Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][CH2:15][N:16]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28]C(C)(C)C)=[O:27])=[O:20])=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl.CCOCC>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:33]([N:16]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:40])[CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([OH:28])=[O:27])=[O:20])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)Cc1ccccc1
Reaction time: 16 h
Yield: 80 %

Procedure:
To a stirred solution of 200 mg (0.36 mmol) (R)-1-[3-[benzyl-[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after trituration in ether, 160 mg (80%) of the title compound as a yellow crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:26][O:25][C:19]1[CH:20]=[C:21]([O:23][CH3:24])[N:22]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(OC)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 52 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4,6-dimethoxypyrimidine, using potassium carbonate as a base. The title compound was isolated in a yield of 52%. MS ISP (m/e): 342.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.70-7.55 (m broad, 2H), 7.35-7.20 (m broad, 3H), 7.04 (s broad, 1H), 3.92 (s broad, 6H), 3.81 (s broad, 3H), 2.14 (s broad, 3H).
Reaction SMILES: CC1NC([N+]([O-])=O)=CN=1.S(OC)(OC)(=O)=O.[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH3:26].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]CC.[Na+]>C(O)C.C1C=CC=CC=1>[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ncc([N+](=O)[O-])n1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cc1ncc([N+](=O)[O-])[nH]1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCO
Solvent: c1ccccc1
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1ccccc1

Procedure:
The novel compounds coming within the scope of the generic formula, supra, are readily synthesized starting with commercially available 2-methyl-5-nitroimidazole. This starting compound is allowed to react with a suitable alkylating agent, such as dimethyl sulfate, in a suitable solvent, for example benzene, to yield the compound identified as 1,2-dimethyl-5-nitroimidazole. This latter compound is in turn allowed to react with benzaldehyde in the presence of a base, for example sodium ethoxide in absolute ethanol, to yield 1-methyl-5-nitro-2-styrylimidazole.
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[C:12]([CH:29]=[O:30])=[N:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:15]=2)=[CH:7][C:6]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>O1CCCC1>[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[C:12]([CH:29]([OH:30])[CH3:1])=[N:13][N:14]([CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)[CH:15]=2)=[CH:7][C:6]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Solvent: C1CCOC1
Product: CC(O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Over a period of 1 minute at −10° C. under nitrogen, a solution of methylmagnesium bromide (1.287 ml, 1.4M in toluene) was added portionwise to a stirred solution of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (0.44 g), dissolved in tetrahydrofuran (10 ml). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was allowed to warm to room temperature under stirring over a period of 1 hour, quenched with a saturated aqueous solution of ammonium chloride and extracted with dichloromethane (2×50 ml). The combined organic phases were washed with water (2×10 ml), dried over magnesium sulfate and concentrated to afford the crude product as a dark orange oil which solidified on standing. The product was purified by flash chromatography on silica gel eluting with 30 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(1-hydroxyethyl)pyrazol-1-yl]piperidine-1-carboxylate (0.120 g) as a solid. NMR Spectrum: (DMSOd6) 1.42 (d, 3H), 1.43 (s, 9H), 1.79 (dd, 1H), 1.85 (dd, 1H), 2.01-2.08 (m, 2H), 2.93 (bs, 2H), 4.06 (bs, 2H), 4.28-4.38 (m, 1H), 4.77-4.87 (m, 1H), 5.22 (d, 1H), 7.40-7.48 (m, 2H), 7.64 (bs, 2H), 7.77 (dd, 1H), 7.84 (dd, 1H), 8.10 (s, 1H), 8.51 (d, 1H), 8.56 (d, 1H); Mass spectrum: M+H+ 505.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)[C:43]([NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44].C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([C:37](=[O:39])[NH:41][C@@H:42]([C:43](=[O:44])[NH:45][C@@H:46]([C:54]2[O:58][N:57]=[C:56]([CH3:59])[N:55]=2)[CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:60][C:61]2[CH:70]=[CH:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:62]=2)[CH2:35][CH2:36]1)=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 87.7 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.92 g, 4.82 mmol) and 1-hydroxybenzotriazole monohydrate (0.74 g, 4.83 mmol) were added to a solution of N-tertbutoxycarbonyl-4-piperidine carboxylic acid (1.10 g, 4.80 mmol) in N,N-dimethylformamide (15 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride (1.50 g, 3.43 mmol) and triethylamine (0.35 g, 3.46 mmol) in N,N-dimethylformamide (15 ml) were added. After 18 h at 20° C. the reaction mixture was poured on ice water (180 ml) and extracted several times with ethyl acetate (total 180 ml). The organic phases were collected and washed with aqueous citric acid (10%, 25 ml), a saturated solution of sodium hydrogencarbonate (3×25 ml) and water (3×25 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from ethyl acetate to give 1.84 g of 4-{(1R)-1-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl}piperidine-1-carboxylic acid tertbutyl ester.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:7]=[CH:6][N:5]=1.[SH:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1>C(O)C.[OH-].[Na+]>[Cl:15][CH2:14][CH2:13][CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[C:9]=1[CH3:10]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCCl)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
One equivalent of 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride (dissolved in 10 ml of water) is added dropwise at 40° C. in the course of 20 min. to a solution of 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 40 ml of ethanol and 21 ml of 1 N sodium hydroxide solution. The mixture is then stirred for 2-3 h at 50-60° C. and a further 3-4 h at room temperature, ethanol is distilled off on a rotary evaporator (1 kPa/40° C.), the residue is extracted 3 times with 20 ml of dichloromethane each time, and the extracts are washed with 0.1 N sodium hydroxide solution, dried over potassium carbonate and concentrated completely in vacuo. For purification, the crude product is chromatographed on silica gel (dichloromethane/methanol 20:1); the collected pure fractions are jointly concentrated in vacuo and the residue is crystallized from dichloromethane/diisopropyl ether. It is then recrystallized from methanol/toluene. Yield 2.67 g (74%) of the title compound as a colorless solid of m.p. 112-114° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]2[C:9]=1[C:10](=[O:28])[N:11]([CH2:19][C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:12]2=[O:18])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]2[C:9]=1[C:10](=[O:28])[N:11]([CH2:19][C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:12]2=[O:18]
Reactant: C[C@H](CN1C(=O)c2cc(Br)cc(NC(=O)OC(C)(C)C)c2C1=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](CN1C(=O)c2cc(Br)cc(N)c2C1=O)c1ccccc1
Yield: 87.5 %

