Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-])=O)[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O.NN.CCOC(C)=O>[Ni].CO>[NH2:23][C:18]1[N:17]=[C:16]([C:15]([NH:14][C@@H:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:10])[F:11])=[C:2]([F:1])[CH:3]=2)[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1O
Temperature: 56 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of Raney Nickel (0.2 g, Monarch, India) in MeOH (10 mL), was added (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxy-6-nitropicolinamide (200 mg, 0.0004252 mol) at room temperature. The temperature was raised to 56° C. and hydrazine hydrate (0.2 mL, Spectrochem, India) was added very slowly over 5 min (exothermic reaction). The reaction mixture was then stirred for 10 min at the same temperature. After completion of the reaction, monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether, uv active), the mixture was cooled to room temperature, filtered through Celite® brand filter agent and concentrated under high vacuum to remove excess hydrazine hydrate. The resulting product was triturated with petroleum ether to give the title compound as a grey solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.23 (d, J=8 Hz, 1H), 8.57 (d, J=4.4 Hz, 1H), 7.87 (t, J=8.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.47 (d, J=11.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 5.53 (br. s., 2H). MS (ESI, positive ion) m/z: 441 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][N:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.Cl.CN(C)CCCN=C=NCC.[CH2:26]([N:28]([CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[N:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:27].[Na+].[Cl-].C(=O)([O-])[O-].[Na+].[Na+]>CN(C1C=CN=CC=1)C.ClCCl.CN(C=O)C>[CH2:40]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[N:38]=[CH:37][C:36]([NH:39][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][N:5]=2)=[O:13])=[CH:35][CH:34]=1)[CH3:41]
Reactant: CCN(CC)CCCOc1ccc(N)cn1
Reactant: O=C(O)c1n[nH]c2c1C(=O)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc(NC(=O)c2n[nH]c3c2C(=O)CCC3)cn1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (2.25 g, 12 mmol), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (2.87 g, 15 mmol), DMAP (1.83 g, 15 mmol), and DMF (10 mL) in dichloromethane (40 mL) is stirred under nitrogen at 20° C. for 2 hours. 6-(3-Diethylamino-propoxy)-pyridin-3-ylamine (2.50 g, 11.2 mmol) is added. The mixture is stirred under nitrogen at 40° C. for 24 hours; and then poured into 10% NaCl, treated with 1 M sodium carbonate to pH 10, and extracted with chloroform (100 mL). The solution is concentrated, diluted with xylenes (100 mL), and the volatiles are thoroughly evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of chloroform-methanol-30% ammonium hydroxide (90:9:1, v/v/v) as an eluent and the residue is recrystallized from ethyl acetate to give pure 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [6-(3-diethylamino-propoxy)-pyridin-3-yl]-amide. 1H NMR (CD3OD) t, J=7.1 Hz, 6H), 1.97 (m, 2H), 2.25 (quintet, J=6.3 Hz, 2H), 2.62 (q, J=7.1 Hz, 4H), 2.71 (m, 4H), 2.99 (t, J=6.3 Hz, 2H), 4.03 (t, J=6.3 Hz, 2H), 6.81 (dd, J=8.9 and 0.5 Hz, 1H), 8.12 (dd, J=8.9 and 2.7 Hz, 1H), 8.56 (dd, J=2.7 and 0.5 Hz, 1H). MW 385.471; MS (M−H)− 384.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].[CH3:32][NH:33][NH2:34]>C(O)C>[CH3:32][N:33]1[C:2]2=[CH:3][N:4]=[CH:5][C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:31])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:14][CH2:13]4)=[C:7]2[C:8]([NH2:9])=[N:34]1
Reactant: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(N)c2c(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)cncc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (80 mg, 0.181 mmol) was added Methyl hydrazine (0.286 mL, 5.43 mmol) to a 5 mL sealable vial with Ethanol (3 mL). The reaction was then capped and heated at 100° C. overnight. Observed incomplete conversion. Additional Methyl hydrazine (0.286 mL, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated, dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 17% ACN/H2O, 0.1% TFA to 42% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and the mixture was extracted with EtOAc (3×15 mL). The organics were combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 1-methyl-4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine (34 mg, 41.6% yield) as a light yellow solid. LC/MS (ES) m/z=452.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.56-7.66 (m, 3H), 7.43 (s, 1H), 7.32 (d, J=8.08 Hz, 1H), 4.67 (br. s., 2H), 4.30 (t, J=8.46 Hz, 2H), 4.05 (s, 2H), 3.92 (s, 3H), 3.29 (t, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[C:3]1=[O:16].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:48][C:49]1[CH:54]=[C:53]([Cl:55])[CH:52]=[CH:51][C:50]=1[CH2:56][NH2:57]>ClCCl>[Cl:48][C:49]1[CH:54]=[C:53]([Cl:55])[CH:52]=[CH:51][C:50]=1[CH2:56][NH:57][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[C:3](=[O:16])[N:2]1[CH3:1])=[O:9]
Reactant: CN1C(=O)N(c2cncn2C)CC1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(c2cncn2C)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
A solution of 3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxylic acid (155 mg, 0.458 mmol) and N-ethylmorpholine (0.348 ml, 2.75 mmol) in dichloromethane (5 ml) was treated with 1-hydroxybenzotriazole hydrate (84 mg, 0.550 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.458 mmol) and stirred at room temperature for 10 minutes. 1-(2,4-Dichlorophenyl)methanamine (81 mg, 0.458 mmol) was then added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine, separated through a hydrophobic frit and the organic layer reduced under vacuum. The residue was purified by mass-directed automated HPLC to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-1-(1-methyl-1H-imidazol-5-yl)-2-oxo-4-imidazolidinecarboxamide (63 mg, 34.2% yield). LC/MS [M+H]+=382, retention time=1.71 minutes.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:26]#[C:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Br)c2C1=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccccc3)ncn2-c2cccc(Br)c2C1=O

