Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CS(Cl)(=O)=O.[CH2:32]([NH2:35])[CH:33]=[CH2:34].[I-].[K+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25][NH:35][CH2:32][CH:33]=[CH2:34])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C=CCN
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCNCc1nnc(CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 1.01 g. (3.00 mmole) of 5-chloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone in 15 ml. of methylene chloride and cooled to 0° C. is treated dropwise with 0.378 g. (3.30 mmole) of methane sulfonylchloride. The mixture is stirred for 1/2 hour, poured onto ice, and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer is removed, dried with anhydrous sodium sulfate and concentrated in vacuo to an oil. This resulting oil, dissolved in 20 ml. of tetrahydrofuran, is treated with 0.56 g. (10 mmole) of allylamine and 0.996 g. (6.0 mmole) of potassium iodide and heated to reflux for 24 hours. The reaction mixture is poured onto a cold (0°-5° C.) 10% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract is dried with anhydrous sodium sulfate and concentrated in vacuo to give 5-chloro-2-[3-[(allylamino)methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]([F:22])[F:21]>CN(C=O)C>[F:21][CH:20]([F:22])[CH2:19][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
10.04 g of isovanillin and 15.5 g of potassium carbonate are placed in an autoclave. 50 ml of DMF are added as well as 12.44 g of 2-bromo-1,1-difluoroethane. The autoclave is closed and heated at 60° C. for 20 h. Then the solids are filtered off and washed with 120 ml of DMF. About 120 ml of the solvent are distilled off and the residue poured on 200 ml of ice/water, where the product precipitates. After stirring the slurry for 30 minutes the product is filtered off and dried to give 13.69 g of the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>CCOC(C)=O>[ClH:2].[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(Cl)c2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1cccc(N2CCCNCC2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 183.7 %

Procedure:
Excess HCl in EtOAc was added dropwise to a solution of intermediate 1 (4.0 g, 11.6 mmol) in EtOAc and the reaction mixture was stirred at rt for 1.5 h. The reaction mixture was filtered to give 1-(2,3-dichlorophenyl)-1,4-diazepane hydrochloride salt (intermediate 2) (3.0 g, 90%) as a white solid. HPLC: 99%, RT 2.108 min. MS (ESI) m/z 245.0 [M+H]+. mp: 186-187° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26][CH3:27])=[O:25])[N:16]([CH3:31])[C:15]=3[CH:32]=2)=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[CH3:33][O-:34].[Na+].O>CO>[Br:1][C:2]1[C:3]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26][CH3:27])=[O:25])[N:16]([CH3:31])[C:15]=3[CH:32]=2)=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[O:34][CH3:33]
Reactant: C[O-]
Reactant: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)c(Cl)c4Br)cc3n2C)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)c(OC)c4Br)cc3n2C)c1
Yield: 8.4 %

Procedure:
The reaction and post-treatment were carried out according to Example (3b) using methyl 3-({6-[(3,5-dibromo-4-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (14c) (1.56 g, 2.68 mmol), sodium methoxide (5.0 M solution in methanol, 5.36 mL, 26.8 mmol), water (5 mL) and methanol (100 mL) to obtain the title compound (0.13 g, 8%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br.[Br:16][CH2:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])O.[Na+]>CC(C)=O.O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH:20][CH2:19][CH2:18][CH2:17][Br:16])(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCBr)cc1
Temperature: 2.5 °C
Yield: 166.7 %