Procedure:
(S)-[6-Bromo-1,3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-carbamic acid tert-butyl ester (160 mg, 0.35 mmol) was stirred in a mixture of DCM (2 mL) and TFA (1 mL) for 3 h at rt. The mixture was concentrated, and the residue was diluted with satd. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give a yellow oil. Purification by flash chromatography (EtOAc/hexanes) gave 110 mg (87%) of the desired amine as a yellow foam. 1H NMR (500 MHz, CDCl3): 7.31-7.23 (m, 4H), 7.22-7.17 (m, 2H), 6.81 (d, J=1.5, 1H), 5.19 (br s, 2H), 3.78 (dd, J=13.6, 7.6, 1H), 3.71 (dd, J=13.6, 8.2, 1H), 3.30 (app sextet, Japp=7.5, 1H), 1.29 (d, J=7.0, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH:14]2[C:28]([O:30][CH3:31])=[O:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+].CCN(CC)CC.[Cl:49][C:50]1[CH:58]=[CH:57][C:53]([C:54](Cl)=[O:55])=[CH:52][CH:51]=1>CO>[Cl:49][C:50]1[CH:58]=[CH:57][C:53]([C:54]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([S:10]([N:13]3[CH2:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH:14]3[C:28]([O:30][CH3:31])=[O:29])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:55])=[CH:52][CH:51]=1
Reactant: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
The compound of Example 56 (0.55 g, 1.2 mmol) was put into 10 mL of a MeOH solution to which SnCl2.2H2O (1.1 g, 4.8 mmol) was added, and stirred for 1 hour while maintaining the temperature at 50° C. A saturated NaHCO3 aqueous solution was introduced and the mixture was stirred for 1 hour, and then it was extracted with ethyl acetate. After distillation under reduced pressure and vacuum drying, the mixture was dissolved in 20 mL of dichloromethane and Et3N (0.41 mL, 2.9 mmol), and 4-chlorobenzoyl chloride (0.31 mL, 2.4 mmol) was added while maintaining the temperature at 0° C. After reaction for 6 hours, the reactant was washed with a saturated NaHCO3 aqueous solution and a 1N HCl aqueous solution, and dried and concentrated under reduced pressure. It was then recrystallized with hexane and ethyl acetate to obtain a white solid (0.62 g, 91%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@H:8]([CH2:9][CH2:10][CH:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)[NH2:12])[CH2:7][CH2:6][NH:5][CH2:4]1)=[CH2:2]>C(O)C.[Pd]>[CH2:1]([C@@H:3]1[C@H:8]([CH2:9][CH2:10][CH:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)[NH2:12])[CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:2]
Reactant: C=C[C@H]1CNCC[C@H]1CCC(N)c1ccnc2ccc(OC)cc12
Agent: [Pd]
Solvent: CCO
Product: CC[C@H]1CNCC[C@H]1CCC(N)c1ccnc2ccc(OC)cc12
Reaction time: 2 h

