Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9]([Si](C)(C)C)=[C:8]2[CH3:20])=[O:4].Cl>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]2[CH3:20])=[O:4]
Reactant: COC(=O)c1cc2c(C)c([Si](C)(C)C)[nH]c2cc1OC
Agent: Cl
Product: COC(=O)c1cc2c(C)c[nH]c2cc1OC

Procedure:
An indole hydrazide can also be prepared by treating a solution of 2-methoxy-4-amino-benzoic acid methyl ester (xvii) in ethanol with N-bromosuccinamide to form 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) (see Scheme VIII). A solution of 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) in DMF is then reacted with trimethyl-prop-1-ynyl silane (xix) in the presence of with palladium acetate, Na2CO3, triphenylphosphine and tetrabutylaminium iodide to form 6-methoxy-3-methyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid methyl ester (xx). Compound (xx) is then treated with an aqueous HCl solution to remove the trimethylsilanyl group and form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid methyl ester (xxi). Compound (xxi) is treated with NaOH in a THF/H2O solution to convert the ester to a carboxylic acid. The carboxylic acid is then activated by treating it with oxalyl chloride in dichloromethane and a catalytic amount of DMF, then the activated carboxylic acid is converted to a hydrazide by treating it with hydrazine hydrate in dichloromethane to form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid hydrazide (xxii). Hydrazide (xxii) can be used in the method of Scheme Vor VI to form a compound of the invention
Reaction SMILES: BrCCBr.[F:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Br.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[C:34]3[CH:35]=[N:36][C:37]([O:39][CH3:40])=[CH:38][C:33]=3[N:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:31]=2Cl)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.CCCCCC.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.Cl[Si](C)(C)C.CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[C:34]3[CH:35]=[N:36][C:37]([O:39][CH3:40])=[CH:38][C:33]=3[N:32]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:31]=2[CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([F:5])[C:7]=2[CH3:14])=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1c(F)cccc1CBr
Reactant: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: BrCCBr
Product: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cc1cccc(F)c1C)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To zinc (167 mg, 2.55 mmol) in dry THF (500 μl) in a dry flask under an argon atmosphere was added 1,2-dibromoethane (5.49 μl, 63.7 μmol). The mixture was heated three times to reflux with a heat gun and allowed to cool to room temperature. Then chlorotrimethylsilane (0.27 μl, 2.12 μmol) was added and the mixture was stirred at room temperature for 20 min. Subsequently the flask was placed in an ice bath and a solution of 3-fluoro-2-methyl-benzylbromide (259 mg, 1.27 mmol) in dry THF (1 ml) was added slowly so that the temperature remained at 0° C. The mixture was stirred at 0° C. for 4.5 h and placed in the refrigerator overnight. Then the cooled mixture was added dropwise to a precooled solution (−78° C.) of B-OM-9-BBN (2.12 ml, 2.12 mmol, 1 M) in hexane. The mixture was stirred at room temperature for 30 min. DMF (5 ml) was added, followed by the compound of step 6 (100 mg, 212 μmol), palladium(II) acetate (4.77 mg, 21.2 μmol) and S—PHOS (17.4 mg, 42.5 μmol). The reaction mixture was stirred at 100° C. for 3 h. After cooling, the mixture was quenched with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA (10 to 60%) HEP) to give 90 mg of the title compound.
Reaction SMILES: C([O-])(=O)C.[Na+].[Br:6]Br.[CH3:8][O:9][C:10]1[N:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>C(O)(=O)C>[Br:6][C:15]1[CH:16]=[N:17][C:10]([O:9][CH3:8])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: COc1ncccc1C#N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ncc(Br)cc1C#N
Temperature: 70 °C
Yield: 73 %

Procedure:
12.23 g (149 mmol) of sodium acetate and then 7.66 ml (149 mmol) of bromine at 0° C. are added to 10 g (74.6 mmol) of a solution of 2-methoxy-nicotinonitrile in 29 ml of acetic acid. The reaction mixture is heated at 70° C. overnight. After returning to room temperature, the reaction medium is added to an ice bath and the precipitate obtained is filtered, rinsed with water and then dried at 50° C. to yield 11.6 g (73%) of 5-bromo-2-methoxy-nicotinonitrile in the form of a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(OCC)C>[O:17]=[C:14]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.5 %

