Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][S:15]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NS(C)(=O)=O)C1
Reaction time: 2 h

Procedure:
tert-Butyl(3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with methanesulfonyl chloride (0.050 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0-10% methanol in dichloromethane) to give tert-butyl(3S)-3-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate, LCMS [M+Na]+: m/z=287.1. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C5H13N2O2S (M+H)+: m/z=165.1; Found: 165.1.
Reaction SMILES: C(OCC)(=O)C.O.O.[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([C:14]([NH:16][C:17]([CH2:24][CH2:25][C:26]#[N:27])([C:21]([O-:23])=[O:22])[C:18]([O-:20])=[O:19])=[O:15])=[CH:12][CH:11]=1.[Na+].[Na+].Cl>O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]([CH2:24][CH2:25][C:26]#[N:27])([C:21]([OH:23])=[O:22])[C:18]([OH:20])=[O:19])=[O:15])=[CH:28][CH:29]=1
Reactant: N#CCCC(NC(=O)c1ccc(Cl)cc1)(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCCC(NC(=O)c1ccc(Cl)cc1)(C(=O)O)C(=O)O
Yield: 100.6 %

Procedure:
Fifty milliliters of ethyl acetate were added to a solution of 4.0 g of disodium 2-(p-chlorobenzoylamino)-2-(2-cyanoethyl)malonate dihydrate in water (50 ml), and the resulting solution was adjusted to pH 2.0 by adding 1N hydrochloric acid at 0°-5° C. The organic layer was separated off and dried over magnesium sulphate. The solvent was distilled off and the resulting residue was recrystallized from diethyl ether, to give 3.2 g of the desired acid (b) as a colourless powder melting at 103°-105° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1I.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(I)c(Cl)s1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Temperature: 80 °C
Yield: 23.5 %

Procedure:
To a solution of methyl 5-chloro-4-iodo-2-thiophenecarboxylate (1.75 g, 5.8 mmol) in dioxane/H2O (50:5 mL) was added K2CO3 (3.4 g, 24.9 mmol), tetrakistriphenylphosphine Pd(0) (0.96 g, 0.83 mmol), and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (3.4 g, 16.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 15 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 4:1) to give the title compound (0.35 g, 24%) as a yellow oil: LC-MS (ES) m/z=257 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[CH:7]=[C:6]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)Cl.B(Br)(Br)Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(-n2cc(-c3ccccc3)c3cc(OC)ccc3c2=O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1c2ccc(O)cc2c(-c2ccccc2)cn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-4-phenylisoquinolin-1(2H)-one (0.36 g, 1.01 mmol) was placed in a dry 150 mL single-necked flask fitted with a stirring bar and septa. Methylene chloride (30 mL) was added via a syringe. Boron tribromide (5.0 mL of 1.0 M methylene chloride solution) was added dropwise with stirring under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 16 hours. Then, 20 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was subjected to flash column chromatography (silica gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.29 g, 87.9% yield. MS: 330.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 10.31 (s, 1H), 9.69 (s, 1H), 8.19 (d, 1H, J=8.7 Hz), 7.52-7.39 (m, 5H), 7.28 (d, 2H, J=8.7 Hz), 7.18 (s. 1H), 7.00 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.87-6.82 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH2:36]([OH:39])[CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([O:38][CH2:37][CH2:36][OH:39])[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(OCCO)ncn2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
50 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 3 mL ethane-1,2-diol were added to 10 mg potassiumcarbonate in 3 mL ethanol. The reaction was stirred 30 min at 150° C. under microwave conditions. The solvent was removed and the precipate was purified by HPLC to give 29 mg of the desired product. Rt: 1.87 min (method C), (M+H)+: 522
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:15]([CH3:17])[CH3:16])=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[CH:10]=1)=[O:4].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH:15]([CH3:17])[CH3:16])=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[CH:10]=3)=[O:4])[CH2:23][CH2:24]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)Nc1cc(C(=O)CCl)ccc1C(C)C
Agent: Cl
Product: CC(=O)Nc1cc(C(=O)CN2CCN(c3nsc4ccccc34)CC2)ccc1C(C)C
Yield: 55.8 %