Procedure:
3-[3(R)-ethenyl-4(R)-piperidyl]-1-(6-methoxy-4 quinolyl)-1(RS)-propanamine (1.2 g) dissolved in absolute ethanol (25 ml) is hydrogenated at atmospheric pressure and at room temperature in the presence of palladium (0.25 g, 10% on carbon). The absorption of hydrogen is complete in 2 hours. The catalyst is filtered off, the solvent is evaporated under reduced pressure, and the residue is recrystallised from isopropanol. 3-[3(R)-Ethyl-4(R)-piperidyl]-1-(6-methoxy-4 quinolyl)-1(RS)-propanamine is thus obtained as the trihydrochloride, m.p. 200° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[NH:5][C:4]=1[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[NH2:1][C:8]([C:6]1[NH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:3]([Cl:2])[CH:7]=1)=[O:9]
Reactant: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(C(N)=O)cc1Cl
Yield: 51.1 %

Procedure:
Ammonia (5.8 mL, 2.9 mmol) was added to a solution of methyl 3-chloro-5-(chlorocarbonyl)-1H-pyrrole-2-carboxylate (0.15 g, 0.58 mmol) in THF and the resulting solution stirred until no starting material was evident by TLC. The solvent was evaporated and purification was accomplished by silica gel column chromatography (30 to 100% EtOAc/hexanes) to afford the title compound (0.060 g, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H), 7.82 (br. s., 1H), 7.47 (br. s., 1H), 6.80 (s, 1H), 3.77 (s, 3H). LCMS: m/z 201.4 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CC(C)COC(=O)Cl
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OCC(C)C)C2=O)cc1

Procedure:
The title compound 26c was prepared from compound 76 (70 mg, 0.17 mmol), isobutyl chloroformate (25 μL, 0.19 mmol) and DIPEA (75 μL, 0.43 mmol) in a manner similar to that described for 25a in 96.4% (65 mg) yield as a light-yellow solid.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1>CCOC(C)=O.[Pd]>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3oc4ccccc4c3c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc3oc4ccccc4c3c2)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(dibenzofuran-2-yloxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[CH3:15][O:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)cc1
Yield: 93 %

