Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=O>C(O)(=O)C>[CH3:7][C:4]1[C:3]([C:8]#[N:9])=[C:2]2[N:1]=[CH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:6]2[N:5]=1
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CN(C)C=CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: Cc1nn2c(-c3ccncc3)ccnc2c1C#N
Yield: 52.5 %

Procedure:
A mixture of 6.1 g of 5-amino-3-methyl-4-pyrazole carbonitrile and 8.81 g of 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one in 50 ml of glacial acetic acid is stirred and heated at reflux for 5 hours. The reaction mixture is cooled and the precipitate which forms is collected by filtration and washed with water and a little dichloromethane to give a solid. The solid is partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer is dried over anhydrous sodium sulfate and passed through a short column of hydrous magensium silicate. The addition of hexane to the eluate crystallizes the product which is collected by filtration to give 6.17 g of the desired product, mp 220°-221° C.
Reaction SMILES: Cl.[CH:2]1([C:6]([NH:8][CH:9]([CH2:15][SH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)[CH2:5][CH2:4][CH2:3]1>C(O)C>[CH:2]1([C:6]2[S:16][CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C(CS)NC(=O)C1CCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1csc(C2CCC2)n1
Reaction time: 8 h

Procedure:
A solution of HCl (4M in 1,4-dioxane, 3.46 mL) was added to a solution of ethyl 2-(cyclobutanecarboxamido)-3-mercaptopropanoate (example 58, step a) (3.2 g) in ethanol (20 mL) and the resulting mixture stirred overnight. The solvent was evaporated and the residue azeotroped twice with toluene. The residue was redissolved in acetonitrile (50 mL), manganese dioxide (12 g) was added and the mixture heated at reflux overnight. The reaction was filtered through a pad of Celite which was then washed with MeCN (3×100 mL). The combined filtrate and washings were evaporated and the residue was purified by silica gel chromatography eluting with 9:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 0.48 g.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)/C=C/c1cccc(F)c1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: Fc1cccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)c1

Procedure:
The product of Example 1B (120 mg, 0.41 mmol) and (E)-2-(3-fluorophenyl)vinylboronic acid (82 mg, 0.50 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.01 (m, 4H), 2.88-3.02 (m, 2 H), 3.04-3.10 (m, 1 H), 3.11-3.22 (m, 2 H), 4.12 (s, 2 H), 6.98 (t, J=7.6 Hz, 1 H), 7.06-7.14 (m, 1 H), 7.22 (d, J=7.6 Hz, 1 H), 7.30 (d, J=16.2 Hz, 1 H), 7.38-7.42 (m, 1 H), 7.42-7.50 (m, 2 H), 7.52-7.58 (m, 1 H), 7.77 (d, J=16.5 Hz, 1 H); MS (DCI) m/z 333 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])(O)=[O:2].Cl.[CH2:29]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>CN(C=O)C>[CH2:29]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH:39][C:1](=[O:2])[CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][Si:18]([CH:19]([CH3:21])[CH3:20])([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 0.1 %

Procedure:
To a solution of methyl (±)-3-carboxy-4-[4-(triisopropylsilyloxy)phenyl]butanoate (5.00 g, 12.67 mmole) in dry DMF (60 mL) at RT was added serine benzyl ester hydrochloride (3.52 g, 15.21 mmole), HOBt (2.06 g, 15.21 mmole), Et3N (5.3 mL, 38.01 mmole), and EDC (2.92 g, 15.21 mmole). After 18 hr the mixture was concentrated. The residue was chromatographed on silica gel (80% EtOAc/hexanes) to give the title compound (5.76 mg, 79%) as a pale yellow oil: MS (ES) m/e 572 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:10]([Cl:30])=[CH:9][N:8]=1.CN(C)[CH:33]=[O:34].[BH4-].[Na+]>CCCCCC.O.CO.C1(C)C=CC=CC=1>[Cl:30][C:10]1[C:11]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:12][C:7]([CH2:33][OH:34])=[N:8][CH:9]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Br)ncc2Cl)c1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.58M hexane solution, 0.33 ml, 0.520 mmol) was added to a toluene (5 ml) solution of 2-bromo-5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.434 mmol) at −78° C. The resulting mixture was stirred for 2 hours. To the reaction mixture was added dropwise dimethylformamide (44 μl, 0.564 mmol). The reaction mixture was stirred for 1 hour. To the reaction mixture were added methanol (5 ml) and sodium borohydride (33 mg, 0.868 mmol). The temperature of the resulting mixture was raised to room temperature, followed by stirring for 2 hours. Water was added to the reaction mixture and then, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (142 mg, 0.344 mmol, 80%) as a colorless amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:6]([Cl:19])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(C(=O)O)cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Cl)cc1OC
Yield: 100 %