Procedure:
A solution of morpholine (8.7 g, 0.1 mole) and triethylamine (15.3 ml, 0.1 mole) in ethyl ether (100 ml) was cooled to +5° C. A solution of acryloyl chloride (9.0 g, 0.10 mole) in 25 ml of ethyl ether was added dropwise over a 30 minute period, resulting in the formation of a white solid. An additional 100 ml of ethyl ether was added and the reaction stirred for 72 hours at room temperature. The white solid was filtered and washed well with ethyl ether. The ethyl ether wash and filtrate were combined and solvent removed, leaving an orange oil which was transferred to a 50 ml Erlenmeyer flask and dried overnight under nitrogen to yield 11.5 g of product. The structure was confirmed by NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][N:2]=1.OS(O)(=O)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:8][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:9])[CH3:16]
Reactant: O=C(O)c1ccnnc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccnnc1
Yield: 79 %

Procedure:
To pyridazine-4-carboxylic acid (1.0 g, 8.1 mmol) in ethanol (10 mL) was added concentrated H2SO4 (4.2 mL) and then heated at reflux for 5 hours. The reaction mixture was cooled, concentrated in vacuo and basified with saturated Na2CO3. After filtration, the aqueous was extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a dark yellow oil (970 mg, 79%).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:26]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:3])[CH2:23][CH3:24])=[CH:15][N:14]=2)=[CH:17][CH:18]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC[C@H](C)CCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ncc(CCCCC[C@@H](C)CC)cn2)cc1
Temperature: 0 °C

Procedure:
Pour 0.33 g of sodium hydride (about 50% oil suspension), 3 ml of dry N,N-dimethylformamide into a 30 ml three-mouth flask equipped with a cooling tube, thermometer, dripping funnel, and calcium chloride tube. Next, slowly drip 1.71 g of optically active (s)-4-[5-(6-methyl octyl)-2-pyrimidinyl]phenol which is dissolved in 6 ml of dry N,N-dimethylformamide, into the flask at room temperature. Furthermore, after reacting it for 30 minutes, add 1.10 g of 1-bromoctane, allow to react for 7 hours at 90° C. After the reaction, pour the mixture into ice water, then extract the product with ethyl acetate. The organic layer is thoroughly washed with water, dried, the organic solvent is evaporated and removed, and then the impure product is obtained. This impure product is refined with silica gel chromatography, and recrystallized to obtain 1.3 g of optically active (s)-2-[4-n-octyloxyphenyl]-5-[6-methyloctyl]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])[CH:11]=[CH:10][C:3]=1[NH:4][CH2:5][C:6]([F:9])([F:8])[F:7].C(#[N:23])C.F[B-](F)(F)F.O=[N+]=O>ClCCl.S1(CCCC1)(=O)=O.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:13]=[C:12]([C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])[CH:11]=[C:10]([NH2:23])[C:3]=1[NH:4][CH2:5][C:6]([F:8])([F:9])[F:7]
Reactant: CC#N
Reactant: Cc1noc(C)c1-c1ccc(NCC(F)(F)F)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: O=[N+]=O
Agent: [Zn]
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Solvent: CC(=O)O
Product: Cc1noc(C)c1-c1cc(N)c(NCC(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-(3,5-dimethylisoxazol-4-yl)-N-(2,2,2-trifluoroethyl)aniline (200 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL) and acetonitrile (10 mL) and cooled to 0° C. under argon. To reaction mixture was added 0.5M nitronium tetrafluoroborate (1.84 ml) slowly over 20 minutes. Reaction mixture was stirred at 0° C., for 1 hour and allowed to warm to room temperature. After 3 hours, the reaction mixture was cooled to 0° C. again and 0.5M nitronium tetrafluoroborate in sulfolane (1.84 ml) was added and the reaction solution was stirred at room temperature overnight. Reaction solvents were removed under reduced pressure and the residue taken up in EtOAc and the solution was washed with aq. NaHCO3, then water, brine and dried over sodium sulfate. Solvents were removed under reduced pressure to yield a dark red oil/liquid. This material was dissolved in 2 mL of ethanol and 2 mL of acetic acid. To the solution was added Zinc dust and suspension was stirred. After 30 minutes of stirring the zinc dust was filtered off and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc and the solution was washed with aq. NaHCO3, then water, brine and dried over sodium sulfate. Solvent was removed and the crude residue was purified by silica gel chromatography (Hexanes/EtOAc as the eluent) to afford 6-chloro-4-(3,5-dimethylisoxazol-4-yl)-N1-(2,2,2-trifluoroethyl)benzene-1,2-diamine as a light colored oil.
Reaction SMILES: FC(OS([C:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:28](=[O:38])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:10]=1)(=O)=O)(F)F.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:58]([O-:61])(=[O:60])C.[K+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][C:28]([C@H:18]2[CH2:17][CH2:16][C@H:15]3[C@H:14]4[C@H:23]([CH2:22][CH2:21][C@:19]23[CH3:20])[C@:24]2([CH3:27])[C:11]([CH:10]=[C:9]([C:58]([OH:61])=[O:60])[CH2:26][CH2:25]2)=[CH:12][CH2:13]4)=[O:38])=[CH:36][CH:35]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(S(=O)(=O)OC(F)(F)F)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCc1ccc(F)cc1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCc1ccc(F)cc1
Temperature: 60 °C
Yield: 53.3 %

