Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[Si:29]([O:36][CH2:37][C:38]([CH3:50])([CH3:49])[O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Si:29]([O:36][CH2:37][C:38]([CH3:50])([CH3:49])[O:39][C:40]1[CH:41]=[CH:42][C:43]([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=2[CH2:27][CH3:28])=[CH:44][CH:45]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 113.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.6 g), [4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronic acid (0.84 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution (6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.99 g, 85%).
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([O:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>O1CCCC1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:28][CH:29]=1
Reactant: CC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(OC(=O)c2ccc(O)cc2)cc1

Procedure:
Subsequently, a 100 ml four-necked flask equipped with a condenser tube and a thermometer was charged with 15.6 g of benzyl p-(p-acetoxybenzoyloxy)benzoate, 30 g of 5% sodium hydroxide and 50 ml of tetrahydrofuran, and they were reacted at 30° C. for 5 hours. The reaction product was extracted with 50 ml of toluene. The extract was washed with water, and toluene was evaporated. The residue was separated on a column to give benzyl p-(p-hydroxybenzoyloxy)benzoate as white crystals having a melting point of 137° to 138.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Li]CCCC.[Br:20]C(F)(F)C(Br)(F)F>C1COCC1>[Br:20][C:7]1[CH:6]=[C:5]([C:4]#[C:3][C:2]([CH3:14])([CH3:13])[CH3:1])[S:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)C#Cc1ccc(C(=O)O)s1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(Br)c(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a of solution of 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (6.5 g, 31.3 mmol, 1.0 equiv) in THF (150 mL) at −78° C. was added n-BuLi (44.9 mL, 1.6 M in heptane, 71.9 mmol, 2.3 equiv) and the resulting solution was stirred at −78° C. for 1 hour. To the solution was then added 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (16.2 g, 62.5 mmol, 2.0 equiv) and the solution was allowed to warm to room temperature over 2 hours. The reaction was quenched by addition of sat. aq. NH4Cl solution and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was continued to the next step with no further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([CH3:12])=[CH:8][C:9]([O-:11])=[O:10].[CH2:13]1COCC1>[Pd]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([CH3:12])[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: CC(=CC(=O)[O-])c1cnccn1
Reactant: C1CCOC1
Agent: [Pd]
Product: COC(=O)CC(C)c1cnccn1
Yield: 98 %

Procedure:
A solution of 11e (2.50 g, 14.03 mmol) in 50 mL dry THF was treated with 10% Pd-C (125.0 mg, 5 wt %) at room temperature under a hydrogen atmosphere (balloon) (30 min). The reaction mixture was then filtered through a Celite plug, washed with EtOAc (150 mL), and concentrated in vacuo. SGC chromatotron (SiO2, 4 mm, 20-50% EtOAc/hexanes) afforded 12e (2.48 g, 2.53 g theoretical, 98%). For 12e: 1H NMR (CDCl3, 250 MHz) d 8.42 (d, 1H, J=1.5 Hz, Pyr C3-H), 8.38 (dd, 1H, J=1.5, 2.5 Hz, Pyr C5-H), 8.31 (d, 1H, J=2.5 Hz, Pyr C6-H), 3.51 (s, 3H, OCH3), 3.39 (m, 1H, J=6.5, 7.0, 8.1 Hz, ArCH), 2.80 (dd, 1H, J=8.1, 16.1 Hz, CHH), 2.54 (dd, 1H, J=6.5, 16.1 Hz, CHH), 1.24 (d, 3H, J=7.0 Hz, CH3); 13C NMR (CDCl3, 125 MHz) d 172.3, 159.6, 143.9, 143.8, 142.4, 51.4, 39.7, 35.2, 20.4; IR (neat) nmax 2978, 2935, 1737, 1473, 1406, 1371, 1280, 1180, 1034, 1015, 849, 769 cm-1. See FIG. 18d.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14]>[Zn].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]2[OH:14]
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1NC(O)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g, 0.08 mmol) and 2M aq NaOH (27 mL) were cooled to 0° C. 5-Bro moisoindoline-1,3-dione (5 g, 22 mmol) was added at the same temperature over the period of 30 min. The reaction mixture was stirred at 0° C. for 30 min and 3 h at ambient temperature. The reaction mixture was filtered and the filtrate was neutralized with concentrated HCl. The reaction mixture was diluted with ethanol and extracted with ethyl acetate. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a brown solid, which was used in the next step without further purification (1.3 g): mp 258-261° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m, 1H), 6.44 (m, 1H), 5.88 (d, J=9.3 Hz, 1H); ESIMS m/z 225.83 ([M−H]−); IR (thin film) 1684, 3246, 606 cm−1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>CCOCC>[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:13])=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCOCC
Product: O=C(c1ccc(I)cc1)N1CCOCC1