Procedure:
To a stirred suspension of 3-methoxy-4-methoxycarbonylbenzoic acid (4.1 g, 19.5 mmol) and oxalyl chloride (2.4 ml, 27.3 mmol) in dry dichloromethane (100 ml) was added 2 drops of dimethylformamide. After 3 h at room temperature the clear solution was evaporated to an oil. The oil was redissolved in dry dichloromethane and evaporated, this procedure was repeated to give 3-methoxy-4-methoxycarbonylbenzoyl chloride as an oil (100%) which was used immediately in the next step.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13](Cl)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C@H:22]([NH2:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([NH:31][C@H:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH3:21])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: COc1ccc([C@H](C)N)cc1
Product: COc1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
136 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and S-(−)-1-(4-methoxyphenyl)ethylamine in accordance with general method 5. MS (ES+): m/z=445 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])c(F)c1
Yield: 58 %

Procedure:
A mixture of 1.1 g (4.2 mmol) of 4-methyl-4′-nitro-3′-fluorobenzophenone, 0.654 g of recrystallized N-bromosuccinimide, 60 mg benzoyl peroxide, and 20 mL CCl4 were refluxed under argon for 3 hours. The hot solution was filtered through a glass sintered filter and rinsed with 20 mL of hot CCl4, until the crystals became colorless. The crystals were washed with 6 mL of cold CCl4 and the solution was concentrated under reduced pressure. The crude product was recrystallized from hexane and dried under vacuum. The resultant yield was 58%. 1H-NMR CDCl3: δ8.18 (dd, aromatic, 2H), 7.78 (d, aromatic, 2H), 7.68 (m, aromatic, 1H), 7.56 (d, aromatic, 2H), 4.57 (s, methyl, 3H). 13C-NMR: δ 192.4 (carbonyl); 156.2, 154.0, 146.7, 144.5, 144.4, 143.7, 143.6, 135.0, 133.0 130.5, 126.5, 125.5, 119.7, 119.4 (aromatic); 31.7 (alkyl). 19F-NMR: δ −118.5 ppm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH3:13])[CH:6]=1)=[O:4].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:13]
Reactant: Oc1ccccc1
Reactant: CCOc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(C(=O)COc2ccccc2)c1
Yield: 76.7 %