Procedure:
Starting with N-[5-(2-chloro-acetyl)-2-isopropyl-phenyl]-acetamide (0.50 g, 1.971 mmol), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.504 g, 1.971 mmol) and following the procedure as outlined in Example 517, N-{5-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-2-isopropyl-phenyl}-acetamide (0.480 g, 1.099 mmol) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas). Yield=56%. 100% purity at 254 nM. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (bs, 1H), 9.63 (s, 1H), 8.12 (d, J=8.13 Hz, 1H), 8.09 (d, J=8.13 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=8.13 Hz, 1H), 7.61–7.52 (m, 2H), 7.45 (t, J=7.47 Hz, 1H), 5.13 (s, 2H), 4.12–4.01 (m, 2H), 3.67–3.49 (m, 8H), 3.40 (bs, H2O), 3.37–3.30 (m, 1H), 3.23 (heptet, J=6.81 Hz, 1H), 2.07 (s, 3H), 1.14 (d, J=6.81 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:12][C:10]([CH3:13])([CH3:11])[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:28]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)COC(C)(C)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.9 %

Procedure:
(4.9 g, 18.2 mmol) 1-(Dibenzylamino)-2-methylpropan-2-ol (CAS 344868-41-3) was dissolved in dichloroethane (50 ml) and ethyl 2-diazoacetate (2.83 ml, 27.3 mmol, 1.5 equiv.) and rhodium(II) acetate dimer (200 mg, 0.455 mmol, 0.025 equiv.) were added carefully at room temperature. The mixture was stirred for 3 hours at 80° C. The reaction mixture was evaporated with isolute and the crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 70:30. The desired (2-dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester (1.03 g, 80% purity, 13% yield) was obtained as a colorless liquid, MS: m/e=356.3 (M+H+).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>N1C=CC=CC=1.C(OCC)C.[Cu]Cl>[C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:17][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccccc1Br
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Agent: Cl[Cu]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)OC)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, methyl 2,4-di-(tert-amyl)phenoxybenzoate was prepared. To a stirred suspension under argon of sodium hydride (60% dispersion in mineral oil, 1.1 g, 46.5 mmol, washed with ligroin to remove the oil) in pyridine (60 mL) was added dropwise a solution of 2,4-di-(tert-amyl)phenol (12.0 g, 51.2 mmol) in 20 mL of pyridine. The mixture was stirred for 2 h at room temperature and then treated dropwise with a solution of methyl 2-bromobenzoate (10 g, 46.5 mmol) in 10 mL of pyridine. Copper (I) chloride (1.15 g, 11.6 mmol) was added, and the mixture was heated at reflux 16 h and then cooled to ambient. The mixture was diluted with diethyl ether, washed successively with 10% aqueous HCl, water, and brine, and then dried over Na2SO4. The solvent was removed at reduced pressure to deposit dark brown oil. This crude product was purified by column chromatography to give 25.5 g, 78% of theory) of a light brown oil. 1H NMR (CDCl3): δ 0.70 (t, 6H), 1.3 (s, 6H), 1.4 (s, 6H), 1.63 (q, 2H), 1.85 (q, 2H), 3.85 (s, 3H), 6.68 (d, 1H), 6.82 (d, 1H), 7.05 (m, 2H), 7.3 (br s, 1H), 7.35 (t, 1H), 7.9 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]2([CH3:26])[CH2:12]OS(=O)(=O)[N:9]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[CH:7]=1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:29][SH:30].CN(C)C(N(C)C)=N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]([NH:9][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])([CH3:26])[CH2:12][S:30][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH:7]=1
Reactant: CCOC(=O)CS
Reactant: COc1ccc(CN2[C@](C)(c3cc(Br)ccc3F)COS2(=O)=O)c(OC)c1
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CSC[C@](C)(NCc1ccc(OC)cc1OC)c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
To a solution of (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (10 g, 21.7 mmol, Eq: 1.00) and ethyl thioglycolate (3.92 g, 3.57 ml, 32.6 mmol, Eq: 1.5) in DMF (134 ml) was added at 23° C. 1,1,3,3-tetramethylguanidine (3.75 g, 4.09 ml, 32.6 mmol, Eq: 1.5). The reaction mixture was stirred at 23° C. for 16 hours. The solution was evaporated at HV. The resulting residue was stirred vigorously overnight between 100 ml of dichloromethane and 20% (v/v) sulfuric acid solution (100 ml). Sat. NaHCO3-solution was slowly added (pH=8), then extracted with dichloromethane twice. The combined organic layers were dried over Na2SO4, filtered and evaporated to give the crude product (14.4 g, 132%). The residue was chromatographed on 70 g silica gel with 0-50% ethyl acetate in heptane to give the (R)-ethyl 2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetate (10.9 g, 21.8 mmol, 100% yield) as a light yellow oil. MS (ISP): m/z=500.2 [M+H]+ and 502.2 [M+2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.C(Cl)(=O)OCC.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])=[O:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: Nc1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Nc2cccc(C(=O)O)c2)cc1OC
Reaction time: 2 h
Yield: 50 %