Procedure:
A mixture of trifluoromethyl -17β-[3-(4-fluorophenyl )-1-oxopropyl]-androsta-3,5-diene-3-sulfonate (0.28 g, 0.5 mmol), palladium (II) acetate (5.6 mg, 0.025 mmol), triphenylphosphine (13 mg, 0.05 mmol), potassium acetate (0.19 g, 2 mmol) and DMF (6 ml) was heated at 60° C. under an atmosphere of CO for 2.5 hours. The cooled mixture was diluted with ice water, acidified with dilute HCl and extracted with CH2Cl2. The organic extract was washed with water, brine, dried (MgSO4), filtered, concentrated in vacuo, and chromatographed (silica gel, 1% AcOH/19% EtOAc/80% hexanes) to yield the title compound 0.12 g (53%). Recrystallized from methanol-acetone. mp 220°-220° C. analysis for C29H35FO3 0.25 H2O(455.1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][CH:30]=[C:31]4[C:34]([O:36]C)=[O:35])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][CH:30]=[C:31]4[C:34]([OH:36])=[O:35])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cccc(C(=O)O)c3c2)cc1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A solution of methyl 7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.052 g, 0.09 mmol) in tetrahydrofuran (0.9 mL) was placed in a microwave reaction tube. Methanol (0.45 mL) was added followed by 1N sodium hydroxide (0.14 mL, 0.14 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.039 g, 74% as 0.40 tetrahydrofuran) 1H NMR (DMSO-d6): 13.13 (s, 1H), 9.10 (s, 1H), 8.17-8.15 (m, 1H), 8.07 (d, J=9 Hz, 1H) 7.87 (dd, J=2, 9 Hz; 1H), 7.71 (d, J=9 Hz, 2H), 7.57-7.54 (m, 1H), 7.41 (d, J=8 Hz, 2H), 7.28-7.24 (m, J=8 Hz, 2H), 7.16 (dd, J=9, 2 Hz, 2H), 4.98 (s, 2H), 3.36 (septet, overlapping H2O, 1H), 3.23-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). HRMS C32H27NO4Cl2 m/z 560.1395 (M+H)+Cal; 560.1375 (M+H)+Obs.
Reaction SMILES: [C:1]1([C:7]2([C:13](O)=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:1]1([C:7]2([CH2:13][OH:14])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
A solution of 4-phenyl-piperidine-4-carboxylic acid (0.168 g, 0.819 mmol) in THF (2 mL) was added dropwise to a 0° C. solution of lithium aluminum hydride (1.0N in THF, 1.63 mL, 1.64 mmol). The reaction was stirred at room temperature for about 16 h. Water (1 mL) was added to the reaction mixture, followed by 2 N NaOH (1 mL). The solution was stirred for about 1 h then filtered. The filtrate was extracted with DCM (25 mL) and the organic layer was separated. The aqueous layer was further extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give (4-phenyl-piperidin-4-yl)-methanol (0.078 g, 0.41 mmol) as brown oil, which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method b) Rt 1.24 min; m/z: (M+H)+ 192.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:34](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:45][CH3:46].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:34][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:45][CH3:46]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CN(C(=O)OC(C)(C)C)C4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CN(C(=O)OC(C)(C)C)C4)ccnc3[nH]1)cn2C
Yield: 65.7 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.2 g of tert-butyl 3-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}azetidine-1-carboxylate instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 1.24 cm3 of 5N potassium hydroxide. 0.1 g of tert-butyl 3-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}azetidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[CH:38]=[N:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:39])[NH:19][C@:18]2([C:41]([O:43]CC)=[O:42])[CH2:40][C@H:17]2[CH2:16][C:15]([F:47])([F:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.C(O)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[CH:38]=[N:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:39])[NH:19][C@:18]2([C:41]([OH:43])=[O:42])[CH2:40][C@H:17]2[CH2:16][C:15]([F:46])([F:47])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cnc4ccccc4n3)C[C@H]1C(=O)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3cnc4ccccc4n3)CN2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1h, 14.6 mg, 0.022 mmol) in tetrahydrofuran (55.3 μl), ethanol (27.6 μl) and Water (27.6 μl) was added lithium hydroxide monohydrate (4.19 mg, 0.100 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and cooled to 0° C. The reaction mixture was neutralized with HCl (4 N in dioxane, 25 μl; diluted with ethyl acetate), stirred at room temperature and dried over anhydrous sodium sulfate. The mixture was filtered and evaporated under reduced pressure and the residue was purified by prep-TLC (elute with dichloromethane/methanol=5/1) to provide the title compound (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (11.04 mg, 0.017 mmol, 79% yield).
Reaction SMILES: [CH:1]1([C:4]2[N:8]3[CH2:9][CH2:10][CH2:11][C@@H:12]([C:13]4[N:17]5[CH:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]6[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=6[O:32][CH3:33])[C:16]5=[C:15]([C:34]5[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=5)[N:14]=4)[C:7]3=[N:6][N:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([C:4]2[N:8]3[CH2:9][CH2:10][CH2:11][C@@H:12]([C:13]4[N:17]5[CH:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]6[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=6[O:32][CH3:33])[C:16]5=[C:15]([C:34]5[CH:42]=[CH:41][C:37]([C:38]([NH2:46])=[O:39])=[CH:36][CH:35]=5)[N:14]=4)[C:7]3=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(CNc2nccn3c([C@@H]4CCCn5c(C6CC6)nnc54)nc(-c4ccc(C(=O)O)cc4)c23)c(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nccn3c([C@@H]4CCCn5c(C6CC6)nnc54)nc(-c4ccc(C(N)=O)cc4)c23)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a solution of (S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoic acid (130 mg, 0.23 mmol) in DMF (2 mL) was added NH4Cl (37 mg, 0.69 mmol), TEA (93 mg, 0.92 mmol) and HATU (175 mg, 0.46 mmol). The mixture was stirred at RT overnight. After the reaction was completed, the solvent was evaporated and the residue was purified by Pre-TLC to give (S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzamide (60 mg, yield 46%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[C:4]=1C(O)=O)[CH3:2].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[CH:4]=1)[CH3:2]
Reactant: CCc1c(C(=O)O)c(O)nc2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cc(O)nc2ccccc12
Temperature: 250 °C
Yield: 85.1 %