Procedure:
4.18 g (10 mmol) of 7-bromo-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 2 hours with 1.12 g (11 mmol) of phenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The solvent was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-bromo-4,5-dihydro-5-methyl-3-(phenylethynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 207°-209°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[Cl:12][O-].[Na+]>Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Cl:12])=[N:6][CH:5]=1
Reactant: [O-]Cl
Reactant: COC(=O)c1cncc(O)c1
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1cnc(Cl)c(O)c1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a flask containing methyl-5-hydroxynicotinate (4.5 g, 29 mmol) was added sodium hypochlorite aqueous solution (6.15%, 26.7 mL, 22 mmol) dropwise under ice bath cooling. After 30 min of stirring, 2 M HCl (20 mL) was added and the resulting white crystals collected by filtration to give 2.31 g of 6-chloro-5-hydroxynicotinic acid methyl ester in 42% yield. 1H NMR (400 MHz, CDCl3) δ 10.32 (bs, 1H), 8.48 (d, 1H), 7.84 (d, 1H), 7.40 (s, 1H), 3.93 (s. 3H); LC-MS (ELSD): mass calcd for C7H6ClNO3 [M]+ 187. Found 187.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[I:16]([O-])(=O)=O.[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[I:16][C:5]1[C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:15]
Reactant: [O-][I+2]([O-])[O-]
Reactant: COc1cnc(C2CCOCC2)cc1N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: COc1cnc(C2CCOCC2)c(I)c1N
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a stirred solution of 590 mg (2.66 mmol) 5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine in 3 ml 65% aqueous sulfuric acid heated to 100° C. was added 728 mg (3.40 mmol) potassium iodate and stirring continued for 2 h at 100° C. The mixture was then cooled in an ice-bath before being made basic by addition of 5 N aqueous sodium hydroxide solution. The mixture was extracted three times with tetrahydrofuran and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane/triethylamine) afforded 516 mg (58%) 3-iodo-5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine as a yellow crystalline solid. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:19]1([O:25][C:26]([N:5]2[C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=[C:4]2[C:8]([F:11])([F:10])[F:9])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1nc(Cl)c(Cl)[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Oc1ccccc1)n1c(C(F)(F)F)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
20.5 g (0.1 mol) of 4,5-dichloro-2-trifluoromethyl-imidazole were dissolved in 150 ml of dioxane. 10.1 g (0.1 mol) of triethylamine were added thereto and 16.05 g (0.1 mol) of chloroformic acid phenyl ester were then added dropwise whilst cooling at 10°-15° C. The mixture was stirred for a further 2 hours at room temperature, the triethylamine hydrochloride which had separated out was filtered off and the filtrate was evaporated in vacuo. The oily residue was distilled. The main fraction boiled at 106.5°-107° C./0.08 mm Hg. 28.6 g (88% of theory) of 4,5-dichloro-2-trifluoromethyl-imidazole-1-carboxylic acid phenyl ester were obtained.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C(=O)CCCCCCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl>[C:17]1([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCCCCCC(=O)N(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1ccc(Nc2ccccc2)cc1
Temperature: 100 °C
Yield: 94.6 %