Procedure:
A solution of 15 ml of morpholine in 20 ml of ether was reacted with a solution of 5.4 g p-iodobenzoyl chloride in 20 ml ether. The excess organic solvent was removed and the crude product recovered as described in Example 3. After recrystallization there was obtained 3.1 g of N-p-iodobenzoyl-morpholine as translucent crystals, m.p. 116°-117°, Rf 0.72.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1)=O)(C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67].Cl>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]1.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4cccnc4)ccc32)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(-c2ccc3c(c2)Oc2ccccc2N3C2CCNCC2)c1

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 4-(3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 3i, for 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a, and a mixture of TFA in methylene chloride for a 4N hydrochloric acid solution, the title compound 10-piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i was obtained as a TFA salt after purification via reverse phase HPLC (eluent gradient: CH3CN in water containing 0.1% TFA). MS m/z (MH+) 344.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:15])[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7]2.[OH-:16].[Na+]>CC#N.O>[CH3:15][N:4]1[C:3]([CH2:2][OH:16])=[C:11]2[C:6]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:10]2)=[N:5]1
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1CBr
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1nc2cc([N+](=O)[O-])ccc2c1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
3-(Bromomethyl)-2-methyl-6-nitro-2H-indazole (4.20 g, ˜14.9 mmol) in CH3CN (500 ml) and water (200 ml) was treated with NaOH to give pH˜11. The solution was stirred at rt for 2 days then conc. in vacuo and repeatedly extracted with dichloromethane and chloroform. The combined organic extracts were evaporated, and the crude product was purified by silica gel column chromatography to give (2-methyl-6-nitro-2H-indazol-3-yl)methanol (1.03 g, 33% TY). MS (ES+, m/z) 208.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[C:19](Cl)[N:18]=[C:17]([Cl:22])[CH:16]=3)[C:11]2=[O:23])[CH2:3][CH2:2]1.[CH:24]1(B(O)O)[CH2:26][CH2:25]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.C1(C)C=CC=CC=1>[Cl:22][C:17]1[CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:23])[CH:20]=[C:19]([CH:24]2[CH2:26][CH2:25]2)[N:18]=1
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)CCN1c1cnccc1C1CC1
Reactant: OB(O)C1CC1
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
Product: O=C1N(c2cc(Cl)nc(C3CC3)c2)CCN1c1cnccc1C1CC1
Yield: 19.7 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropyl pyridin-3-yl)-3-(2,6-dichloropyridin-4-yl)imidazolidin-2-one (I-46a: 100 mg, 0.2865 mmol) was reacted with cyclopropyl boronic acid (74 mg, 0.8593 mmol), Pd(PPh3)4 (7 mg, 0.0057 mmol), sodium carbonate (69 g, 0.6590 mmol) and toluene (5 mL) in seal tube at 120° C. for 12 hours. Purification by column chromatography on silica gel (1% methanol in chloroform), followed by preparative HPLC afforded 20 mg of the product (20% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](OC)=[CH2:4].[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH3:32])[CH:27]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:26]2=[O:44])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH:32]=[C:3]([N:2]([CH3:7])[CH3:1])[CH3:4])[CH:27]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:26]2=[O:44])=[O:23])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2SC1
Reactant: C=C(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2SC1)N(C)C
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-dimethylamino-1-methoxyethylene (1.62 g) in dimethylformamide (3 cc) is added, in the course of 45 minutes, to a solution of 2-benzhydryloxycarbonyl-3-methyl-7-phenoxyacetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.06 g) in dimethylformamide (15 cc) at 80° C. The mixture is then stirred for 10 minutes at 80° C. This yields a solution of 2-benzhydryloxycarbonyl-7-phenoxyacetamido-3-(2-dimethylaminoprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, which is poured into a stirred mixture of ethyl acetate (100 cc), distilled water (50 cc) and 1N citric acid (50 cc) at 0° C. The organic phase is separated off by decantation, washed with distilled water (2×100 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 30° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (20 g) (diameter of the column: 2 cm; height: 16 cm). Elution is carried out with a 28/72 (by volume) ethyl acetate/cyclohexane mixture (600 cc), 30 cc fractions being collected. Fractions 7 to 16 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields 3-acetonyl-2-benzhydryloxycarbonyl-7-phenoxyacetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.53 g) in the form of a hard yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br.Br[CH2:20][CH2:21][CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Yield: 63.6 %