Procedure:
A mixture of 4-ethyl-2-hydroxyquinoline-3-carboxylic acid (0.84 g) and diphenyl ether (2.5 mL) was heated at 250° C. for 2 h with stirring. The mixture was cooled to room temperature and purified by silica gel column chromatography (chloroform/methanol=50:1) to obtain the title compound (0.57 g).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC>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>[C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:24]4[S:25][CH:26]=[CH:27][N:28]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Yield: 84.1 %

Procedure:
5-Cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole (54) was synthesized as described in Example 18 but using 5-cyano-1-(3-iodophenyl)benzimidazole (2.0 g, 5.9 mmol) instead of (52), (PPh3)2PdCl2 (100 mg, 0.14 mmol) and (50) (3.6 g, 9.7 mmol). The reaction gave 5-cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole (1.5 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl.Cl.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([NH2:23])[CH2:16]2.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([NH:23][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12])[CH2:16]2
Reactant: NC1CN2CCC1CC2
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)NC2CN3CCC2CC3)nc1Cl

Procedure:
A solution of 3,5-diamino-6-chloropyrazine-2-carboxylic acid (Intermediate 1.1.1, 2.50 g, 13.1 mmol), 1-aza-bicyclo[2.2.2]oct-3-ylamine dihydrochloride (2.87 g, 14.4 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.62 g, 14.4 mmol) and triethylamine (6.72 mL, 39.3 mmol) in dry N,N-dimethylformamide (25 mL) is stirred overnight at room temperature under nitrogen atmosphere. The resulting solid is collected by filtration, washed with diethyl ether and dried at 50° C. under vacuum.