Procedure:
0.01 mmol of the complex 1 produced in Example 1 and 5 mmol of N,N-diphenyloctanamide were placed in a 50 mL-autoclave equipped with a stirrer, and the autoclave was purged with nitrogen. 1.5 mL of methanol and 2.5 mL of methanol solution of 2.0 M sodium methoxide were added to the autoclave, and the autoclave was purged with hydrogen. The resulting mixture was stirred under hydrogen atmosphere (5 MPa) and 100 degrees C. for 16 hours to obtain a reaction solution. After the completion of reaction, the reaction solution was cooled, diluted with 40 mL of dichloromethane, and subjected to silica gel filtration (eluting solvent: dichloromethane/methanol=10/1). The thus obtained solution was concentrated, and then the resulting residue was purified by silica gel column chromatography (silica gel: 40 g, hexane/ethyl acetate=8/1 to 4/1). As a result, 1-octanol (500 mg, 77%) and N,N-diphenylamine (800 mg, 95%) were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(F)c1F
Temperature: 25 °C

Procedure:
2,3-difluorobenzoic acid (9.47 g, 59.90 mmol) and H2SO4 (0.3 mL) in methanol (100 mL) were heated for 3 days in a 70° C. oil bath. The reaction was cooled to RT, then the solvent was removed under vacuum at 35° C. The crude residue was transferred to a separatory funnel with ether, washed with saturated sodium bicarbonate solution (2×50 mL), brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was redissolved in CH2Cl2, dried (MgSO4), filtered and concentrated under vacuum to yield 8.66 grams of methyl 2,3-difluorobenzoate as a clear liquid.
Reaction SMILES: [C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17]([C:31]5[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=5)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 90 °C
Yield: 73.5 %

Procedure:
A mixture of 250 mg of 25a, 72 mg of pyridine-3-boronic acid, 135 mg of K2CO3 and 5 ml of degassed 90% aqueous DME was heated under N2 for 16 h at 90° C. The reaction was then cooled and diluted with water, and the product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the remainder was chromatographed over silica gel (using a gradient of heptane/ethyl acetate as eluent). The product isolated was triturated with diethylether, to provide 183 mg of 25b; NMR (CDCl3) δ 8.85, 8.56, 7.91, and 7.35 (4×m, 4, pyridyl-H), 8.37 and 6.87 (2×s, 2, Ar—H), 4.45 and 3.40-3.90 (br.m, 4, 2×CH2), 3.05 (bm, 2, CH2), 2.60 (br.m, 2, CH2), 1.90 and 1.70 (2×br.m, 4, 2×CH2), 1.58 (s, 9, tertC4H9).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](N)=[O:5].N([O-])=[O:14].[Na+].[N+]([O-])=O.O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=N[O-]
Reactant: Cc1cc(F)cc(Br)c1C(N)=O
Agent: O=S(=O)(O)O
Agent: O=[N+][O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)cc(Br)c1C(=O)O
Temperature: 20 °C
Yield: 96.7 %

Procedure:
2-Bromo-4-fluoro-6-methylbenzamide (0.9 g, 3.9 mmol) was dissolved in 75% aqueous sulfuric acid (4 mL) at 80° C. sodium nitrite (0.5 g, 7.2 mmol) was carefully added in small portions during 1 hour. At the end of addition a persistent color of nitrogen dioxide appeared. The reaction mixture was chilled to 20° C. and cold water (15 mL) was added to the reaction mixture. The product was extracted with ethyl acetate (6×2 mL). The organic phase was washed with water (4×2 mL), brine (2×2 mL), dried with sodium sulfate, filtered and concentrated to give 0.879 g (97%) of pure acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:33]>C(O)(C(F)(F)F)=O.CO.C(Cl)Cl.CCOCC>[ClH:33].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C@H:14]4[CH2:18][CH2:17][CH2:16][O:15]4)=[O:13])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCO4)c23)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@H]4CCCO4)c23)C1
Yield: 21 %

