Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (Maybridge; 1.05 g, 4.75 mmol) in DMF (20 ml) was added 4-amino-1-methylpiperidine (Fluorochem; 604 mg, 5.29 mmol) followed by DIPEA (1.6 ml, 9.19 mmol) and HATU (2.06 g, 5.42 mmol). The reaction mixture was stirred at ambient temperature O/N. The reaction mixture was evaporated to dryness and the residue partitioned between DCM (75 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The aqueous phase was re-extraced with DCM (50 ml) and the combined organic phases washed with brine, dried over magnesium sulphate, filtered and evaporated to give the title compound as an amber gum (1.17 g, 78%)
Reaction SMILES: [CH2:1]([CH:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][C:10](OCC4C=CC=CC=4)([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:9][C:8]=3[C:7]=2[CH2:6][CH:5]([C:32]([OH:34])=[O:33])[CH2:4]1)[CH3:2].CO>[OH-].[Na+]>[CH2:1]([CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:11][CH:12]=3)[C:7]=2[CH2:6][CH:5]([C:32]([OH:34])=[O:33])[CH2:4]1)[CH3:2].[CH2:17]([O:16][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:14][C:15]1[CH2:3][CH2:4][CH:5]([C:32]([OH:34])=[O:33])[CH2:6][C:7]2=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC1CC(C(=O)O)Cc2c1[nH]c1c2CC(OCc2ccccc2)(OCc2ccccc2)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1CC(C(=O)O)Cc2c1[nH]c1ccc(OCc3ccccc3)cc21
Product: O=C(O)C1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Yield: 90.8 %

Procedure:
To a suspension of 3.107 gm (8.9 mMol) ethyl 6-benzyloxy-3-carboxy-6-benzyloxy-1,2,3,4-tetrahydro-9H-carbazole in 100 mL 2N sodium hydroxide were added 100 mL methanol and the reaction mixture stirred at reflux for 3.5 hours. The reaction mixture was concentrated to about half volume and the pH adjusted to between 5 and 7 by the addition of concentrated hydrochloric acid. The mixture was extracted well with 4:1 dichloromethane:isopropanol. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give 2.71 gm (95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[Br:28]N1C(=O)CCC1=O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6]1[C:15]([Br:28])=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1cc2oc(=O)[nH]c2cc1Br)NC(=O)OCc1ccccc1
Temperature: 105 °C
Yield: 34.4 %

Procedure:
A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (1.07 g, 2.89 mmol), N-bromosuccinimide (643 mg, 3.61 mmol), and acetic acid (150 mL) was heated at 105° C. for 14 h. After cooling to room temperature, the solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (2:3), then (1:1) as eluent to afford the title compound (446 mg, 34%). The structure of the title compound was confirmed by 2D NMR. 1H-NMR (CD3COCD3, 500 MHz) δ 10.46 (s, 1H), 7.36-7.28 (m, 7H), 6.82 (d, J=8.5 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 5.00 (d, J=12.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J=14.0, 5.0 Hz, 1H), 3.10 (dd, J=14.0, 10.5 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 154.2, 143.7, 137.6, 131.1, 130.6, 128.7, 128.2, 128.0, 118.2, 113.9, 112.9, 66.2, 54.3, 52.1, 38.3; Mass spec. 448.03 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13]COC)=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COCOc1ccc(-c2cc(Cl)nn2-c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(O)cc2)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-chloro-5-[4-(methoxymethoxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazole obtained by Example 21 (2.35 g) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 36% hydrochloric acid (0.34 ml) . The reaction mixture was stirred at room temperature for 1 hr, at 50° C. for 1.5 hrs, and at 60° C. for 1.5 hrs.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C([Li])CCC.[C:23]1([CH:33]=O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[O:35]1CCCC1>>[OH:35][C:23]1([CH2:33][C:14]2[CH:15]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=[CH:5][C:6]=2[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH2:24]1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1CC1(O)CC=Cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirred solution of 4'-trifluoromethyl-2,2-dimethylpropionanilide (37 g, 0.15 mol) in anhydrous tetrahydrofuran (400 ml) cooled to 0° C. under nitrogen was added slowly a solution of n-butyllithium (160 mL of 2.5M solution in hexane, 0.4 mol). The reaction mixture was stirred at 0° C. for 2 hr, then a solution of 1-naphthaldehyde (40.7 ml, 0.3 mol) in tetrahydrofuran (50 ml) was slowly added. The resulting solution was stirred at room temperature overnight, quenched with water, diluted with ethyl acetate and separated. The aqueous phase was extracted with ethyl acetate (2×) and the combined ethyl acetate extracts were washed with water and brine, dried (anhydrous sodium sulfate) and concentrated. in vacuo to an oil (74 g). The crude product was chromatographed on 2 kg silica gel, eluting with 8:2 hexane/ethyl acetate to yield the title compound as a tan solid (31 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][OH:22])[C:9]2=[O:23])[CH:7]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[N+:44]([C:41]1[CH:40]=[CH:39][C:38]([O:37][C:35](=[O:36])[O:22][CH2:21][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])([F:24])[C:9]2=[O:23])=[CH:43][CH:42]=1)([O-:46])=[O:45]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(COC(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL round bottom flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-hydroxymethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-IV) (0.397 g, 1.02 mmol) was added 5 mL anhydrous dichloromethane, triethylamine (0.204 g, 2.04 mmol), and 4-nitrophenyl chloroformate (0.246 g, 1.22 mmol). The reaction was allowed to stir overnight at room temperature, affording carbonic acid 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-ylmethyl ester 4-nitro-phenyl ester (VIII), after which 2-aminoethanol (0.186 g, 3.05 mmol) was added and the reaction was allowed to stir for an additional 24 hours. The solvent was removed in vacuo, and the crude residue was purified by column chromatography (silica gel; 1:1 Hex:EtOAc to 4:1 EtOAc:Hex) producing 0.250 g (51%) of the title compound. 1H NMR (CDCl3 400 MHz): δ=7.78 (s,1H), 7.51 (s, 1H), 7.33 (d, 2H, J=7 Hz), 7.22 (d, 1H, J=7 Hz), 6.74 (d, 1H, J=7 Hz), 5.88 (d, 1H, J=12 Hz), 5.83 (d, 1H, J=12 Hz), 3.75 (m, 2H), 3.50 (s, 3H), 3.39 (m, 2H, J=7 Hz).
Reaction SMILES: I[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C([O-])(O)=O.[Na+].O>O1CCOCC1.CCOC(C)=O.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>[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[N:3]=2)=[CH:21][CH:20]=1)([CH3:17])[CH3:16]
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Reactant: CC(C)Oc1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nn(C3CCCCO3)cc2C=O)cc1
Yield: 90.2 %