Procedure:
To a stirred solution of N-acetylsulfanilyl chloride (57.15 g, 0.244 mol) in acetone (500 mL) and H2O (187.5 mL) at 0° C. was added 3-bromopropylamine hydrobromide (25.0 g, 0.114 mol). When a clear solution was obtained, a solution of sodium hydrogencarbonate (44.15 g, 0.526 mol) in H2O (550 mL) was added dropwise, maintaining the internal temperature at 0-5° C. When the addition was completed, the reaction mixture was heated at 50° C. for 5 h, then cooled to room temperature and poured into ice H2O with stirring. After stirring at 5° C. for 4 h, the suspension was filtered and the filter cake was washed with H2O and dried in vacuo to give 34.6 g (90%). An additional reaction was performed to give an additional 63.7 g of similar material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:30])(=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified by HPLC. 1H-NMR (CDCl3) δ 10.75 (br s, 1H, NH), 8.64 (dm, 1H, J=4.8 Hz), 7.79 (dd, 1H, J=9.2 Hz, J=1.1 Hz), 7.75 (d, 2H, J=7.3 Hz), 7.49 (dm, 1H, J=9.2 Hz), 7.1-7.3 (m, 5H), 3.65 (s, 3H), 2.97 (t, 2H, J=7.6 Hz), 2.61 (t, 2H, J=7.6 Hz), 2.35 (s, 3H). MS: m/z 473 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([Sn:7](I)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[CH2:3]([SnH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCC[Sn](I)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCC[SnH](c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
In a Schlenk tube, a suspension of NaBH4 (1.31 g, 34 mmol) in 50 mL of absolute ethanol was cooled at 0° C. under nitrogen. Then, a solution of BuSnPh2I (22.2 g) in ethanol was added slowly under stirring. After 3 hours at room temperature in the dark, petroleum ether was added, the solution was washed and dried over MgSO4. Solvents were eliminated under reduced pressure. A colourless oil was obtained (6.67 g, 0.02 mol).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.CCCCCC.[CH3:34][C:35](=[O:38])[CH2:36][CH3:37]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:35]([OH:38])([CH2:36][CH3:37])[CH3:34])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: CCC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (5.0 g, 15 mmol) in THF (100 mL) was cooled to −42° C. and treated with a solution of 2.5M n-Butyllithium (n-BuLi) in hexane (12.35 mL, 31 mmol) dropwise over 5 minutes. After 15 min at −42° C., 2-butanone (3.1 mL, 34 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 2 hr. The mixture was quenched with water, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)butan-2-ol as a yellow-orange foam (quant). LC/MS (ESI+): m/z 396 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH2:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]([CH2:26][CH3:27])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: CCNc1ccccn1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: CCN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccccn1
Yield: 64 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 2-(ethylamino)-pyridine, the title compound was isolated as a yellow solid in 64% yield (96% purity by HPLC).
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH3:11])[C:3]#[C:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:1][CH:2]([CH2:10][CH3:11])[C:3]#[C:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CCC(O)C#CCC(=O)OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C#CCC(=O)OC)OC(C)=O
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A solution of 355 mg (2.5 mmol) of methyl 4-hydroxyhex-2-ynecarboxylate (cf. J. Kunes et al., Coll. Czech. Chem. Comm. 66, 1809-1830, 2001) and 243 μl (3 mmol) of pyridine in 25 ml of dichloromethane is slowly admixed at 0° C. with 196 μl (3 mmol) of acetyl chloride. After 16 h at room temperature, the mixture is washed successively with dilute aqueous sulphuric acid and sodium hydrogencarbonate solution. Drying over magnesium sulphate and concentrating the organic phase affords 410 mg (89% of theory) of methyl 4-acetoxyhex-2-ynecarboxylate.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:54]([NH2:56])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52]>C(Cl)Cl>[NH2:56][C:54](=[O:55])[C@@H:49]([NH:48][C:4](=[O:6])[C@@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:2]([CH3:30])([CH3:1])[CH3:29])[CH2:50][CH:51]([CH3:53])[CH3:52]
Reactant: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 71 (40 mg) in DCM was added DIEA (45 uL) followed by isobutylchloroformate (26 uL). After stirring at room temperature for 30 min, leucine amide (18 mg) and DIEA (25 uL) was added and stirred for 1 h. The reaction mixture was evaporated and dissolved in MeOH, and purified with a preparative LC-MS to give compound 72. LCMS (+ESI) m/z=537.3 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:44]([C:47]([N:53]([CH3:68])[C:54]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:58][CH:57]=1)=[O:55])([CH3:52])[C:48]([NH:50][CH3:51])=[O:49])(O)=[O:45].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:35]([O:42][NH:43][C:44](=[O:45])[C:47]([N:53]([C:54]([C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:60][CH:61]=1)=[O:55])[CH3:68])([CH3:52])[C:48]([NH:50][CH3:51])=[O:49])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CNC(=O)C(C)(C(=O)O)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C(=O)NOCc1ccccc1)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
DIPEA (0.30 mL), HATU (0.35 g) and O-benzylhydroxylamine hydrochloride (0.14 g) were added in this order, under ice cooling, to a DMF (5.0 mL) solution of 4-{[2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}biphenyl (0.23 g) as obtained in Example 12-(2), and the mixture was stirred for 1 hour under ice cooling and for 3 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, whereafter the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=70/30→0/100) and (gradient elution with chloroform/methanol=98/2→95/5) to obtain N-(benzyloxy)-2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N′,2-dimethylpropanediamide (light brown oil) (0.22 g, 75%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:18]=[C:19]([N:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[C:12]2=[N:11][C:10]=1[C:33]1[S:34][C:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([Cl:46])[CH:40]=2)=[CH:36][N:37]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:46][C:41]1[CH:40]=[C:39]([CH:44]=[CH:43][C:42]=1[F:45])[CH2:38][C:35]1[S:34][C:33]([C:10]2[N:11]=[C:12]3[C:19]([N:20]4[CH2:24][CH2:23][N:22]([CH3:25])[C:21]4=[O:26])=[CH:18][C:17]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[OH:8])=[N:37][CH:36]=1
Reactant: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)c(Cl)c5)s4)nc23)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(O)c(-c4ncc(Cc5ccc(F)c(Cl)c5)s4)nc23)C1=O
Yield: 92.2 %