Procedure:
A solution of tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate in TFA (3 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue obtained was purified by C-18 reverse phase chromatography (Biotage Flash 12 M+, C-18) on Biotage SP4 unit eluting with a gradient of 1-50% CH3CN/water (14 CV). The pure fractions containing the R-isomer (by comparing the retentions times of S-isomer, Example 71A) were pooled, concentrated in vacuo and evaporated from CH3CN (3×5 mL). The solid residue obtained was dissolved in minimal methanol, diluted with CH2Cl2 (1 mL) and treated with 2M HCl in ether (3 mL). The resulting suspension was concentrated in vacuo and evaporated from CH2Cl2 (3×5 mL) and dried under high vacuum for 24 hours to provide (R)-N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydro furan-2-carboxamide hydrochloride (16 mg, 21% yield) as a solid. NMR (400 MHz, (CD3)2SO) δ 11.72 (s, 1H), 9.83 (s, 1H), 8.21 (s, 1H), 8.16 (br s, 3H), 7.89 (s, 1H), 4.37 (t, 1H), 3.96-3.91 (m, 1H), 3.85-3.79 (m, 1H), 3.55-3.48 (m, 3H), 3.26-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.28-2.20 (m, 1H), 2.15-2.09 (m, 1H), 1.94-1.81 (m, 5H), 1.48-1.40 (m, 1H); LCMS (APCI+) m/z 408.1, 410.1 (M+H)+, Retention time=2.32 minutes (Method 2).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][CH3:22])=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[N:7]=[C:6]([C:27]#[N:28])[C:5]=2[N:4]=[CH:3]1.C(N(CC)CC)C.Cl.[CH3:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[C:44]([OH:46])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:27]([C:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:22])[C:44]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][N:38]3[CH3:37])=[O:46])=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)[N:7]=1)#[N:28]
Reactant: CN1CCCCC1C(=O)O
Reactant: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)C1CCCCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
A mixture of 1-methyl-6-(4-(3-(methylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (50 mg), triethylamine (71 μL), 1-methylpiperidine-2-carboxylic acid hydrochloride (17 mg), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (58 mg) in DCM (1.5 ml) was stirred overnight at room temperature. The mixture was washed with sodium bicarbonate and then purified by prep HPLC (acidic) to give the expected product (11 mg). NMR (CD3OD) δ: 8.29-8.52 (m, 4H), 7.27-7.40 (m, 1H), 4.16-4.36 (m, 2H), 4.06 (s, 3H), 3.58-3.92 (m, 2H), 2.86-3.27 (m, 5H), 2.14-2.37 (m, 6H), 1.26-1.90 (m, 6H). MS m/z 515 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([OH:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][C@@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:15][CH2:14]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (1.476 g, 6.79 mmol) from Step B and triethylamine (1.420 mL, 10.19 mmol) were combined in dichloromethane (30 mL). Methanesulfonyl chloride (0.635 mL, 8.15 mmol) was added as a solution in 20 mL of dichloromethane dropwise via addition funnel. The reaction was stirred at room temperature for 30 minutes and concentrated. The crude material was absorbed onto silica gel and chromatographed on a silica gel cartridge (Analogix®, Burlington, Wis., RS25-25) eluting with 20-100% ethyl acetate/hexanes to give (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate: 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.27 (m, 4H), 7.27-7.20 (m, 1H), 4.96 (ddd, J=6.1, 7.6, 9.1, 1H), 3.71-3.44 (m, 1H), 2.94 (s, J=13.5, 3H), 2.85 (ddd, J=4.9, 8.1, 16.0, 1H), 2.75-2.68 (m, 2H), 2.67-2.55 (m, 1H), 2.54-2.44 (m, 1H), 2.31 (dd, J=4.1, 8.7, 1H), 2.20-2.04 (m, 1H), 1.97 (dtd, J=3.4, 6.2, 9.6, 1H), 1.79-1.63 (m, 1H), 1.61-1.49 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(C)cc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3cc(C)ccc3OC)cccc2c1N
Yield: 83 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-methoxy-5-methyl-phenylboronic acid (166 mg, 1.000 mmol) were reacted to afford the title compound (141 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.88-7.82 (m, 1H), 7.76-7.65 (m, 2H), 7.22-7.12 (m, 2H), 6.93 (m, 1H), 3.67 (s, 3H), 3.45 (apparent q, J=7.0 Hz, 2H), 2.34 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=351 (M+H). HPLC 1.96 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][C:15]=2[CH2:28][CH3:29])=[O:10])[CH:5]=[CH:6][CH:7]=1>C1COCC1.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[CH2:28][CH3:29])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(OCc2ccccc2)ccc1C(=O)NNC(=O)Cc1cccc(O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(O)ccc1C(=O)NNC(=O)Cc1cccc(O)c1

Procedure:
57.4 g of N′-[2-(3-hydroxyphenyl)acetyl]-4-benzyloxy-2-ethylbenzohydrazide are dissolved in 1.5 l of THF and hydrogenated for 24 h. The catalyst (5% Pd/C, 35 g) is added in 3 portions. The catalyst is filtered off with suction, the solution is evaporated, and the residue is crystallised from MeCN, giving 41.1 g of “60” (92%); m.p. 199-200°.