Procedure:
To a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (8 g, 26.1 mmol) in 1,4-dioxane (240 mL) were added 4-isopropoxy phenylboronic acid (5.3 g, 27.36 mmol) and sat. NaHCO3 solution (50 mL). The reaction mixture was degassed under argon for 0.5 h. Tetrakis(triphenylphosphine)palladium (1.2 g, 1.03 mmol) was added under an argon atm. and the resultant suspension was heated for 8 h at 90° C. The reaction was poured into water (500 mL) and extracted with EtOAc (100 mL×3). The combined extracts was washed with brine (300 mL) dried and concentrated under vacuum. The residue was purified by SGC using Hex:EtOAc (0%-40%) as eluent to obtain 3-(4-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (7.4 g, Yield 90%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C:10](Br)=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:20]([NH:22][NH2:23])=[S:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N12CCCC1=NCCC2.C(OCC)(=O)C>C1C=CC=CC=1.CN(C)C=O>[CH:14]1([C:20]2[S:21][CH2:11][CH:10]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:13])[NH:23][N:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NNC(=S)C1CCCCC1
Reactant: C=C(Br)C(=O)OCc1ccccc1
Agent: C1CN=C2CCCN2C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C1CSC(C2CCCCC2)=NN1
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
A solution of 2-bromoprop-2-enoic acid benzyl ester (1.68 g) in dry benzene (10.2 ml) was added to cyclohexane carbothioic acid hydrazide (1.0 g) in dry dimethylformamide (10 ml). The mixture was cooled to 0° and stirred, under an atmosphere of nitrogen, during the gradual addition of 1,5-diazabicyclo[4.3.0]non-5-ene (0.78 g) and then for a further 20 minutes at 0°. Ethyl acetate (100 ml) was added and the mixture was washed with brine and dried over magnesium sulphate The solvent was evaporated under reduced pressure and the resulting oil purified by flash chromatography using 10% ethyl acetate/90% petroleum ether as eluent to yield the sub-title product (1.0 g) as a pink solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:13]3[N:22]=[CH:21][C:20]4[N:19]([CH3:23])[C:18](=[O:24])[C@:17]5([CH2:28][CH3:29])[CH2:25][CH2:26][CH2:27][N:16]5[C:15]=4[N:14]=3)[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C(Cl)Cl.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>[CH2:28]([C@@:17]12[CH2:25][CH2:26][CH2:27][N:16]1[C:15]1[N:14]=[C:13]([N:9]3[CH:10]=[CH:11][N:12]=[C:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)[CH:3]=3)[N:22]=[CH:21][C:20]=1[N:19]([CH3:23])[C:18]2=[O:24])[CH3:29]
Reactant: OB(O)c1cccnc1
Reactant: CC[C@@]12CCCN1c1nc(-n3ccnc3-c3cccc(Br)c3)ncc1N(C)C2=O
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: ClCCl
Solvent: O
Solvent: COCCOC
Product: CC[C@@]12CCCN1c1nc(-n3ccnc3-c3cccc(-c4cccnc4)c3)ncc1N(C)C2=O
Yield: 37.5 %

