (33 mg, 0.20 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), toluene (0.4 mL), ethanol (0.1 mL) and 2M Na2CO3 (0.15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the tube sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified with reverse phase HPLC to give 6′-(dimethylamino)-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)-3,3′-bipyridine-6-carboxamide 38 as a white powder. MS m/z 429.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.52 (t, 1H, J=6.4 Hz), 8.94 (d, 1H, J=2.4 Hz), 8.73 (d, 1H, J=2.0 Hz), 8.60 (d, 1H, J=2.4 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.22 (m, 1H), 8.15 (d, 1H, J=8.0 Hz), 8.06-7.93 (m, 4H), 7.80 (s, 1H), 6.78 (d, 1H, J=9.2 Hz), 4.60 (d, 2H, J=6.4 Hz), 3.09 (s, 6H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]2O.C(N(CC)CC)C.[NH2:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31]>CN(C)C=O.O1CCCC1.O>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]2[NH:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31]
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
Phosphorous oxychloride (5.45 mL, 58.5 mmol) was added to a slurry of 6-bromo-3-nitroquinolin-4-ol (15 g, 55.7 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was heated to 100° C. for 10 minutes and then cooled to ambient temperature. The solution was poured into ice water (400 mL) and stirred for 20 minutes. The resulting precipitate was filtered, washed with water, and dried. The recovered solid was transferred to a round bottomed flask and tetrahydrofuran (100 mL) was added. A solution of triethylamine (11.6 mL, 83.5 mmol) and 1-amino-2-methylpropan-2-ol (5.21 g, 58.5 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction was stirred for 16 hours. The mixture was poured into water and stirred for 15 minutes. The resulting yellow solid was filtered and dried to provide 17.2 g of 1-[(6-bromo-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br.[OH-].[Na+]>C(O)(=O)C.O>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(-c2ccc(-c3ccc(OC)cc3)cn2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(-c2ccc(-c3ccc(O)cc3)cn2)cc1
Yield: 68.9 %

Procedure:
This 2-(4-heptylphenyl)-5-(4-methyloxyphenyl)pyridine (15 g, 0.042 mol) was dissolved in acetic acid (120 ml), followed by adding a 48% solution of hydrobromic acid (50 ml), refluxing the mixture for 30 hours, cooling the resulting material, pouring it in water, dissolving deposited crystals in 2N-NaOH aqueous solution on heating, adding acetic acid to obtain an acidic solution, filtering off the residue and recrystallizing from EtOH to obtain 2-(4-heptylphenyl)-5-(4-hydroxyphenyl)pyridine (10 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])[CH:14]=1.[CH:25]([O:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[CH3:44])([CH3:27])[CH3:26]>CCCCCC.C1COCC1>[OH:41][C:38]1([CH2:22][C:21](=[O:23])[CH2:20][C:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[O:24])[CH2:39][CH2:40][N:35]([C:33](=[O:34])[C:32]2[CH:42]=[CH:43][C:29]([O:28][CH:25]([CH3:26])[CH3:27])=[C:30]([CH3:44])[CH:31]=2)[CH2:36][CH2:37]1
Reactant: Cc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Reactant: CC(=O)CC(=O)c1cccnc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCC(O)(CC(=O)CC(=O)c3cccnc3)CC2)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To an oven-dried round bottom flask was added diisopropylamine (6.4 mL, 46 mmol) and THF (125 mL). It was cooled to −78° C., and a solution of nBuLi (18 mL of 2.5 M, 46 mmol) in hexane was added. It was stirred at 0° C. for 30 minutes and again cooled to −78° C. 1-(3-pyridyl)butane-1,3-dione (3.40 g, 21.0 mmol) in a solution of THF (25 mL) was added dropwise. After 30 minutes at −78° C., a solution of 1-(4-isopropoxy-3-methyl-benzoyl)piperidin-4-one (5.74 g, 20.8 mmol) in THF (25 mL) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (100 mL). Volatiles were removed under reduced pressure to one-third volume. It was extracted with ethyl acetate (2×75 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude brown oil was purified by column chromatography (100% ethyl acetate) to provide 4-[4-hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione (5.85 g) as a yellow foaming solid. 1H NMR (400 MHz, CDCl3) δ 15.81 (s, 1H), 9.08 (d, J=1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.19 (dd, J=8.0, 1.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.24-7.17 (m, 2H), 6.80 (d, J=8.2 Hz, 1H), 6.20 (s, 1H), 4.55 (m, 1H), 4.51-4.25 (br s, 1H), 3.52-3.26 (m, 4H), 2.68 (s, 2H), 2.20 (s, 3H), 1.75-1.51 (m, 4H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.22, found 439.5 (M+1)+; Retention time: 1.37 minutes (3 min run).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]=[O:3].[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[C:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2](=[O:3])[NH:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(NC(=O)NCCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (8.12 mmol) of ethyl 3-isocyanatobenzoate (78%) are dissolved in 10 ml of DMF..A solution of 1.42 g (8.12 mmol) of 1-amino-3-tert-butyloxycarbonylaminopropane in 20 ml of DMF is slowly added dropwise at 2°-8°C. After stirring at room temperature for 2 h, the solvent is removed in vacuo, and the residue is treated with ethyl acetate and the mixture is washed with water. After drying (MgSO4), solid is filtered off and the solvent is removed in vacuo. The residue is chromatographed on silica gel.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=O.[C:10](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:7]1[O:9][CH2:10][N:1]2[C:5](=[O:6])[CH2:4][CH:3]=[C:2]12
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1CC=C2COCN12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3S,7aR)-3-Phenyl-5,6,7,7a-tetrahydro-#1H-pyrrolo[1,2-c]oxazol-5-one was prepared in three steps from D-Pyroglutamic acid by a known procedure (Thottathil, J. K. et al. J. Org. Chem. 1986, 51, 3140) and was converted to (3S,7aR)-3-Phenyl-1H-pyrrolo[1,2-c]oxazol-5-one in two steps (selenylation and oxidative elimination) by the method reported by Hamada et al. (J. Am. Chem. Soc. 1989, 171, 1524). (3S,7aR)-3-Phenyl-1H-pyrrolo[1,2-c]oxazol-5-one was then converted to (3S,7S,7aS,1′S)-7a-(1′-acetoxy-2′-methylpropyl)-7-hydroxy-3-phenyl-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-5-one in 6 steps by analogy to the sequence reported by Uno et al. (J. Am. Chem. Soc. 1994, 116, 2139). (3S,7S,7aS,1′S)-7a-(1′-acetoxy-2′-methylpropyl)-7-hydroxy-3-phenyl-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-5-one (70 mg, 0.21 mmol) was dissolved in 1.0 mL pyridine and treated at room temperature with 32.0 mL acetic anhydride (0.34 mmol, 1.6 equiv.). The mixture was stirred at room temperature overnight and the solvent was removed in vacuo affording 77 mg of desired (3S,7S,7aS,1′S)-7a-(1′-acetoxy-2′-methylpropyl)-7-acetoxy-3-phenyl-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-5-one (97%), a yellow oil which was used as such in the followingstep.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[F:19][C:20]([F:25])([F:24])[CH:21]=[CH:22][CH3:23].C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[F:19][C:20]([F:25])([F:24])[CH2:21][C:22]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)=[CH2:23]
Reactant: CC=CC(F)(F)F
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(CC(F)(F)F)c1ccc(C(=O)OC)cc1
Temperature: 125 °C