Procedure:
2 Grams of 3,4-dimethoxycinnamic acid were dissolved in a mixture of 20 ml of dry dimethylformamide and 1.5 g of triethylamine. To this solution was added under ice cooling and agitation 1.1 g of ethyl chlorocarbonate and the mixture was then reacted for one hour. To this mixture were added 10 ml of dimethylformamide containing 1.5 g of 3-aminobenzoic acid and the mixture was stirred for 2 hours. After completion of the reaction, the reaction liquid was concentrated approximately to 1/2 volume and poured into an aqueous solution of hydrochloric acid. The precipitated crystals were separated by filtration, washed with water and recrystallized from an equivolume mixture of ethanol and water to obtain a yield of 50% 3-(3',4'-dimethoxycinnamoylamino)-benzoic acid having a melting point of 225°-226° C.
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH2:11])[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1>>[N:1]1([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH:11][C:21](=[O:22])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1-n1cccn1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cccn2)cc1

Procedure:
The title compound was prepared from 2-(1H-pyrazol-1-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B. The solution was directly purified by HPLC to yield N-(2-(1H-pyrazol-1-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide. Method [7] Retention time 5.22 min by HPLC (MH+ 314). 1H NMR (300 MHz, CDCl3) δ 9.94 (broad s, 1H), 8.00 (d, J=5.7 Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.27 (m, 2H), 6.94 (m, 3H), 6.35 (t, J=2.4 Hz, 1H), 3.87 (s, 3H), 3.71 (s, 2H).
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:65])([C:58]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:65])([F:52])[C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: COC(O)C(F)(F)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(F)(F)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (500 mg, 0,92 mmol) from Step C in THF (7.2 mL) was stirred at rt for 30 min. A 0.5 M toluene solution of potassium bis(trimethylsilyl)amide (1.8 mL, 0.90 mmol) was added over 3 min., giving an orange suspension. After 30 min., crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol (95 mg, 0.46 mmol) was added in THF (1.0 mL). After an additional 30 min, the mixture was quenched by the addition of saturated aq. NH4Cl (2 mL). The mixture was partitioned between ethyl acetate (50 mL) and water (75 mL), and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were washed in succession with saturated aq. brine (25 mL), dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 10% ether in hexane to give 117 mg of the title compound as a 95:5 mixture of cis and trans isomers, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)cnc2C1