Procedure:
(S)-2-(2-(3-bromophenyl)-1H-imidazol-1-yl)-6a-ethyl-5-methyl-6a,7,8,9-tetrahydropyrrolo[2,1-h]pteridin-6(5H)-one (Example 252, 0.118 mmol, 0.053 g) was added to a solution of 3-pyridyl boronic acid (0.593 mmol, 0.072 g), Na2CO3 (0.593 mmol, 0.063 g), and Pd(PPh3)4 (0.029 mmol, 0.034 g) in 1 mL of DME and 0.5 mL of H2O. The reaction mixture was microwaved for 40 minutes at 135° C. The reaction mixture was diluted with 15 mL of DCM, washed with 5 mL of H2O, dried with Na2SO4, filtered and concentrated. The resulting residue was purified by reverse phase HPLC to give the title compound as a white solid (0.020 g, 38%); 1H NMR (400 MHz, CDCl3) δ: 9.18 (s, 1H), 8.77 (m, 1H), 8.70 (m, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.73 (s, 1H), 7.56 (m, 3H), 3.38 (m, 3H), 3.29 (m, 1H), 2.24 (m, 2H), 2.00 (m, 2H), 1.77 (m, 1H), 1.62 (m, 1H), 0.78 (t, J=7.4 Hz, 3H); LCMS: 452.3 m/z (M+H)+; ret. Time: 3.758 min (Analytical Method C).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.Cl.[NH:24]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27]>>[NH:24]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:25]([C:29]([NH:1][C@H:2]([C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1)=[O:30])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)(C)Oc1ccc(C[C@H](N)C(=O)N2CCCCC2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N1CCCCC1