Procedure:
A solution of 3-Benzyloxy-2-[5-(3-chloro-4-fluoro-benzyl)-thiazol-2-yl]-9-(3-methyl-2-oxo-imidazolidin-1-yl)-7-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one (50 mg, 0.076 mmol) in trifluoroacetic acid (1 ml) was refluxed for 3 h. Then trifluoroacetic acid was removed under reduced pressure and MeOH (3 ml) was added. The resulting precipitate was collected by filtration and washed with MeOH to give title compound (40 mg, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[OH:16])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[OH:16])[CH3:2]
Reactant: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c(CO)cnc(C)c1O
Yield: 72.5 %

Procedure:
The 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-acrylic acid ethyl ester (34) (15.2 g, 64 mmol) in ethyl acetate (250 mL) was hydrogenated in the presence of 10% palladium on carbon (8.0 g) at room temperature overnight. The product was filtered through a celite pad and evaporated. The crude product thus obtained was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane:methyl alcohol (7:7:1 to 4:4:1) to give 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-propionic acid ethyl ester (35) (11.1 g, 62% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]-piperazin-1-yl)methyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, (Example 8c, 0.080 g) was dissolved in methanol (3 ml), 4N HCl in dioxane (1 ml) was added and the mixture stirred at room temperature for 1.5 h. The solvent was removed under vacuum and the resulting solid was triturated with ether to afford the title compound as a white powder (0.062 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([OH:14])=[C:9]([Br:15])[N:8]=1)=[O:6].Cl>O>[Br:13][C:11]1[C:10]([OH:14])=[C:9]([Br:15])[N:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:12]=1
Reactant: COC(=O)c1cc(Br)c(O)c(Br)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Br)c(O)c(Br)n1
Yield: 53 %

Procedure:
A solution of 0.5 g sodium hydroxide in 15 ml of water was added to 2 g of 4,6-dibromo-5-hydroxy-2-pyridine-carboxylic acid methyl ester and refluxed for 2 hours. The product was isolated, by cooling and acidifying with concentrated hydrochloric acid, in 53% yield; m.p. 195° -197° C.
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]>>[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
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 5 °C
Reaction time: 4 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. The stirred mixture was added to a solution of fumaric acid (0.033 g, 0.28 mmol) in TFE (1 mL) at 40° C. Stirring of the resulting clear solution was continued for about 4 h at 40° C. and the solution was subsequently cooled to 5° C. and kept at this temperature overnight to obtain a precipitate. The precipitate was filtered to give Nilotinib fumarate form II.
Reaction SMILES: C(OC(=O)N(CC1C=CC2OCCOC=2C=1)C1CCN(CC[N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:26])CC1)(C)(C)C.[ClH:39].C(OCC)(=O)C>>[ClH:39].[NH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]1=[O:26]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2ccccc2[nH]1
Reaction time: 72 h