Procedure:
Following the same procedure as described in example 31.5, a portion of crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (100 mg, 0.45 mmol) in CH2Cl2/pyridine 9/1 (20 ml) was treated with 4-isopropylbenzenesulfonyl chloride (130 μl, 0.72 mmol). Purification by flash column chromatography (CH2Cl2:methanol, 97:3) gave the title compound (85 mg, 47% for steps 31.4 and this step) as a gum.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH:13]([CH2:22][OH:23])[CH2:14][O:15][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH:13]([OH:12])[CH2:14][O:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCC(O)COc1ncccn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)COc2ncccn2)cc1
Temperature: -10 °C
Reaction time: 15 h

Procedure:
13.6 g of p-toluenesulphonyl chloride are introduced over the course of 15 minutes, whilst stirring, into a solution of 11.8 g of 2-(2',3'-dihydroxy-propoxy)-pyrimidine in 18 ml of pyridine which is cooled to -10° C. The reaction mixture is kept at 0° C. for 15 hours. Ice is then added followed by 20 ml of 6 N hydrochloric acid introduced whilst stirring. The mixture is then twice extracted with 150 ml of methylene chloride at a time. The extracts are washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. 2-(3'-p-Toluenesulphonyloxy-2'-hydroxy-propoxy)-pyrimidine is obtained as a yellowish oil.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[O-:24][Si:25]([O-:27])=[O:26].[Na+].[Na+]>>[Si:25]([OH:7])([OH:27])([OH:24])[OH:26].[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: O=[Si]([O-])[O-]
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: O[Si](O)(O)O

Procedure:
An aqueous solution containing sucrose and sodium metasilicate (sucrose content 20% and SiO2 cntent 5%) was passed through a column packed with a cation-exchange resin, Amberlite 200C (H+ form), to effect removal of sodium. There was obtained an aqueous silicic acid/sucrose solution (sucrose content 19% and SiO2 content 4.5%). Twenty (20) g of this solution was spray dried and then heated in an atmosphere of helium at 1440° C. for four hours. Consequently, there was obtained silicon carbide powder having a particle diameter of about 1μ. The crystalline phase was composed of 93% of 3C and 7% of 2H.
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.[Cl:40][C:41]1[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=1[CH:43]([OH:47])[C:44]([OH:46])=[O:45]>>[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.[Cl:40][C:41]1[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=1[CH:43]([OH:47])[C:44]([O-:46])=[O:45]
Reactant: O=C(O)C(O)c1ccccc1Cl
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])C(O)c1ccccc1Cl
Temperature: 5 °C
Reaction time: 1 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 2-chloromandelic acid (0.106 g, 0.57 mmol) in TFE (1 mL) at 40° C. Stirring of the resulting solution was continued for about 1 h and it was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then a sample (1 ml) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give amorphous Nilotinib 2-chloromandelate.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[OH:1][C:2]([C:3]1[O:4][N:62]=[C:61]([NH:60][C:55]2[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]3[C:43](=[O:65])[N:42]([CH3:41])[C:51]4[C:46]([CH:45]=3)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=4)[CH:54]=2)[N:64]=1)([CH3:7])[CH3:6]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)(C)O)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Hydroxy-2-methylpropanoic acid (16.1 mg, 0.15 mmol), HATU (59 mg, 0.15 mmol), and DIPEA (0.027 mL, 0.15 mmol) were stirred in dry DMF (3 mL) for 1 h before 17 (50 mg, 0.14 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A32) as a solid. 1H NMR (400 MHz, d4-MeOH) δ 8.90 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.62 (dd, J=8, 4 Hz, 1H), 7.52 (d, J=8, 4 Hz, 1H), 7.35 (d, J=4 Hz, 1H), 7.26 (dd, J=8, 4 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 3.79 (s, 3H), 2.75 (s, 3H), 2.06 (s, 3H), 1.35 (m, 6H). MS m/z 406.2 (M+1).