Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]1[N:16]=[N:17][NH:18][N:19]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[CH2:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59])[CH2:54][CH2:55][CH3:56]>CN(C=O)C>[CH2:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][N:63]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH2:62][CH2:61]1)=[O:59])[CH2:54][CH2:55][CH3:56]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1nn[nH]n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 222 mg (S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyric acid in 5 ml DMF were added 300 mg HATU, 541 μl DIPEA and 245 mg piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate. After 1 h the solution was concentrated, taken up with dichloromethane and washed with aqueous LiCl (4%) and 0.1 M HCl. The crude product thus obtained was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].F[C:13]1[C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[CH2:32]([O:31][CH:27]([O:28][CH2:29][CH3:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:18]1[C:13]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:20])[CH3:33]
Reactant: CC(C)=NO
Reactant: CCOC(OCC)c1ccccc1C(=O)c1cccnc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(=O)c1cccnc1ON=C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.49 g of acetone oxime in 8 ml of dry tetrahydrofuran was added 0.75 g of potassium tert-butoxide. The solution was stirred for 15 min. then a solution of 1.86 g of (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenylmethanone in 8 ml of tetrahydrofuran was added. The solution was stirred at room temperature for 30 min. then quenched by the addition of 25 ml of a 1:1 water-saturated ammonium chloride solution. The solution was extracted with two 50 ml portions of ether and the combined ether extracts were washed with brine and dried over sodium sulfate. Evaporation afforded the intermediate 3-[2-(diethyloxymethyl)-benzoyl]-2-[((isopropylidene)amino]oxy]-pyridine which was not characterised but dissolved in 30 ml of ethanol and 20 ml of 2 M hydrochloric acid added and the solution refluxed for 15 min. The solution was cooled to room temperature and the crystals of 2-(isoxazolo[5,4-b]pyridin-3-yl)-benzaldehyde were collected by filtration and dried in vacuo, 1H-NMR (200 MHz, CDCl3) d 10.26 (CHO).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: C1CNCCN1
Product: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(N3CCNCC3)n1-2

Procedure:
In the manner given in Example 1, 1,8-dibromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with piperazine to give 8-bromo-1-piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([CH3:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].CO[Na].CO>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7])[N:9]=[C:10]3[CH3:27])=[CH:15][CH:14]=2)=[CH:25][CH:24]=1
Reactant: CCCCOC(=O)c1nc(C)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CO[Na]
Solvent: CO
Product: Cc1nc(C(=O)N[C@@H](C)C(=O)O)c(O)c2ccc(Oc3ccc(F)cc3)cc12
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
A mixture of 7-(4-Fluoro-phenoxy)-4-hydroxy-1-methyl-isoquinoline-3-carboxylic acid butyl ester (92 mg, 0.25 mmol), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in MeOH (5 ml, 2.5 mmol) was heated in a microwave oven with stirring for 20 min at 140° C. before the mixture was concentrated in vacuo. To the residue was added water (10 ml) and the mixture was washed with EtOAc (2×25 ml). The so purified aq. solution was acidified by the addition of 6 N HCl and extracted with EtOAc (1×25 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (69 mg); MS-(+)-ion M+1=385.1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:18]=O)[CH2:8][C:9]=1[NH:10]2.C([O-])(=O)C.[NH4+:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>C(Cl)Cl>[NH2:24][CH2:18][CH:7]1[CH2:6][CH2:5][C:4]2[C:3]3[C:11](=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:2]=3[Br:1])[NH:10][C:9]=2[CH2:8]1
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(C=O)CC3
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NCC1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reaction time: 0.17 h
Yield: 13 %

