Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28](O)=[O:29])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12].Cl.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[C:37]([C@@H:39]([NH:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH:38]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O>[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28]([N:48]2[CH2:47][CH2:46][CH:45]([C:36]3[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][C:37]=3[C@@H:39]([NH:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH2:50][CH2:49]2)=[O:29])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reactant: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCNCC1
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: O
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
N,N-diisopropylethylamine (5.86 mL, 33.6 mmol) was added to a stirred suspension of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochloride (3-9) (3.07 g, 9.61 mmol), N-[(1S)-1-(5-chloro-2-piperidin-4-ylphenyl)ethyl]acetamide hydrochloride (3.05 g, 9.61 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (4.38 g, 11.5 mmol) in N,N-dimethylfoimamide (20 mL) at ambient temperature. After approximately 18 h, the reaction mixture was poured water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) provided 3-10 (5.2 g) as a foam m/z (ES) 546 (MH+).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:35]=[CH:34][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH:23]([CH3:25])[CH3:24])[N:19]=3)=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>CO>[N:1]1([C:5]([C:7]2[CH:35]=[CH:34][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH:23]([CH3:25])[CH3:24])[N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)n1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO)c2)n1
Solvent: CO
Product: CC(C)n1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.7 %

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide (0.33 g, 0.644 mmol) was dissolved in methanol (4 mL) and THF (4 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (0.033 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite, and the filtrate concentrated in vacuo. The residue was chromatographed on silica eluting with a gradient of 0-100% ethyl acetate in isohexane to give the desired compound (0.15 g);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CO)c1
Temperature: 0 °C
Yield: 99.7 %

Procedure:
Dissolve 2-bromo-5-methoxy-benzoic acid (2.25 g, 9.7 mmol) in THF (10 mL) and cool to 0° C. Add 1M borane in THF (48 mL, 48 mmol) and warm to room temperature. Upon completion, slowly pour reaction onto ice and saturated aqueous sodium bicarbonate. Extract with ethyl acetate and wash organic layer with water and saturated aqueous sodium bicarbonate. Dry with sodium sulfate, filter and concentrate in vacuo to yield 2.1 g (100%) of the title compound. 1H NMR (CDCl3) δ7.42 (d, J=8.8 Hz, 1H), 7.06 (d, J=3.1 Hz, 1H), 6.72 (dd, J=8.8, 3.1 Hz, 1H), 4.71 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]1([CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:22](OC)=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:25][C:26]([O:28]CC)=O)(=[O:16])=[O:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:1][O:2][C:20]1[CH:21]=[CH:22][C:17]2[S:14](=[O:15])(=[O:16])[N:13]([CH2:12][CH2:11][CH2:10][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:26](=[O:28])[CH2:25][C:18]=2[CH:19]=1
Reactant: CCOC(=O)Cc1cccc(OC)c1S(=O)(=O)NCCCc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CC(=O)N(CCCc1ccccc1)S2(=O)=O