Procedure:
To 0.13 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 10 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and left to stand at room temperature for 3 days. The solvent was removed under reduced pressure, 2-propanol was added to the residue obtained and the solvent was removed under reduced pressure. Ethyl acetate was added to the residue thus obtained and the resulting solid was filtered to afford 0.10 g of 1-(2-(4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-quinolin-2(1H)one hydrochloride as a yellow solid.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH2:9]([O:11][CH2:12][CH2:13]OCCOCC)[CH3:10].C1(C(=CC=CC=1)O)O.C1(O)C=CC=CC=1>>[CH2:9]([O:11][CH:12]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:13])[CH3:10]
Reactant: CCOCCOCCOCC
Reactant: Oc1ccccc1O
Solvent: Oc1ccccc1
Product: CCOC(C)Oc1ccccc1O

Procedure:
127 parts by weight of pyrocatechol-[(1-ethoxy)-ethyl]-ether and 55 parts by weight of pyrocatechol are reacted and processed as described in Example 3(c). The yield is 179 parts of the phenol compound. The boiling point is 79° to 80° C. at 1 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:21]=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.[OH-].[NH4+]>C(#N)C>[C:15]([C@@H:9]1[CH2:10][C@H:11]([O:13][CH3:14])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:17])[NH2:21]
Reactant: CCN=C=NCCCN(C)C
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CO[C@H]1C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
(2S,4S)-1-(tert-Butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (2.9 g, 11.82 mmol) was dissolved in acetonitrile (150 mL) and cooled in an ice bath. N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.72 g, 14.19 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (2.17 g, 14.19 mmol) were added, and the mixture was stirred at ambient temperature for 15 hours, becoming clear. 28% Ammonium hydroxide (4.93 mL, 35.5 mmol) was added dropwise resulting in a precipitate. After stirring for 2 hours, then mixture was concentrated, diluted with water and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 100% yield of (2S,4S)-tert-butyl 2-carbamoyl-4-methoxypyrrolidine-1-carboxylate as a white waxy solid.
Reaction SMILES: C(N1C(C2SC3CCOC4C=C(C5CN([CH2:27][CH2:28][O:29][CH:30]6[CH2:35][CH2:34][CH2:33][CH2:32][O:31]6)C5)C=CC=4C=3N=2)=NC=N1)(C)C.[NH:36]1[CH2:39][CH:38]([C:40]2[CH:41]=[CH:42][C:43]3[O:52][CH2:51][CH2:50][C:49]4[S:48][C:47]([C:53]5[N:54]([CH:58]([CH3:60])[CH3:59])[N:55]=[CH:56][N:57]=5)=[N:46][C:45]=4[C:44]=3[CH:61]=2)[CH2:37]1.[I-].[K+]>>[CH:58]([N:54]1[C:53]([C:47]2[S:48][C:49]3[CH2:50][CH2:51][O:52][C:43]4[CH:42]=[CH:41][C:40]([CH:38]5[CH2:39][N:36]([CH2:27][CH2:28][O:29][CH:30]6[CH2:35][CH2:34][CH2:33][CH2:32][O:31]6)[CH2:37]5)=[CH:61][C:44]=4[C:45]=3[N:46]=2)=[N:57][CH:56]=[N:55]1)([CH3:59])[CH3:60]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCOC4CCCCO4)C3)ccc1-2
Agent: [I-]
Agent: [K+]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CCOC4CCCCO4)C3)cc1-2
Yield: 45 %

Procedure:
The title compound (110 mg, 45%) was prepared by a similar method to 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene instead of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and adding potassium iodide (0.2 eq.) to the reaction mixture. LCMS: RT=3.57 min, [M+H]+=496