Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][C:17]4([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3]1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:18]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:16][CH:15]1[N:12]1[CH2:11][CH2:10][CH:9]([C:7]([NH:6][C:2]2([CH3:1])[CH2:5][CH2:4][CH2:3]2)=[O:8])[CH2:14][CH2:13]1
Reactant: CC1(NC(=O)C2CCN(C3CC4(CCN(C(=O)OC(C)(C)C)C4)C3)CC2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(NC(=O)C2CCN(C3CC4(CCNC4)C3)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.747 g, 1.84 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(6-azaspiro[3.4]oct-2-yl)-N-(1-methylcyclobutyl)piperidine-4-carboxamide trifluoroacetate as a dark yellow oil which was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.56 g, 0.77 mL, 5.52 mmol) and 4-nitrophenyl chloroformate (0.555 g, 2.76 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM (15 mL) and 1 N NaOH sol. (15 mL). The aqueous layer was extracted with DCM (4×20 mL), dried over MgSO4 and the solvent evaporated. The residue was semi-purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give 4-nitrophenyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.60 g, 69%) as a yellow gum as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH3:44])[C:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br)=[O:37])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>CN(C)C=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH3:44])[C:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:16][C:13]2[CH:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:15][N:14]=2)=[O:37])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Reactant: COc1ccc(CCN(C)C(=O)CCCCCBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)C(=O)CCCCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Temperature: 100 °C
Yield: 84.5 %

Procedure:
3.85 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one were dissolved in 50 ml of anhydrous dimethylformamide. 3.15 g of finely ground potassium carbonate were added to the solution, and the reaction mixture was heated under a nitrogen atmosphere to 100° C. with stirring. A solution of 5.6 g of 5-{N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminocarbonyl}-pentyl bromide in 10 ml of anhydrous dimethyl formamide was slowly added dropwise to the solution, and the reaction mixture was stirred at 100° C. for a further 2 hours. In order to work up the reaction mixture, it was cooled and then the precipitated salts were filtered out and the filtrate was concentrated by evaporation. The oily residue which remained was dissolved in ethyl acetate and washed with 7% strength sodium hydroxide solution in order to remove unreacted 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one. The organic phase was separated, dried with sodium sulfate and concentrated by evaporation. 6.5 g of 3-{5-[N-(2-(3,4-dimethyloxyphenyl)-ethyl)-N-methylaminocarbonyl]-pentyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (11%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O>[CH3:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH:25][CH:1]=[O:3])[S:23][CH:24]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A mixture of acetic anhydride (6.1 g) and formic acid (2.8 g) was stirred for 2 hours at 50° C. The resulting mixture was cooled and ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (4.6 g) was added thereto at 15° C. After the mixture was stirred for 3.5 hours at ambient temperature, cooled water (100 ml) was added thereto. The resulting mixture was extracted with ethyl acetate (200 ml). The extract was washed with water and then with a saturated aqueous solution of sodium bicarbonate until the washing was changed to weakly alkaline solution. The extract was further washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to give ethyl 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate (syn isomer) (4.22 g), mp 122° to 124° C. (dec.).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:12])[CH2:10][CH3:11])[C:3]([O:5]CC)=O.[Cl-].C[C:15](=[NH2+:17])C.N>>[OH:1][C:2]1[C:3](=[O:5])[NH:17][CH2:15][C:8]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CC(C)=[NH2+]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Agent: N
Agent: [Cl-]
Product: CCC(=O)C1=C(O)C(=O)NC1