Procedure:
Step 3 A solution of crude 5-bromo-2-formyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (1 g, 3.11 mmol) in DCM (20 mL) was treated with ammonium acetate (3.60 g, 46.7 mmol) and sodium triacetoxyborohydride (0.990 g, 4.67 mmol) at rt and stirred for 10 min. THF (2 mL) was added to try to dissolve the starting material, but no reaction was observed after 1 h. The mixture was concentrated and the residue was dissolved in DMSO (10 mL). Additional sodium triacetoxyborohydride (500 mg) was added and the mixture was stirred at rt overnight. The mixture was diluted with water and the precipitate was removed by filtration. The filtrate was treated with 1 M aqueous sodium hydroxide and extracted three times with EtOAc. The combined organic phases were washed with water, dried and concentrated to provide 2-(aminomethyl)-5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a white solid (130 mg, 13%), used without further purification. Mass spectrum m/z 322, 324 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH:10]=1)=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[C:13]1([C@@H:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cnn([C@@H](C)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)n1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Intermediate (6f), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.525 g, 6.2 mmol) was stirred in a mixture of tetrahydrofuran (20 mL) and water (20 mL). Lithium hydroxide (0.524 g, 12.5 mmol) was added and the reaction stirred at ambient temperature for 24 hours. The reaction mixture was reduced in volume and extracted with diethyl ether (3×20 mL). The aqueous layer was carefully acidified using an aqueous 6N hydrochloric acid solution. The resulting precipitate was filtered, washed with copious amounts of water and dried in vacuo to afford intermediate (6g), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid as a white solid, 0.664 g, 49%.
Reaction SMILES: [Cl:1][CH:2]([C:8](=O)[CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:17]>CO>[NH2:17][C:8]([CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C(Cl)=C(N)C(C)C
Yield: 88 %

Procedure:
59.5 g (0.31 mol) of ethyl 2-chloro-4-methyl-3-oxo-pentanoate are reacted with 59.8 g (0.78 mol) of ammonium acetate in 120 ml of methanol and worked up in analogy to Example 2. Yield: 88.0% [GC]
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O>C(#N)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:32]([CH3:34])[CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)=O
Solvent: CC#N
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccc(F)cc2)CC1
Yield: 75.7 %

Procedure:
Using alkylation method A, 3-chloro-N-[1-(4-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.4 mmol) and acetone (10 mL, 135 mmol) afforded, after trituration (acetonitrile), 500 mg (76%) of the title compound.
Reaction SMILES: N12CCCN=C1CCCCC2.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(NC1C=CC(S([N:41]=[N+:42]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[N+:41](=[C:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[N-:42]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (10.6 g, 10.5 ml, 69.6 mmol, Eq: 1.04) in THF (59.0 ml) at 5° C. was added dropwise a solution of allyl 2-(3-nitrophenyl)acetate (intermediate B3a) (14.8 g, 66.9 mmol, Eq: 1.00) and 4-acetamidobenzenesulfonyl azide (16.6 g, 68.9 mmol, Eq: 1.03) in THF (118 ml) within 40 min and the mixture was stirred at 23° C. for 18 h protected from light. Quenched with sat. NH4Cl-sol., diluted with ethyl acetate, separated phases, the organic layer was washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left an orange semisolid, diluted with diethyl ether, filtered the solid off, washed with diethyl ether, the filtrate was concentrated in vacuum to give an orange semisolid. The crude material was purified by flash chromatography (silica gel, 300 g, 25% to 30% EtOAc in heptane) to give the title compound as a yellow solid (15.62 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15](O)[CH2:16]O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:9][CH2:16][CH2:15][O:10]2)=[CH:4][C:3]=1[C:11]([F:14])([F:12])[F:13]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: Fc1ccc(B2OCCO2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 115.4 %