Procedure:
8.52 g (25 mmoles) of H-Tyr(But)-piperidide.HCl and 6.27 g (25 mmoles) of Z-Val-OH are subjected to a condensation reaction analogously to Example 35 C. The substance crystallizes from ether. Yield 7.97 g (70%), melting point 142° C., [α]D23 =-32.8° (c=1, methanol).
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.[NH2:62][CH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:6][C:5](=[O:14])[CH2:4][CH2:3][C@H:2]([NH:1][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15](=[O:17])[NH:69][CH2:68][C:67]1[CH:70]=[CH:71][C:64]([C:63]#[N:62])=[CH:65][CH:66]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
A solution of Boc-Glu(OBzl)-OH (7.08 g, 21.0 mmol), BOP (9.72 g, 22.0 mmol) and DIEA (12.18 ml, 70.0 mmol) in DMF (50 ml) was maintained at room temperature for 20 min, followed by the addition of 4-(aminomethyl)benzonitrile hydrochloride (3.38 g, 20.0 mmol). The reaction mixture was stirred at room temperature for an additional 1 h and diluted with EtOAc (500 ml). The obtained solution was extracted with water (100 ml), 5% aq. NaHCO3 (100 ml) and water (2×100 ml). The organic layer was dried over MgSO4, evaporated and dried in vacuo to provide compound Q (9.65 g, yield exceeded quantitative) as yellowish oil. LC-MS [M+H] 452.0 (C25H29N3O5+H, calc: 452.4). Compound Q was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([OH:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([O:19][CH3:23])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(C)C(O)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCC1(C)C(OC)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
A suspension of 49 mg (0.15 mmol) of 1-tert-butoxycarbonyl-4-(4-ethyl-3-hydroxy-4-methyl-(4H)-pyrazol-5-yl)piperidine (from Step A), 50 mg (0.36 mmol) of potassium carbonate and 0.06 mL (0.96 mmol) of methyliodide in 0.3 mL of acetonitrile was stirred at rt for 17 hours and 85° C. for 7 hours. The reaction was partitioned between 25 mL of EtOAc and 25 mL of brine. After separating phases, the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 4:1 v/v of hexanes/acetone as the eluant to afford the title compound as a colorless film: RF: 0.21 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 0.65 (t, J=7.4, 3H), 1.21 (s, 3H), 1.45 (s, 9H), 1.57–1.66 (m, 2H), 1.73–1.81 (m, 4H), 2.37 (m, 1H), 2.73–2.78 (m, 2H), 3.27 (s, 3H), 4.15–4.20 (m, 2H); 13C-NMR (125 MHz) δ 54.4 (O—CH3).
Reaction SMILES: C(N(C(C)C)[P:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)C.[C:25](=[O:61])([O:57][CH2:58][CH2:59][OH:60])[O:26][CH2:27][O:28][C:29]1[C:30](=[O:56])[C:31]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])=[O:45])=[CH:32][N:33]2[C:38]=1[C:37](=[O:39])[N:36]1[C@@H:40]([CH3:43])[CH2:41][O:42][C@@H:35]1[CH2:34]2.N1C=NN=N1.C1C=C(Cl)C=C(C(OO)=[O:75])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:25](=[O:61])([O:26][CH2:27][O:28][C:29]1[C:30](=[O:56])[C:31]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])=[O:45])=[CH:32][N:33]2[C:38]=1[C:37](=[O:39])[N:36]1[C@@H:40]([CH3:43])[CH2:41][O:42][C@@H:35]1[CH2:34]2)[O:57][CH2:58][CH2:59][O:60][P:5]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:75]
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCCO)c3C(=O)N12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCCOP(=O)(OCc4ccccc4)OCc4ccccc4)c3C(=O)N12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dibenzyl N, N-diisopropyl-phosphoramidite was added to a mixture of {[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl 2-hydroxyethyl carbonate (49.4 mg, 0.094 mmol) and tetrazole (79 mg, 1.13 mmol) in dichloromethane at ambient temperature and stirred 3 hours. Additional dibenzyl N,N-diisopropyl-phosphoramidite (0.08 mL) was added and the mixture was stirred for 14 hours at ambient temperature. The reaction was cooled in an ice-water bath, and m-CPBA (130 mg, 0.755 mmol) was added carefully and the mixture was stirred for 30 minutes letting the ice-bath expire. Sodium thiosulfate solution was added, and the mixture was extracted with dichloromethane, washed with sodium bicarbonate solution and brine, and dried over sodium sulfate. Purification by silica gel chromatography afforded the title compound as a colorless residue. 1H NMR (CDCl3) δ 10.17 (m, 1H), 8.28 (s, 1H), 7.35-7.23 (m, 11H), 6.78 (m, 2H), 5.95 (d, J=6.4 Hz, 1H), 5.89 (d, J=6.4 Hz, 1H), 5.20 (dd, J=10, 3.6 Hz, 1H), 5.03-4.60 (m, 3H), 4.58 (m, 1H), 4.45-4.12 (m, 5H), 3.73 (m, 1H), 3.58 (m, 1H), 1.30 (d, J=6.4 Hz, 3H). ES+ MS: 784 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH2:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
To a solution of 1-fluoro-2-methyl-4-nitrobenzene (2.02 g, 13.0 mmol) and 4-amino-3-nitrophenol (2.22 g, 14.4 mmol) in DMF (20 mL) was added cesium carbonate (5.28 g, 16.2 mmol). After heating to 60° C. for 10 hours, the mixture was diluted with water (100 mL) and filtered. The precipitate was washed with water and air-dried to provide the product (3.28 g, 87%) as dark solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([Cl:21])(=[O:20])=[O:19].[Cl:22]C1C=CC(C(O)=O)=CC=1>>[Cl:22][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([Cl:21])(=[O:20])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(=O)(=O)Cl)c2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)Cl)c2)cc1

Procedure:
The title compound is prepared as described above for 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride, starting with 4-chloro-benzoic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[O:14][CH2:13][CH2:12][CH2:11]3)[CH2:7][CH2:6]1)=[O:4].O[Li].[OH2:20].[CH3:21][OH:22]>O>[OH:20][C:11]1([O:22][CH3:21])[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:5]3([C:3]([OH:2])=[O:4])[CH2:7][CH2:6]3)[CH:9]=2)[O:14][CH2:13][CH2:12]1
Reactant: O
Reactant: CO
Reactant: COC(=O)C1(c2ccc3c(c2)CCCO3)CC1
Agent: [Li]O
Product: COC1(O)CCOc2ccc(C3(C(=O)O)CC3)cc21
Yield: 76 %

Procedure:
To a solution of 1-chroman-6-yl-cyclopropanecarboxylic methyl ester (1.4 g, 60 mmol) in MeOH (20 mL) and water (20 mL) was added LiOH.H2O (1.0 g, 240 mmol) in portions at room temperature. The mixture was stirred overnight at room temperature before the MeOH was removed by evaporation under vacuum. Water and Et2O were added and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL×3). The combined organic extracts dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid (1.0 g, 76%). 1H NMR (400 MHz, DMSO) δ 12.10 (br s, 1 H), 6.95 (d, J=2.4 Hz, 2 H), 6.61-6.59 (m, 1 H), 4.09-4.06 (m, 2H), 2.70-2.67 (m, 2 H), 1.88-1.86 (m, 2 H), 1.37-1.35 (m, 2 H), 1.04-1.01 (m, 2H). MS (ESI) m/z (M+H+) 217.4.