Procedure:
A mixture of 4-ethoxycarbonyl-4-phenylpiperidine (30.5 g, 0.131 mol), 3-bromopropylamine hydrobromide (42.93 g, 0.196 mol), potassium carbonate (36.14 g, 0.241 mole), and KI (10.8 g, 0.065 mol) in 1,4-dioxane (500 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6N NaOH (400 mL) and extracted with CH2Cl2 (4×120 mL). Solvent was evaporated from the combined dried (K2CO3) CH2Cl2 extracts and the residue was purified by column chromatography on silica gel using CHCl3 /MeOH/2M NH3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (24.2 g, 83.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28](O)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[CH2:41][C@H:40]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[C:48]([O:47][C:46]([NH:45][C@H:40]1[CH2:41][C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:29])[CH2:39]1)=[O:52])([CH3:49])([CH3:50])[CH3:51]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (0.014 g, 0.034 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.041 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (0.14 mL) and DIPEA (0.018 mL, 0.10 mmol) was stirred at room temperature for 2 h. The mixture was diluted with 5 mL of EtOAc and 3 mL of 1 M NaOH. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel column, eluting with 0-30% MeOH in EtOAc, to yield an amide intermediate, benzyl (2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-morpholin-4-ylquinolin-3-yl)carbamate. LCMS calc. for C38H46N7O6 [M+H]+: m/z=696.3. found: 696.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CN1C(=O)CCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.Br[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45][CH:46]([CH3:50])[CH2:47][O:48][CH3:49])[CH:44]=1)[C:40]#[N:41]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45][CH:46]([CH3:50])[CH2:47][O:48][CH3:49])[CH:44]=1)[C:40]#[N:41]
Reactant: COCC(C)Oc1cc(Br)cc(C#N)c1
Reactant: Oc1cc(F)cc(F)c1
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCC(C)Oc1cc(C#N)cc(Oc2cc(F)cc(F)c2)c1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
3,5-Difluorophenol (2.00 equiv; 51.8 mmol; 6.74 g) was charged to a 100 ml round-bottomed flask (3 necks, 2 stoppers, air condenser with argon inlet, magnetically stirred, oven dried) followed by NMP (471 mmol; 45.3 ml; 46.7 g) and cesium carbonate (51.8 mmol; 16.9 g). The mixture was sparged with argon for 10 minutes then cuprous monochloride (6.48 mmol; 641 mg), 2,2,6,6-tetramethyl-3,5-heptanedione, (1.30 mmol; 271 μl; 239 mg) and 3-bromo-5-(2-methoxy-1-methylethoxy)benzonitrile (1.00 equiv; 25.9 mmol; 7.00 g) were charged sequentially. The mixture was sparged with argon for 5 minutes then heated to 120° C. and stirred for 24 hours. The reaction mixture was cooled and partitioned between HCl solution (1M, aqueous, 200 ml) and MTBE (200 ml). The layers were separated and the organic portion washed with NaOH solution (1M, aq, 200 ml), water (200 ml) and brine (200 ml). The resultant organic solution was dried over MgSO4, filtered and the solvent removed in vacuo affording a brown oil. This material was purified by flash column chromatography affording 3-(3,5-difluorophenoxy)-5-(2-methoxy-1-methylethoxy)benzonitrile as a pale yellow oil (5.17 g, 63%). 1H NMR (400 MHz, CDCl3) δ: 7.01 (s, 1H), 6.86 (m, 2H), 6.62 (m, 1H), 6.53 (m, 2H), 4.54 (m, 1H), 3.53 (m, 2H), 3.39 (s, 3H), 1.32 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[C:7]=1[N+:22]([O-])=O)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[C:7]=1[NH2:22])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cccc(Nc2cccc(N)c2)c1N
Reaction time: 20 h