Procedure:
A mixture of methyl 4-iodobenzoate (2.62 g, 10 mmol), Et3N (5 ml), acetonitrile (6 ml), Pd(OAc)2 (100 mg, 0.4 mmol) added 1,1,1-trifluoro-2-butene (2.20 g, 20 mmol) was sealed and heated at 125° C. for 20 h. After cooling, the mixture was treated with sat. Aq. Na2CO3 solution and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography on silica gel to give methyl (e)-methyl 4-(4,4,4-trifluorobut-2-en-2-yl)benzoate and methyl 4-(4,4,4-trifluorobut-1-en-2-yl)benzoate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:34])=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][CH:16]=[N:17][C:18]=1[OH:19])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:18](=[O:19])[N:17]([CH3:5])[CH:16]=[N:15][C:14]=1[C:20]([O:22][CH3:23])=[O:21])=[O:11]
Reactant: COC(=O)c1ncnc(O)c1OC(=O)C(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1ncn(C)c(=O)c1OC(=O)C(C)(C)C

Procedure:
Dimethyl sulfate (1.5 eq.) was added to a solution of the product of Step 3 (1 eq.) in THF containing cesium carbonate (1.5 eq.). The reaction was carried out at 50° C. for thirty minutes. The solvent was evaporated and the resulting oil was dissolved in ethyl acetate, washed with 1N HCl solution. The crude title compound was recovered as yellow solid and used in the next step without purification.
Reaction SMILES: [BH4-].[Na+].[C:3]1(=[O:15])[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[CH2:4]1)[CH:11]=[CH:10][CH:9]=[CH:8]3>CO>[CH:3]1([OH:15])[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[CH2:4]1)[CH:11]=[CH:10][CH:9]=[CH:8]3
Reactant: O=C1Cc2ccc3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1Cc2ccc3ccccc3c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
1.4 g of sodium borohydride are added to a suspension, at 0-5° C., of 5.2 g of the product obtained in Step 2 in 150 ml of methanol. After 15 minutes at that temperature and then 1 hour at room temperature, the reaction mixture is poured into 300 g of ice and extracted with dichloromethane. After customary treatment, 5.2 g of the expected product are isolated.