Procedure:
To a solution of p-toluic acid (175 g, 1.28 mol) in methanol (2 L) was added dropwise thionylchloride (612 g, 5.14 mol) under stiring at 5° C. The mixture was refluxed overnight, then the solvent evaporated. The residue obtained was treated with a 10% aqueous NaHCO3 solution (pH˜8) The product was extracted with ethyl acetate, washed-with water and dried. The solvent was removed and the crude was purified by column chromatography (pet ether/ethyl acetate) to give methyl-p-toluate as colorless liquid (180 g, 93%).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH2:8][N:7]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:6]2[CH2:5]1)([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:14][C:12]1[CH:13]=[C:6]2[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:9](=[O:10])[CH2:8][N:7]2[N:11]=1
Reactant: [H][H]
Reactant: CC(C)N1Cc2cc([N+](=O)[O-])nn2CC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1Cc2cc(N)nn2CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 151d (220 mg, 1.0 mmol) in ethanol (20 mL) was added Pd/C (10%, 22 mg). The reaction mixture was charged with hydrogen gas (via balloon) and stirred at room temperature for 1 h. The reaction mixture was filtered through a plug of CELITE® and the filtrate was concentrated under reduced pressure to afford 151e as a yellow solid (180 mg, 92%), which was used without further purification. MS-ESI: [M+H]+ 195.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:16]=[CH:15][C:14]=1[C:25]([NH:27][CH2:28][C:29]([CH2:35][NH2:36])([OH:34])[C:30]([F:33])([F:32])[F:31])=[O:26].C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[NH2:12][C:13]1[N:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[N:16]=[CH:15][C:14]=1[C:25]([NH:27][CH2:28][C:29]([CH2:35][NH:36][C:4]([C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:5])([OH:34])[C:30]([F:33])([F:32])[F:31])=[O:26]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(F)cccc2Cl)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A solution of 2-chloro-6-fluorobenzoyl chloride (0.169 g) in dry tetrahydrofuran (1 ml) was added to a stirred mixture of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.289 g) and diisopropylethylamine (0.21 ml) in a mixture of dichloromethane (4 ml) and tetrahydrofuran (3 ml) cooled to <5° C. After the addition, the cooling bath was removed and the reaction mixture stirred at room temperature for 20 minutes. Water (10 ml) and dichloromethane (10 ml) were added to the reaction mixture and the resultant mixture stirred vigorously. The phases were separated using a hydrophobic frit and the aqueous phase washed with additional dichloromethane (10 ml). The organic phase was evaporated and the residue purified by chromatography on silica (20 g cartridge) eluting with 0-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated to give the title compound (0.409 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1(C)C=CC=C[C:12]=1[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH3:12])=[CH:18][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1ccccc1-c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
2-chloro-3-nitropyridine (100 mg, 0.63 mmol) was dissolved in dioxane (4 mL) in a round bottom flask to which p-tolylaniline (68 mg, 0.63 mmol) was added followed by addition of diisopropylethylamine (0.22 mL). The reaction mixture was heated to 80° C. for 24 hours and stopped when complete as observed by LCMS. After cooling to room temperature, the solvent was removed under reduced pressure to afford an oily residue. The residue was dissolved in ethyl acetate (20 mL) and washed with water and brine (5 mL each respectively). The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product was carried on to the next step without further purification. LCMS [M+H]: 230.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[OH:3][CH2:4][C@H:6]1[C@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1
Reactant: CCOC(=O)[C@@H]1OCC=C[C@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC[C@@H]1OCC=C[C@H]1O
Reaction time: 0.5 h

Procedure:
To a stirred solution of trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (0.480 g, 2.79 mmol) in THF (20 ml) at RT, was added in portions LiAlH4 (0.126 g, 3.384 mmol) and the resulting mixture was stirred for 30 min. EtOAc (10 ml) was added, the mixture was stirred for 10 min and extracted with water (10 ml×2). The organic layer was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product purified by flash chromatography (25-30% EtOAc in hexane).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]([F:20])([F:19])[CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>CC(C)=O>[Br:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]([F:19])([F:20])[CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)=[CH:5][CH:4]=1
Reactant: FC(F)(Oc1ccc(Br)cc1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(C(F)(F)Oc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4 N HCl (4.23 mL, 16.9 mmoles) was added to a solution of 8-((4-bromophenoxy)difluoromethyl)-1,4-dioxaspiro[4.5]decane (1230 mg, 3.387 mmoles) in acetone (11.3 mL, 0.3M) and was allowed to stir overnight at room temperature. The reaction mixture was concentrated onto silica gel and purified via chromatography (9:1 heptane:ethyl acetate to 3:7 heptane:EtOAc over 40 minutes followed by 100% EtOAc for 10 minutes) afforded the desired material (1081 mg, 97.13%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.27 (br. s., 2H) 1.39-1.51 (m, 2H) 1.96-2.10 (m, 5H) 3.32-3.38 (m, OH) 3.47-3.55 (m, 1H) 7.05-7.13 (m, 2H) 7.45-7.53 (m, 2H)