Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)C.O>[C:27]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1)(=[O:29])[CH3:28]
Reactant: c1ccc2ncccc2c1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Quinoline (19.37 g, 150 mmol) was dissolved in anhydrous diethyl ether (500 ml) and cooled to 0° C. under inert atmosphere. DIBAL, 1.5 M in toluene (100 ml, 150 mmol) was added dropwise over 2 hrs and the reaction mixture was stirred at 0° C. for 30 min. Acetic anhydride (500 ml) was added dropwise over 30 min and the reaction mixture was stirred at 0° C. for 30 min. H2O was added cautiously. The reaction mixture was extracted with diethyl ether and concentrated to give N-acetyl-1,2-dihydroquinoline (11.5 g, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[NH2:15][C:16]1[N:21]=[C:20](Cl)[C:19]([C:23]#[N:24])=[C:18]([CH3:25])[N:17]=1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:15][C:16]1[N:21]=[C:20]([NH:10][C@H:8]([C:7]2[N:6]=[C:5]3[CH:11]=[CH:12][N:13]([CH3:14])[C:4]3=[CH:3][C:2]=2[Br:1])[CH3:9])[C:19]([C:23]#[N:24])=[C:18]([CH3:25])[N:17]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2Br)c1C#N
Temperature: 75 °C
Yield: 93.8 %

Procedure:
A microwave vial was charged with (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (2 g, 7.87 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (1.592 g, 9.44 mmol), acetonitrile (40 mL), and DIPEA (5.50 mL, 31.5 mmol). The reaction mixture was heated to 75° C. for 1 hour in an oil bath and then cooled to room temperature. A precipitate was isolated by vacuum filtration and washed with acetonitrile to give the title compound as an off-white solid (2.85 g, 94%). ESI-MS m/z [M+H]+ calc'd for C16H16BrN7, 386. found 386.
Reaction SMILES: [C:1]1([C:15](O)=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C1COCC1.CO.Cl>O>[C:1]1([CH2:15][OH:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2cc3ccccc3cc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1cccc2cc3ccccc3cc12
Yield: 66.6 %

Procedure:
To a 500 mL 2-neck flask equipped with condenser, addition funnel with N2 inlet, and stirring bar was added 1-anthracenecarboxylic acid (6.88 g, 31 mmol) and dry THF (250 mL). To the addition funnel, was added a 1M solution of BH3 in THF (Aldrich, 50 mL, 50 mmol) via cannula. The BH3 solution was added over 1 h and the solution stirred overnight at RT. CH3OH was then added until H2 evolution ceased. H2O (5 mL) and then 1N HCl (5 mL) was added to the flask. The solvents were removed and then PhCH3 (100 mL) added to the flask. The PhCH3 was then also removed. The resulting solid was recrystallized from EtOAc/hexane to give 4.3 g (67%) of (1-anthryl)methanol mp 124°-125°, (C, H), (lit. 124°-125°, S. Akiyama et. al., Bull. Chem. Soc. Jap. 35 1826 (1962)).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>ClCCl>[Br:12][C:10]1[N:11]=[C:7]([C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[S:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1csc(Br)n1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Br)cs2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 1.48 mL, 2.37 mmol) was added dropwise to a −78° C. solution of 2,4-dibromothiazole (0.524 g, 2.16 mmol) in dichloromethane (11 mL). The mixture stirred at −78° C. for 20 minutes, and then tert-butyl 4-oxopiperidine-1-carboxylate (0.516 g, 2.59 mmol) was added in 8 portions. The reaction mixture stirred at −78° C. for 10 minutes. The cooling bath was removed, and the reaction was allowed to warm to rt over 1 h. The reaction mixture was cooled to −30° C. and was then quenched by the addition of saturated aqueous ammonium chloride solution. The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 5-60% ethyl acetate-hexane) to afford tert-butyl 4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.744 g, 95%). MS (ESI, pos. ion) m/z 363, 365 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[C:12]1[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2ccnc(Cl)n2)s1
Reaction time: 0.33 h

Procedure:
2-Chloropyrimidin-4-amine 49-1 (0.30 g, 2.32 mmol) and sodium hydride (0.093 g, 2.32 mmol) were suspended in dry THF and stirred for 20 minutes before adding 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.33 g, 2.32 mmol) and more sodium hydride (0.093 g, 2.32 mmol) simultaneously. This was refluxed for 1.5 hour and then quenched with methanol and water, and concentrated to dryness. The residue was partitioned between DCM, MeOH, and water. The aqueous layer was evaporated to dryness and then purified on a silica column. 1H-NMR (CD3OD): 8.50(d, 1H); 8.42(s, 1H); 7.11(d, 1H). By 1H-NMR this material is a mixture of the desired product and 2-chloropyrimidin-4-amine in a ratio of 5:8, which was used as is in the next step.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>ClCCCl>[CH2:1]([C:8]1[C:9]([NH:22][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCCl
Product: COc1ccc(NC(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 19 h
Yield: 59.2 %

Procedure:
Under an argon atmosphere, to a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (306 mg, 1.05 mmol) in anhydrous 1,2-dichloroethane (10 mL) was added 4-methoxyphenyl isocyanate (13) (191 μL, 1.00 mmol) at room temperature, and the mixture was heated with stirring at 80° C. for 19 hours. After cooling to room temperature, the solid precipitated was collected by filtration and dried in vacuo to give the crude product (293 mg, <664 μmol, <63.2%) as a colorless solid. An aliquot (93.0 mg, <211 μmol) was recrystallized from methanol to give Compound 11u (54.9 mg, 125 μmol, 59.2%) as a colorless solid. Rf=0.50 (n-hexane/ethyl acetate=1/1); 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 3.81 (s, 3H), 4.36 (s, 2H), 6.98-6.93 (AA′BB′, 2H), 7.02-7.08 (AA′BB′, 2H), 7.17-7.25 (m, 1H), 7.28-7.32 (m, 4H), 7.43-7.48 (AA′BB′, 2H), 7.95-8.01 (AA′BB′, 2H), 8.79 (s, 1H), 9.04 (s, 1H), 10.58 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ 38.5, 55.18, 55.24, 114.0 (2C), 114.4 (2C), 121.1 (2C), 126.3, 127.2 (2C), 128.2, 128.3 (2C), 129.0 (2C), 131.7, 134.5, 137.9, 144.4, 145.0, 145.4, 152.2, 155.1, 160.1; IR (KBr, cm−1) 704, 746, 824, 1038, 1173, 1242, 1329, 1369, 1416, 1481, 1510, 1570, 1607, 1668, 2833, 3030, 3261; Anal. Calcd. For C26H24N4O3: C, 70.89; H, 5.49; N, 12.72. Found: C, 70.66; H, 5.49; N, 12.61.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH2:12][C:13]#[CH:14])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]#[C:27][C:28](O)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(Cl)CCl.Cl.CN(C)CCCN=C=NCC>CO>[NH2:8][C:7]1[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[N:4]([CH2:12][C:13]#[CH:14])[C:3](=[O:15])[C:2]=1[NH:1][C:28](=[O:29])[C:27]#[C:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1ccc(C#CC(=O)O)cc1OC
Reactant: C#CCn1c(=O)c(N)c(N)n(CC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCCl
Product: C#CCn1c(=O)c(NC(=O)C#Cc2ccc(OC)c(OC)c2)c(N)n(CC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the 5,6-diamino-1-ethyl-3-propargyluracil (4.2 g, 20 mmol), 3,4-dimethoxyphenylacetylencarboxylic acid (4.2 g, 20 mmol) and EDC ((1-(3-dimethylaminopropyl)-3-ethyl-carbodiimid hydrochloride; 4.2 g, 22 mmol) in methanol (100 ml) was stirred at room temperature for 2 h. The colorless product was precipitated by adding water (ca. 150 ml), filtered under reduced pressure, washed thoroughly with ether (TLC-control indicated the purity of the product; eluent: dichloromethane/methanol 9:1) and dried at 60° C. Yield: 6 g (76%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([OH:15])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]([NH2:31])=[NH:30].C1COCC1>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([NH:30][C:29]([NH2:31])=[NH:28])=[O:15]
Reactant: N=C(N)N
Reactant: Cc1nc2c(cc1C(=O)O)CCCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
In an atmosphere of argon, metallic sodium (446.6 mg, 0.019 g atom) was dissolved in anhydrous methanol (15.0 ml) at room temperature, and the solution was mixed with guanidine hydrochloride (1.89 g, 19.7 mmol) at 0° C. After 30 minutes of stirring at room temperature, the thus precipitated sodium chloride was removed by filtration using a glass filter and the resulting filtrate was evaporated under reduced pressure to obtain free guanidine. In an atmosphere of argon, 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylic acid (406.3 mg, 1.98 mmol) was suspended in THF (8.0 ml) and mixed with CDI (491.5 mg, 2.97 mmol) at room temperature. This was stirred at room temperature for 2 