Procedure:
To a solution of [2-nitro-3-(3-nitro-phenylamino)-phenyl]-acetic acid ethyl ester (0.62 g, 1.8 mmol) in ethanol (50 ml) is added Pd/C (10%, wet, 0.50 g). It is placed under a hydrogen balloon and stirred for 20 hours. The catalyst is filtered and the solvent is removed to give the desired compound: LC-MS: 286.1 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([C:31]=3[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=4[O:33][CH3:34])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C[O:36][C:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)=[O:38].O[Li].O>>[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][C:23]([C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:45]([C@H:42]4[CH2:41][CH2:40][C@H:39]([C:37]([OH:38])=[O:36])[CH2:44][CH2:43]4)=[O:46])[CH2:13][CH2:12]3)=[CH:15][CH:16]=1)=[O:22])=[C:31]2[CH3:32]
Reactant: COc1cccc2c(C)c(C(=O)Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Li]O
Solvent: O
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(C4CCN(C(=O)[C@H]5CC[C@H](C(=O)O)CC5)CC4)cc3)[nH]c12

Procedure:
With a procedure similar to the example above, trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester and trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester, followed by a standard LiOH—H2O saponification procedure to remove the methyl ester. LCMS calcd for C30H35N3O5 (m/e) 517, obsd 518 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:13]([O-])=[CH:12][C:11]=2[N:10]=[CH:9]1)[CH3:7])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O>ClCCl>[C:1]([O:4][CH2:5][CH:6]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([Cl:24])[C:11]=2[N:10]=[CH:9]1)[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)n1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OCC(C)n1cnc2c(Cl)nc3ccccc3c21

Procedure:
To a stirred mixture of 10.2 g (0.036 mole) of 1-(2-acetoxy-1-methylethyl)-1H-imidazo[4,5-c]quinolin-5-oxide (prepared according to the method of Example 8) in 100 mL of dichloromethane was added in portions, 4.2 mL, 6.9 g (0.45 mole) of phosphorus oxychloride. After 4 hours the mixture was evaporated in vacuo. The residue was added to a saturated sodium bicarbonate solution, and that solution was extracted with chloroform. The chloroform layer was washed with both saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo to yield light brown solid 1-(2-acetoxy-1-methylethyl)-4-chloro-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[S:21][C:22]([NH:30]C(=O)OC(C)(C)C)=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]=2[CH:11]=[CH:10]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:30][C:22]1[S:21][C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:8])[CH:10]=[CH:11][C:12]=2[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of the compound of Example 80 (170 mg, 0.406 mmol) in DCM (2 mL) and the reaction mixture stirred for 2 h at r.t. The mixture was added to saturated NaHCO3(aq) (20 mL) and the product extracted with DCM (2×20 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (EtOAc), followed by radial chromatography (20% EtOH in DCM) to give the title compound as a buff solid (30 mg, 23%). δH (CDCl3) 7.8–7.3 (13H, m), 6.58 (1H, d, J 9 Hz). m/z (ES+) 319 (M+H)+.