Procedure:
Reaction of ethyl 2,4-dioxohexanoate with dimethylmethylene ammonium chloride and ammonia, analogous to the procedure in Preparation 8, gave the title compound as an amorphous solid. 1H nmr (250 MHz, DMSO-d6) δ0.99 (t, J=7.3 Hz, 3H), 2.75 (q, J=7.3 Hz, 2H), 3.81 (s, 2H), 8.84 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.O.O.[NH2:17][NH2:18]>O>[CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[N:17][NH2:18]
Reactant: NN
Reactant: CC(C)C(=O)c1cccc([N+](=O)[O-])c1
Solvent: O
Product: CC(C)C(=NN)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a partially dissolved solution of 2-methyl-1-(3-nitrophenyl)-1-propanone (Preparation 55, 1.0 g, 5.2 mmol) in industrial methylated spirits (6 ml) was added dropwise hydrazine hydrate monohydrate (0.5 ml, 10.4 nmuol). The reaction mixture was refluxed for 16 h, before cooling to room temperature and pouring into ice and water (50:50, 15 ml) giving a very fine white precipitate in a yellow solution. The mixture was extracted with diethyl ether (2×50 ml), the combined organic extracts were washed with brine and dried (MgSO4), before concentrating to give an amber oil. The crude product was purified by chromatography on silica gel cluting with dichloromethane:ethyl acetate (19:1) to give the title compound as a mixture of cis and trans hydazones (0.54 g, 50%).
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+:18].[K+].Br[CH:21](C(OCC)=O)[C:22]([O:24]CC)=[O:23]>CC(=O)CC>[N+:11]([C:7]1[CH:8]=[C:9]([Br:10])[C:2]2[O:1][C:21]([C:22]([O-:24])=[O:23])=[CH:4][C:3]=2[CH:6]=1)([O-:13])=[O:12].[K+:18]
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C([O-])c1cc2cc([N+](=O)[O-])cc(Br)c2o1
Temperature: 25 °C
Yield: 108.1 %

Procedure:
A mixture of 11.0 gm (44.7 mMol) 2-hydroxy-3-bromo-5-nitrobenzaldehyde, 5.56 gm (40.24 mmol) potassium carbonate, and 8.0 mL (46.95 mMol) diethyl bromomalonate in 55 mL 2-butanone was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between 450 mL diethyl ether and 250 mL water and the aqueous phase was adjusted to pH of about 1 by the addition of dilute sulfuric acid. The phases were separated and the aqueous phase was extracted with two 150 mL portions of diethyl ether. The organic phases were combined, washed with 50 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was dissolved in 200 mL ethanol to which were added 4.8 gm (85.5 mMoL) potassium hydroxide. The resulting suspension was warmed on a steam bath for 1 hour. The suspension was then cooled to room temperature. After about 18 hours the mixture was filtered and dried under reduced pressure to provide 14.1 gm (98%) of the desired compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9](F)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:24][C@H:25]1[O:30][C@@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:27]3[CH2:26][C@H:25]([CH3:24])[O:30][C@H:29]([CH3:31])[CH2:28]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=Cc1cc2c(Cl)noc2c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Temperature: 85 °C

Procedure:
To an ice cooled and stirred solution of 3-chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 532, 1.0 g, 8.75 mmol) in anhydrous acetonitrile was added DIPEA (1.8 mL, 10.5 mmol) followed by cis 2,6-dimethylmorpholine (1.3 mL, 10.5 mmol) and the mixture heated at 85° C. for 4 hours. It was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulfate. It was filtered and the filtrate evaporated under reduced pressure. The residue was purified over silica gel column using a gradient of ethylacetate in pet.ether to give title compound as solid. Yield: 2.3 g (85%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][C:10]([CH3:13])([CH3:12])[O:11][C:5]2=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:22]=[O:23])C.O>C1COCC1>[CH3:12][C:10]1([CH3:13])[O:11][C:5]2[C:6](=[N:7][C:2]([CH:22]=[O:23])=[CH:3][CH:4]=2)[CH:8]=[CH:9]1
Reactant: CN(C)C=O
Reactant: CC1(C)C=Cc2nc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C=Cc2nc(C=O)ccc2O1
Reaction time: 0.58 h
Yield: 23 %

Procedure:
To a solution of 23 (200 mg, 0.83 mmol) in anhydrous THF (5 mL) at −78° C. was added BuLi (2.5M, 0.35 mL) and stirred for 35 minutes, then DMF (0.08 mL, 0.1 mmol) was added dropwise. The reaction was stirred at −78° C. for 30 additional minutes. Water (3 mL) was added to quench the reaction and was extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography; 20:1 Hx/EtOAc. To give the product as a yellowish solid (23% yield). 1H NMR δ 1.53 (s, 6H), 6.01 (d 1H, J=10.4), 6.58 (d, 1H, J=10.4), 7.13 (d, 1H, J=8.4), 7.77 (d, 1H, J=8.4), 9.93 ppm (s, 1H). 13C NMR δ 28.8, 78.7, 123.0, 123.3, 123.4, 136.3, 145.8, 153.7, 191.9 ppm
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[I:9]N1C(=O)CCC1=O.O>CS(C)=O>[I:9][C:7]1[C:2]([NH2:1])=[N:3][C:4]([NH2:8])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cccc(N)n1
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(I)c(N)n1
Temperature: 25 °C
Yield: 23 %