hours and then at 50° C. for 1 hour, mixed with the previously obtained guanidine THF suspension (6.0 ml) by its dropwise addition and then stirred at room temperature for 18 hours After evaporation of the solvent under reduced pressure, the thus obtained residue was mixed with waterandextractedwith ethyl acetate. The thus obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the thus formed crystals were washed with ether to obtain the title compound (192.5 mg, 39.5%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:40](Cl)(=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:43])[CH2:41][CH3:42])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 16.7 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (85 mg, 0.15 mmol) in dichloromethane (2 mL) was added propanoyl chloride (15.6 mg, 0.17 mmol). Triethylamine (30 mg, 0.30 mmol) was added, and the resultant mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 25 to 55% over 15 min, UV detection at 214 nm) to give 15.7 mg (17%) of the title compound as an off white solid. MS (ES) m/e 625.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:6][C:7](O)=[O:8])=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1COCC1>[CH2:14]([O:13][C:11]([NH:10][C@@H:5]([CH2:6][C:7]([Cl:29])=[O:8])[C:3]([O:2][CH3:1])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Z-asp-OMe (175 g, 622 mmol) was dissolved in THF (1750 ml) and admixed with 2 ml of DMF. 86.9 g (684 mmol) of oxalyl chloride were dissolved in 200 ml of THF (slightly exothermic), cooled back to room temperature (RT) and added dropwise to the solution of the amino acid over 1 hour (h). After a further hour at RT, the solution was initially sparged with nitrogen for 10 min, concentrated on a rotary evaporator at a maximum of 30° C. and coevaporated repeatedly with toluene. The resulting dirty white solid was dried to constant weight under in-house vacuum (about 1.5 mbar) and reacted further without further purification. Yield: 186.6 g (quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2].[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:17][CH:16]=[CH2:15])([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=CCBr
Agent: [Ti+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
A dry round bottom flask was purged with nitrogen and charged with 1-t-butoxycarbonyl-4-piperidinone (20 g, 100 mmol), titanocene dichloride (1.2 g, 5 mmol) and zinc dust (7.8 g, 120 mmol) in 100 mL dry THF. Allyl bromide (11.3 mL, 130 mmol) was added and the mixture was stirred for 5 h at rt. The mixture was diluted with 700 mL EtOAc, washed with 2.0 M HCl (2×200 ML), 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography (650 g silica, 10/1 CH2Cl2/Et2O eluant) afforded 10.9 g (45%) of the title compound: 1H NMR (300 MHz) δ 1.4-1.6 (13H), 2.2-2.25 (d, 2H), 3.1-3.2 (m, 2H), 3.75-3.85 (m, 2H), 5.1-5.25 (m, 2H), 5.78-5.92 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[Br-].C([N+]1(C)[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)C1C=CC=CC=1>C(O)C.O>[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCC(=O)CC2)cc1
Temperature: 100 °C

Procedure:
Anhydrous potassium carbonate was added to a solution of 4-methoxyaniline (1.2 g, 9.8 mmol) in ethanol (10 mL) followed by a dropwise addition of a solution of compound of example 116 (2.77 g, 9.8 mmol) in water (3.0 mL). The reaction mixture was heated at 100° C. for 1 h., allowed to cool to room temperature, poured into ice water (100 mL) and extracted using EtOAc (3×50 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated to get the title compound.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=[O:15])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH:18](Br)([CH3:20])[CH3:19].C(O)(=O)C>CN(C)C=O.O>[CH:18]([N:11]1[CH:12]=[C:13]([CH:14]=[O:15])[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10]1)([CH3:20])[CH3:19]