Procedure:
A mixture of 2-bromo-3′-ethoxyacetophenone (2.4 g, 10 m mol), phenol (1.0 g, 10.6 m mol), potassium carbonate (2.0 g, 14.5 m mol) and acetone (30 ml) was heated under reflux for 6 hours. After insoluble matter was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform (40 ml), washed with water (2×20 ml), and dried. Thereafter, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (50 g) using chloroform. Thus, the desired compound (1.94 g, 75%) was obtained as an oily material.
Reaction SMILES: [Br:1][C:2]1[N:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=[O:26])C>>[Br:1][C:2]1[N:12]=[CH:11][CH:10]=[C:9]([C:13]([C:14]2[N:15]=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([O:20][CH3:21])[N:19]=2)=[O:26])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(Cc2nc(OC)cc(OC)n2)ccnc1Br
Reactant: CC(=O)O
Product: CCOC(=O)c1c(C(=O)c2nc(OC)cc(OC)n2)ccnc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.28 g of ethyl 2-bromo-4-[(4,6-dimethoxy-2-pyrimidinyl)methyl]nicotinate, 3.61 g of SeO2 and 100 ml of glacial acetic acid are combined under nitrogen, heated to 110° for 1.5 hrs and slowly cooled to RT still under nitrogen. The mixture is filtered, washed through with 10 ml of acetic acid and the filtrate evaporated to remove the acetic acid. 100 ml of methylene dichloride is added to the residue and the mixture washed twice with 100 ml of sat. aqueous NaHCO3. The CH2Cl2 phase is filtered and evaporated and the residue digested with 25 ml of 25% ethyl acetate/hexane at 50° for 15 mins. This solution is then poured onto a silica gel column and eluted with 3×125 ml of 25% ethyl acetate/hexane. Evaporation of combined fractions 1 and 2 yields the title product mp 98°-99°.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.O.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C>[NH2:8][C@@H:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)=[CH:19][CH:20]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ccc(C(F)(F)F)cn3)cc2)COC1(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)CCc1ccc(Nc2ccc(C(F)(F)F)cn2)cc1
Temperature: 80 °C
Yield: 100.7 %

Procedure:
To a solution of (S)-2,2-dimethyl-4-{2-[4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl]-ethyl}-oxazolidine-3-carboxylic acid tert-butyl ester (54 mg) in acetonitrile (0.5 ml) were added water (1.5 ml) and trifluoroacetic acid (0.071 ml). The mixture was heated at 80° C. for 2 h. The mixture was then cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed sequentially with 1 N aq. sodium hydroxide solution and saturated brine, the phases were then separated and the organic phase was dried over sodium sulphate and concentrated in vacuo to afford (S)-2-amino-4-[4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl]-butan-1-ol (38 mg, quant.) as a yellow oil which was used in the next step without further purification. MS (ISP): 326.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:5][S:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH2:21])[N:15]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([S:7]([NH:10][C:11]([NH:21][C:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[N:15]=2)=[O:12])(=[O:8])=[O:9])=[CH:5][S:4][N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1csnc1Cl
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2csnc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 10 ml portion of the methylene chloride solution of 3-chloro-4-isothiazolesulfonyl isocyanate, prepared in Example 2, was added to 0.2 g of 4.6-dimethyl-2-pyrimidinamine, and the mixture stirred 0.5 hour at ambient temperature. The solvent was evaporated and the residual solid triturated with ether, collected and dried giving 0.5 g of the title compound, m.p. 136°-140°. IR: 1720 and 1700 cm-1 (C=O).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:12][C:11]1[C:2]([NH:25][S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)(=[O:24])=[O:23])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Temperature: 150 °C

Procedure:
2,3-Dichloroquinoxaline (26.1 g, 131.1 mmol), m-Nitrobenzene sulfonamide (26.5 g, 131.1 mmol) and potassium carbonate (18.1 g, 131.1) were dissolved in anhydrous DMSO (500 mL). The reaction was heated to 150° C. for 2 h. The reaction mixture was poured into water (400 mL), followed by addition of 2M HCl (60 mL). The product was extracted with EtOAc (3×500 mL). The organic layers were combined and washed water (2×500 mL) and brine (2×500 mL). The product was then dried with sodium sulfate to give N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide. MS (EI) m/z for C14H9ClN4O4S: 364.94, 366.97 (MH+)
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH:41][C:42]4[C:43]5[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=5[N:45]=[CH:46][N:47]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=3)=[O:40])=[CH:27][C:26]=2[NH:41][C:42]2[C:43]3[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=3[N:45]=[CH:46][N:47]=2)=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of the product of Example 52F (167 mg, 0.2185 mmol) in 1,4-dioxane (4 mL) was treated with a solution of lithium hydroxide monohydrate (18.3 mg, 0.437 mmol) in water (2 mL) at ambient temperature, then heated at 60° for 40 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (30 mL), adjusted the aqueous pH to 6 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 5% methanol/methylene chloride afforded the title compound as a yellow solid (84 mg, 71%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.15-3.30 (m, 1 H) 5.62 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.77-6.89 (m, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.64 (d, J=8.09 Hz, 1 H) 7.87 (d, J=8.46 Hz, 1 H) 7.95 (dd, J=8.82, 2.57 Hz, 1 H) 8.04 (s, 1 H) 8.21 (d, J=9.19 Hz, 1 H) 8.42 (d, J=2.57 Hz, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.92 (s, 1 H); MS (ESI+) m/z 542/544 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F-:10].[K+]>CS(C)=O>[F:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: N#Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(F)cc1
Temperature: 180 °C
Yield: 75 %