Procedure:
2,6-Diaminopyridine (100 g) was dissolved in DMSO (400 mL), and N-iodosuccinimide (100 g) was added thereto all at once under stirring at room temperature. The reaction solution was stirred for 10 minutes at room temperature, after which water (3.5 L) was added thereto and the precipitated solids were filtered off. The aqueous layer thus obtained was extracted with ethyl acetate (1.3 L) 3 times. The ethyl acetate layers were combined, and which was concentrated under a reduced pressure, and the residue thus obtained was purified by silica gel chromatography (heptane:ethyl acetate=2:3) to obtain the titled compound (24 g).
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[C:20](=[O:21])[CH2:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:51][O:50][CH2:49][CH2:48]1>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH:17]([CH3:22])[CH2:18][CH2:19][C:20]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:48][CH2:49][O:50][CH2:51][CH2:40]3)=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: C1COCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-methyl-5-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 837 and morpholine (39 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (18 mg) was obtained.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]([C:12]1[CH:33]=[CH:32][C:15]([C:16]([N:18]([CH3:31])[C:19]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])=[O:17])=[CH:14][CH:13]=1)#[N:11].Cl.[NH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[CH3:42][O:41][C:39]([CH2:38][CH2:37][CH2:36][NH:35][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:18]([CH3:31])[C:16](=[O:17])[C:15]2[CH:32]=[CH:33][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[C:20]([N+:28]([O-:30])=[O:29])[CH:21]=1)=[O:40]
Reactant: COC(=O)CCCN
Reactant: CN(C(=O)c1ccc(C#N)cc1)c1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCNC(=O)c1ccc(N(C)C(=O)c2ccc(C#N)cc2)c([N+](=O)[O-])c1
Reaction time: 64 h

Procedure:
2.84 g of N-ethyl-diisopropylamine are added, with cooling to 0° C., to a mixture of 3.2 g of 4-[N-(4-cyano-benzoyl)-methylamino]-3-nitro-benzoylchloride, 1.68 g of methyl 4-aminobutyrate-hydrochloride and 50 ml of methylene chloride. The mixture is stirred for 64 hours and allowed to return to ambient temperature. The methylene chloride is evaporated off and the residue is purified over silica gel (eluant:ethyl acetate/ethanol=200:1). Yield: 3.9 g (100% of theory), Rf value: 0.62 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][OH:7])=[O:5])[CH3:3].CO.[CH3:10][C:11]([CH:13]=O)=O.[OH-].[Na+]>O>[CH3:3][C:2]1[N:1]=[C:11]([CH3:13])[CH:10]=[N+:6]([O-:7])[C:4]=1[OH:5]
Reactant: CC(=O)C=O
Reactant: C[C@H](N)C(=O)NO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c[n+]([O-])c(O)c(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.6 %

Procedure:
407 mmol (42.4 g) alanine hydroxamic acid were cooled to −10° C. in 200 ml water and methanol each, 400 mmol (57 ml 40% solution) methylglyoxal were added dropwise and subsequently the pH was adjusted to approximately pH 11 with 19 ml 30% NaOH. Heating up to 0° C. was carried out within 2 h and then pH 3 was adjusted with 20% NaOH. The solution was concentrated until dryness under vacuum distillation, the residue was heated to reflux with 50 ml ethanol, after cooling filtering was carried out and the filtrate again concentrated until dryness. 44 g of the solid residue were dissolved in 50 ml water and 15 mmol (4.06 g) FeCl3*6H2O were added, heated up to 50° C. for 30 minutes, concentrated and stored at 5° C. for 4 h. The precipitated solid was filtered off and dried. 3.7 g solid in 50 ml water and 10 ml ethanol were adjusted to pH 11 with 6 ml 1 M NaOH, stirred over night and centrifugalized. The supernatant was decanted, pH 3 was adjusted with 3 ml 1 M HCl and concentrated until dryness. 4.2 g solid were refluxed in 20 ml ethanol, cooled and filtered off. The filtrate was again concentrated until dryness and the obtained 2.8 g solid were suspended with 10 ml water, heated up to 50° C. and left for cooling over night. The suspension was centrifugalized, the supernatant decanted and concentrated until dryness. 2.0 g (3.5% yield) of the title compound were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](OC)=[O:5].O.[NH2:16][NH2:17]>>[CH3:1][CH:2]([CH3:14])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:16][NH2:17])=[O:5]
Reactant: NN
Reactant: COC(=O)C(c1ccccc1)C(C)C
Solvent: O
Product: CC(C)C(C(=O)NN)c1ccccc1
Yield: 47 %