Procedure:
The mixture of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (2.08 g, 10 mmol) and ethane-1,2-diol (3.72 g, 60 mmol) in toluene (150 ml) was refluxed with a Dean-stark trap for 2 h, then cooled to rt. The solvent was concentrated to dryness to afford the crude product (2.7 g, 100%). 1H NMR (300 MHz, CDCl3): δ 8.08-8.05 (d, 1H), 8.01-7.96 (t, 1H), 7.24-7.17 (t, 1H), 4.40 (s, 4H) ppm.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Br:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Br:15])=[CH:24][C:23]=3[Br:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: COC[C@@H](C)n1cc(Cl)nc(Cl)c1=O
Reactant: Brc1cc(Br)c2c(c1)CCN2
Product: COC[C@@H](C)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 119–120° C.; 1H NMR (300 MHz, CDCl3): δ 7.47 (d, J=1.8 Hz, 1 H), 7.27 (d, J=1.8 Hz, 1 H), 7.06 (s, 1 H), 5.14–5.09 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.62–3.52 (m, 2 H), 3.34 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.40 (d, J=7.0 Hz, 3 H); HRMS (CI) calcd for C16H16N3O2Br2Cl (M+H)+: 474.9298; found m/z 474.9285.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:8]2[CH2:9][O:10][CH2:11][CH:4]1[CH2:5][NH:6][CH2:7]2.Br[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH3:2][N:3]1[CH:8]2[CH2:9][O:10][CH2:11][CH:4]1[CH2:5][N:6]([C:13]1[CH:18]=[N:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CN1C2CNCC1COC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 112h (800 mg, 5.6 mmol) and 5-bromo-2-nitropyridine (1.37 g, 6.86 mmol) in DMSO (50 ml) was added Cs2CO3 (5g) and t-BuNH4I (cat.). The reaction mixture was stirred at 120° C. overnight. Then it was cooled to room temperature, and extracted with EtOAc (300 ml). The organic layer was washed with water (3×100 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to get crude product, which was purified through a silica gel column eluting with DCM:MeOH=100:1 to 50:1 to give 112i as a yellow solid (850 mg, 72%) MS: [M+H]+: 265
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Li+].[Li+]>C(OCC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:3](=[O:4])[CH2:2][Br:1])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: Clc1ccc(OCc2cc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(CBr)c1c(COc2ccc(Cl)cc2)[nH]c2ccccc12
Temperature: 55 °C

Procedure:
Under a nitrogen atmosphere bromoacetylbromide (1.31 ml, 0.015 mol) was added to a slurry of 2-[4-chlorophenoxymethyl]-1H-indole (0.81 g, 0.003 mol), and lithium carbonate (2.22 g, 0.03 mol) in diethyl ether (37.5 ml). The resulting mixture was heated to 55° C. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between diethyl ether and a sodium bicarbonate solution. The organic fraction was washed with water and then brine, and then dried over sodium sulfate. The solvents were removed in vacuo. Yield: 1.34 g. NMR was consistent with the proposed title structure.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2
Reactant: Cn1ccc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc2cc(O)ccc21
Yield: 90.9 %

Procedure:
A solution of 5-benzyloxy-1-methylindole (3.5 g, 15.7 mmol), in ethanol (100 ml) was hydrogenated at ambient temperature and 1 atmosphere pressure hydrogen for 4 hours using 10% palladium on carbon (0.5 g) as catalyst. The catalyst was filtered off and the filtrate evaporated in vacuo. The residue was purified by silica column chromatography eluting with ethyl acetate/dichloromethane (10/90) to give 5-hydroxy-1-methylindole (2.1 g, 97%).
Reaction SMILES: [NH2:1][NH2:2].[N:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[CH2:11][C:12](=O)[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO>[N:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:1]=[N:2][C:12]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])[CH2:17][CH2:18]3)=[CH:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)=[CH:7][CH:8]=1
Reactant: O=C(CC(C(=O)c1ccncc1)c1cccc(C(F)(F)F)c1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3cccc(C(F)(F)F)c3)c(-c3ccncc3)nn2)CC1
Reaction time: 4 h
Yield: 36.8 %