Procedure:
Sodium Methoxide (280 mg, 5.1 mmol) and ethyl 2-[(N-3-phenylpropylamino)-sulfonyl]-3-methoxyphenylacetate (2.0 g, 5.1 mmol) are dissolved in toluene (200 mL) and the resulting solution is refluxed for 24 hours. An additional portion of sodium methoxide (60 mg, 1.1 mmol) is added and the reaction is once again refluxed for 24 hours. The reaction mixture is subsequently diluted with EtOAc (200 mL) and H2O (200 mL). The organic phase is then washed with saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo to give 6-methoxy-2-(3-phenylpropyl)-3-oxo-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.C[CH2:24][N:25](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:24][NH:25][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of N-Benzyloxycarbonyl-L-leucine (1.18 g, 4.45 mmol), methylamine hydrochloride (0.60 g, 8.90 mmol) and DIEA (3.0 mL, 17.2 mmol) in DMF (40 mL) was added TBTU (1.43 g, 5.6 mmol) at 0° C. in two batches over 10 minutes. After stirring at room temperature overnight, the reaction was quenched with water (5 mL) and evaporated under vacuum. The residue was partitioned between brine and EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was filtered through a short pad of silica gel with EtOAc to give crude product 20A (1.20 g) which was used in the next step without purification. LCMS (+ESI) m/z 301.1 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH:8]([C:10](O)=[O:11])[O:9][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH:8]([CH2:10][OH:11])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OC(C(=O)O)C2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OC(CO)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
A solution of (RS)-6-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid (158 mg, 0.813 mmol) in THF (2 ml) was added dropwise in a 0° C. suspension of LiAlH4 (31 mg, 0.813 mmol) in THF (2 ml). After 30 min stirring at 0° C., the reaction mixture was allowed to reflux for 30 minutes. The reaction mixture was then cooled to 0° C. and treated successively with H2O (0.05 ml), 5N NaOH (0.05 ml), H2O (0.15 ml). After 20 minutes stirring at room temperature, EtOAc was added followed by Na2SO4. The so obtained solid was filtered and the filtrate was evaporated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with nHexane-EtOAc (4:1) to provide (RS)-(6-methoxy-2,3-dihydro-benzofuran-2-yl)-methanol (102 mg, 70%) as a colorless oil, MS:m/e=180 (M+).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][N:21]=3)[C:16](=[O:23])[C:15]([C:24]([NH2:26])=[O:25])=[CH:14]2)[CH:10]=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:6]([C:7]1[CH:8]=[C:9]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][N:21]=3)[C:16](=[O:23])[C:15]([C:24]([NH2:26])=[O:25])=[CH:14]2)[CH:10]=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc(-n2cc(C(N)=O)c(=O)c3cccnc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc(-n2cc(C(N)=O)c(=O)c3cccnc32)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2 in THF (30 mL/mmol) at 0° C. was added 1M tetrabutylammonium fluoride in THF (1.5 eq) and the resulting mixture was stirred at 0° C. for 30 minutes. The mixture was partitioned between methylene chloride and water and the organic phase was dried and evaporated. The crude 1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin4-one-3-carboxamide product was used as such in the next step.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:33][C:32]1[CH:31]=[CH:30][C:29]([S:34](=[O:36])(=[O:35])[NH:37][C:38]([CH3:41])([CH3:42])[CH2:39][OH:40])=[CH:28][C:27]=1[NH:26][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-4-chloro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.10) according to general procedure II. Light yellow solid. MS (ISP) 616.2 [(M−H−]; mp 234° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>[Na]>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CCC[C@H]1CC[C@H](CO)CC1