Procedure:
A stirred solution of methyl 3-methyl-2-phenylbutanoate (0.87 g, 1 eq) and hydrazine hydrate (10 mL) was heated at 110° C. for 12 h. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (0.17 g, 47%) that was purified by column chromatography over silica gel to yield the product (0.61 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(=O)OC(C)CO1>C(OCC)C>[C:2]1([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1COC(=O)O1
Solvent: CCOCC
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 155 °C
Reaction time: 17 h

Procedure:
Under argon, a solution containing 122 mg of chlorobenzene, 106 mg of sodium carbonate, 157 mg of styrene and 1 ml of propylene carbonate stabilized 0.001 M colloid solution is heated at 155° C. with stirring in a sealed vessel for 17 h. At the end of the reaction, 2 ml of diethyl ether is added, and the mixture is filtered. The yield of isolated trans-stilbene is 15%.
Reaction SMILES: [CH:1](=[C:5]1/[C:6](=[O:11])[CH2:7][C:8](=[O:10])[NH:9]/1)\[CH:2]([CH3:4])[CH3:3].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>ClCCl>[C:12]([O:11][C:6]1=[CH:7][C:8](=[O:10])[NH:9]/[C:5]/1=[CH:1]\[CH:2]([CH3:4])[CH3:3])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)Cl
Reactant: CC(C)/C=C1\NC(=O)CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)OC1=CC(=O)N/C1=C\C(C)C
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
31.8 g of (Z)-5-isobutylidenepyrrolidine-2,4-dione was suspended in 318 ml of dichloromethane and cooled to -5° C. Then first 23.22 g of butyryl chloride was added and then 27.32 g of triethylamine was added. After the addition the mixture was stirred another 10 minutes at 0° C., then diluted with 100 ml of dichloromethane, and washed twice with 100 ml of 5 percent NaHCO3 solution each and twice with 100 ml of 0.4M hydrochloric acid each. The aqueous phases were extracted separately with dichloromethane and the combined organic phases were dried on magnesium sulfate. After the distilling off of the solvent, the crude product (46 g) was recrystallized from hexane. The yield of the title compound was 38.8 g (84 percent of theory). The title compound had a melting point of 111° to 112° C. Other data concerning the title compound was:
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:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>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-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]
Reactant: O=C(O)/C=C\C(=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-])/C=C\C(=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 maleic acid (0.132 g, 1.13 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and 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 60° C. in a vacuum oven for two days to give amorphous Nilotinib maleate.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH3:31][S-:32].[Na+]>CN(C=O)C>[CH:27]1([C:25]([N:22]([CH2:21][C:15]2[CH:16]=[C:17]([S:32][CH3:31])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:30])[CH:7]=2)[CH2:23][CH3:24])=[O:26])[CH2:29][CH2:28]1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(SC)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To {2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester 0.186 g, 0.45 mmol) in DMF (0.5 mL) was added sodium thiomethoxide (0.035 g, 0.50 mmol), and the reaction was stirred at 85° C. for 2 hours. Additional sodium thiomethoxide (0.070 g, 1.0 mmol) was added, and the reaction was stirred at 85° C. for another 2 hours. An aqueous work-up was performed, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: C([O:4][C:5]1[C:6]([Br:25])=[CH:7][C:8]([F:24])=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:10]=1)C=C.O.Cl.C(N(CC)[C:31]1[CH:36]=CC=C[CH:32]=1)C>>[CH2:36]([C:10]1[C:5]([OH:4])=[C:6]([Br:25])[CH:7]=[C:8]([F:24])[C:9]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[N:13]([CH3:22])[C:12]1=[O:23])[CH:31]=[CH2:32]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Agent: Cl
Solvent: O
Product: C=CCc1c(O)c(Br)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O

Procedure:
3-(5-Allyloxy-4-bromo-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (3.17 g) was dissolved in N,N-diethylaniline (11 ml) and allowed to react at 210° C. for 2.5 hours. After the completion of the reaction, the reaction solution was poured into water, and diluted hydrochloric acid was added thereto for acidification. It was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:2 v/v) to obtain the objective 3-(2-allyl-4-bromo-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluor-omethyl-2,4(1H,3H)-pyrimidinedione (2.57 g).