Procedure:
Under Ar, hydrazine (0.5 mL, 0.51 g, 15.9 mmol) was added to a solution of 34 (3.3 g) in EtOH (75 mL). After 4 h, the solution was concentrated to dryness and the residue treated with toluene (60 mL) dioxane (60 mL) and DDQ (0.8 g, 3.5 mmol). After 15 h, the reaction was concentrated to dryness. The residue was chromatographed on a Still column (50 mm) and the product eluted with 100% EtOAc to yield 1.2 g of 35.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[N:25][C:26]=3[NH2:28])[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:20]=2)=[CH:15][C:14]=1[O:42][CH3:43]>N1C=CC=CC=1>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:9](=[O:10])[CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:14]([O:42][CH3:43])[CH:15]=3)[C:27]=12
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reaction time: 5 h
Yield: 18.4 %

Procedure:
3-Phenylpropanoyl chloride (77 mg, 0.458 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.229 mmol) in pyridine (1.2 mL). After 5 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-{4-[4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-3-phenylpropanamide (24 mg, 18%). 1H NMR (CDCl3-d) δ 1.70 (m, 2H), 1.85 (m, 2H), 2.04 (m, 4H), 2.30 (s, 3H), 2.41 (m, 5H), 2.75 (m, 2H), 2.97 (m, 2H), 3.08 (m, 4H), 3.90 (s, 3H), 4.75 (m, 1H), 5.71 (bs, 2H), 7.24 (m, 8H), 7.76 (s, 1H), 8.34 (s, 1H), 8.52 (d, J=8.12, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.0 mL/min.): MH+=569.5, Rt=1.65 min.
Reaction SMILES: [OH-].[Na+].O1CCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([Cl:34])[N:24]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CO>[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:34])[N:24]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c(C(=O)O)cc1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
A 1N sodium hydroxide aqueous solution (15 ml) was added to a solution of tetrahydrofuran (30 ml) and methanol (30 ml) containing methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinate (3.00 g), followed by stirring at 65° C. for 2 hours. The reaction mixture was cooled to room temperature, the solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution, tetrahydrofuran, and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Colorless oily matter of 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid (3.00 g) was thus obtained.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7](O)=[O:8].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:24]12([NH2:34])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CC(C)=O>[C:24]12([N:34]3[C:7](=[O:8])[CH2:2][CH2:3][C@H:4]3[C:5]([NH2:1])=[O:6])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCC(=O)N1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.25 h

Procedure:
10 g of (L)-pyroglutamic acid (77 mmol) and 10.7 ml of triethylamine are mixed with 100 ml of anhydrous acetone, 9.29 g of pivaloyl chloride (77 mmol) are run in slowly at -5° and then, after 15 minutes at 0° C., 11.65 g (77 mmol) of adamantanamine are added in several portions.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][C@H:21]([C:32]([O:34]C)=[O:33])[CH2:20]1)=[O:17].[OH-].[Na+]>CO>[C:28]([O:27][C:25]([N:23]1[CH2:24][C@@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:20][C@@H:21]([C:32]([OH:34])=[O:33])[CH2:22]1)=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (15 g) was dissolved in methanol (150 ml), 4N-aqueous sodium hydroxide solution (250 ml) was added, and the mixture was stirred at 50° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was ice-cooled, neutralized with 2N hydrochloric acid, and extracted twice ethyl acetate (500 ml). The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (15.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:11][C:12]1[CH2:13][C:14](=[O:19])[O:15][C:16](=[O:18])[CH:17]=1)(=[O:10])[CH3:9].O>C(O)(=O)C>[C:8]([O:11][C:12]([CH2:13][C:14](=[O:19])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][C:16]([OH:18])=[O:15])(=[O:10])[CH3:9]
Reactant: CC(=O)OC1=CC(=O)OC(=O)C1
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(=CC(=O)O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
65.7 g (0.705 mol) of aniline are added to a stirred suspension of 120 g (0.705 mol) of 4-acetyloxy-2H,3H-pyran-2,6-dione in 250 ml of acetic acid. The reaction medium is stirred for 1 h at room temperature and is then diluted by adding 500 ml of water. The solid is drained, washed with water and dried in an oven (50° C.) for 24 h. 150 g (81%) of the expected compound, melting point 125°-126° C., are obtained.