Reactant: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Add 10 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde to a suspension of 1.6 g of 80% sodium hydride in 100 ml of dimethylformamide under nitrogen at 10° to 20° C. Add 7.1 g of isopropyl bromide to the resulting admixture and then stir it for 4 hours at 40° C and 7 hours at 50° C. Mix 0.8 ml of glacial acetic acid therein to obtain (after addition to 190 g of ice and water) 8.9 g of product. Recrystallize three times from dimethylformamide and water to obtain 1-isopropyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde [m.p. 168.5° to 170.5° C]. Evaporate the mother liquor and chromatograph the residue to obtain 1-isopropyl-5-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:27](O)=[O:28])[C:14]3[C:19]([CH3:20])=[N:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:15]=3[N:16]=2)=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][C@H:48]([CH2:52][C:53]([F:56])([F:55])[F:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl.O>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:27]([C:13]2[C:14]3[C:19]([CH3:20])=[N:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:15]=3[N:16]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=3)[CH:12]=2)=[O:28])[C@H:48]([CH2:52][C:53]([F:55])([F:56])[F:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: COCOc1ccc(-c2cc(C(=O)O)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CC(F)(F)F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(-c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)C[C@H]3CC(F)(F)F)c3c(C)nn(C4CCCCO4)c3n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a suspension of 0.80 g of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 12 ml of DCM were added 1 ml of Hünig's base, 0.48 g of BEP and 0.50 g of (R)-3-(2,2,2-trifluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester. The reaction was stirred at r.t. for 2 d. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 0.58 g (60%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:49])(=[O:48])[CH2:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:49])(=[O:48])[CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O-:47])=[O:46]
Reactant: O=C(O)CCCCC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: O=C([O-])CCCCC(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of adipic acid (0.041 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and the solution was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give a white solid of Nilotinib adipate form I.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[C:23]=3[CH3:30])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1([S:37]([OH:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([S:37]([OH:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:31]1([S:37]([OH:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl:29][C:24]1[C:23]([CH3:30])=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[O:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:20][CH2:19]1
Reactant: Cc1c(OC2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc(Cl)c1Cl
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCO
Product: Cc1c(OC2CCN(CC3CCNCC3)CC2)ccc(Cl)c1Cl
Temperature: 75 °C
Yield: 91.6 %

Procedure:
A suspension of 4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (120 g) and ethanol (600 mL) were heated to 75° C. to give a solution. Benzenesulfonic acid (70% in water, 144.2 g) in ethanol (120 mL) was added dropwise over 45 min followed by a rinse with ethanol (60 mL). The solution was heated at 75° C. for 1 h and was then cooled to 20° C. over 1 h 45 min. The resultant solid was collected, the filter cake was washed with ethanol (480 mL) then dried under vacuum overnight at 40° C. to give 4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine di-benzenesulfonate salt as a white solid (161.9 g).
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].[Cl:16][C:17]([SH:20])(Cl)Cl.ClCCl>O>[Cl:16][C:17]1[S:20][N:13]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:15][CH:14]=2)[N:12]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nsc(Cl)n2)cc1
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution of 75.6 gm of sodium hydroxide in 100 ml of water was added to a stirred mixture of 101.4 gm of p-nitrobenzamidine hydrochloride, 70 gm of perchloromethyl mercaptan and 760 ml of dichloromethane, while keeping the temperature below -5° C. After additional 2 hours at -5° C., the resulting suspension was filtered, and the organic phase was separated, evaporated to dryness, and the residual solid was recrystallized from 95% ethanol, yielding 45 gm of the title compound, m.p. 143°-145° C.