Procedure:
200 g of 4-chlorobenzonitrile, 101.4 g of potassium fluoride, 25 g of dimethyl sulfoxide, and 5.60 g of (N,N-dimethylimidazolidino)tetramethyl-guanidinium chloride were placed in a 1 liter 4-neck flask equipped with anchor stirrer, thermometer, and reflux condenser with bubble counter. The mixture was then heated with stirring to 180° C. and this temperature was maintained for 16 hours. The mixture was then cooled to room temperature, water was added to the reaction mixture in a volumetric ratio of 1:1, and the mixture was extracted with diethyl ether. After washing, concentration, and drying the separated organic phase, 4-fluorobenzo-nitrile was isolated in a yield of 75%.
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:52])(=[O:51])[CH2:41][C:42]([CH2:47][C:48]([OH:50])=[O:49])([C:44]([OH:46])=[O:45])[OH:43]>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-:52])(=[O:51])[CH2:41][C:42]([CH2:47][C:48]([O-:50])=[O:49])([C:44]([O-:46])=[O:45])[OH:43]
Reactant: O=C(O)CC(O)(CC(=O)O)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-])CC(O)(CC(=O)[O-])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 citric acid (0.218 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 citrate as characterized by the powder X-ray diffractogram depicted in FIG. 31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.Br[CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].CC(C)([O-])C.[Na+].[OH-].[Li+]>C(Cl)Cl.O.CO>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([N:1]3[CH2:29][CH2:30][CH2:31][CH2:32][C:33]3=[O:34])[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: O=C(Cl)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-amino-4′-methylbiphenyl-3-carboxylate (410 mg, 1.7 mmol) in CH2Cl2 (30 mL) and N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) at 0° C. was added 5-bromopentanoyl chloride (370 mg, 1.9 mmol). The mixture was stirred at room temperature overnight and then washed with aq. Na2CO3 solution and brine, dried (Na2SO4), and concentrated. The residue was dissolved in THF (30 mL) and cooled to 0° C. Sodium tert-butoxide (200 mg, 2.0 mmol) was added and the mixture was stirred at room temperature for 3 h. LC-MS indicated the cyclization reaction was complete. MeOH (20 mL) and water (10 mL) were added followed by lithium hydroxide (120 mg, 5.1 mmol). The mixture was stirred at room temperature for another 3 h, and LC-MS indicated the saponification was complete. The mixture was concentrated in vacuo. The residue was treated with water and acidified to pH 2-3 with 1N HCl, extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to afford a white solid. LC-MS: 310.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([C:15]([OH:17])=O)[CH:10]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([CH2:24][N:25]([CH3:27])[NH2:26])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([CH2:24][N:25]([CH3:27])[NH:26][C:15]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[O:13][C:12]=2[CH3:14])=[O:17])=[CH:22][CH:21]=1
Reactant: COc1ccccc1-c1cc(C(=O)O)c(C)o1
Reactant: COc1ccc(CN(C)N)cc1
Product: COc1ccc(CN(C)NC(=O)c2cc(-c3ccccc3OC)oc2C)cc1

Procedure:
5-(2-Methoxyphenyl)-2-methylfuran-3-carboxylic acid prepared in the Step 20-1-3 and N-(4-methoxybenzyl)-N-methylhydrazine prepared in the Step 14-1-2 were used and subjected to the same procedure as in Example 16-1 to give the title compound.