Procedure:
Trans-4-n-propylcyclohexane-1-carboxylic acid (0.14 mole) was dissolved in sodium dried ether (150 ml) and added dropwise to a vigorously stirred suspension of lithium aluminium hydride (0.3 mole) in sodium dried ether (300 ml). When addition was completed the mixture was heated under reflux for 2 hours. On cooling, water was cautiously added to destroy the excess of lithium aluminium hydride. The mixture was then poured into a 20% hydrochloric acid solution and stirred until the inorganic salts were dissolved. The product was extracted into ether, which was then washed with water and dried (MgSO4). The ether was evaporated off and the residue distilled. The product boils at 148° C. at a pressure of 25 mm Hg.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17]C)=[O:16])[CH2:4]1)[CH3:2].[Li+].[OH-]>CO>[C:11]([O:10][C:8]([N:6]1[CH2:7][CH:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[C:15]([OH:17])=[O:16])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCC1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A mixture of (2S)-1-tert-butyl 2-methyl 4-ethylpyrrolidine-1,2-dicarboxylate (49.5 g, 0.19 mol), LiOH (950 mL, 1M) in MeOH (1500 mL) was stirred at room temperature overnight. TLC showed the reaction was completed. The mixture was concentrated, adjusted the pH to 2 with 1N HCl. The mixture was extracted with EA, the combined organic layer was washed with brine, dried over Na2SO4, concentrated to afford (2S)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-2-carboxylic acid (45.5 g, 97%) as white solid without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:24][CH:25]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(CCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(CCc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
Under reflux, 45 ml of a 3.5 M solution of lithium aluminium hydride in toluene were slowly added dropwise to a solution of 35.4 g (136.98 mmol) of methyl 4-[2-(4-fluorophenyl)ethyl]benzoate in 500 ml of dry THF. After the addition had ended, the reaction mixture was stirred under reflux for one hour. The reaction mixture was then cooled to 0° C., and 500 ml of ice-cooled 1 M hydrochloric acid were added slowly and carefully. 750 ml of ethyl acetate were then added, the aqueous phase was removed and the organic phase was washed successively in each case once with 1 M hydrochloric acid and saturated sodium chloride solution. The organic phase was then dried over magnesium sulphate, filtered and concentrated to dryness. This gave 31.5 g (136.7 mmol, 99.9% of theory) of the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH2:41])[CH2:33][CH2:32]1.C(Cl)(Cl)Cl>N1C=CC=CC=1.CC=C(C)C>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH:41][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:22][CH:21]=2)[CH2:35][CH2:36]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: CC=C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
1,1′-carbonyldiimidazole (0.18 g, 1.1 mmol) was added to a solution of the 4-hydroxy benzoic acid (0.15 g, 1.1 mmol) in absolute pyridine and the mixture was stirred at room temperature under Argon for 1 h. After that time a solution of 4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-but-2-enylamine (0.33 g, 1.1 mmol) in 3 ml amylene-stabilized chloroform was added and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was purified by chromatography to give 0.23 g (51%) of the title compound.
Reaction SMILES: O=C([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)CC(CS(CC1C=CC=CC=1)(=O)=O)C(O)=O.OC(C(F)(F)F)=O.N[CH:33]([CH2:45]C)[CH:34]([C:36]1[O:37]C2C=CC=CC=2[N:40]=1)O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[N:19]1([NH:40][C:36](=[O:37])[CH2:34][CH2:33][CH3:45])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCC(N)C(O)c1nc2ccccc2o1
Reactant: O=C(O)C(CC(=O)N1CCCCC1)CS(=O)(=O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)NN1CCCCC1
Reaction time: 14 h

Procedure:
To a stirred mixture of 4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (141 mg, 0.4 mmol), 2-amino-1-benzooxazol-2-yl-butan-1-ol TFA salt. (129 mg), prepared as in reference 20, and HOBt (74 mg, 0.48 mmol) in MeCl2 (5 mL), was added EDC (115 mg, 0.6 mmol) and N-methylmorpholine (0.25 ml) at room temperature. After stir-ring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 157 mg of N-piperidin-1-yl-butyramide. Without further purification, the crude product was used for next reaction; MS: 540.4(M−1), 542.6(M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:31])(=[O:30])[NH:28][CH3:29])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+]>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:31])(=[O:30])[NH:28][CH3:29])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)NC)c1
Agent: [Na+]
Agent: [OH-]
Product: CNS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1

Procedure:
Ethyl 3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoate (0.5 g) was dissolved in 1N sodium hydroxide (8 ml) and heated on a steam bath for 1 hour. After cooling, the 3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoic acid was precipitated by addition of 4N hydrochloric acid until a pH of 2.5. The precipitate was collected by suction and recrystallized from aqueous ethanol. After drying in vacuo, the melting point of the compound was 231-233°C.
Reaction SMILES: [Mg].II.[CH:4]1(Br)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:11][N:12]1[CH2:35][CH2:34][C:15]2[N:16]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:26])[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.C1([Mg]Br)CCCCC1>C1COCC1>[CH:4]1([C:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)([OH:26])[CH2:24][N:16]2[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=3[C:14]3[CH2:13][N:12]([CH3:11])[CH2:35][CH2:34][C:15]2=3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Reactant: BrC1CCCCC1
Agent: Br[Mg]C1CCCCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccc(F)cc2)C2CCCCC2)CCN(C)C1
Reaction time: 0.25 h

Procedure:
Activated magnesium turnings (480 mg, 20 g/atom) and 2-3 crystals of iodine were stirred under anhydrous conditions. The excess of iodine was removed by heating with a heat gun. The magnesium turnings were now yellow in color. To this was added diethyl ether (15 mL) at 0° C. and stirred for 15 min (until the color of the magnesium becomes white). To this was added cyclohexyl bromide (2.5 mL, 20 mmol) dropwise with constant stirring. The reaction mixture was stirred until a dark grey-colored solution was obtained. Into a separate flask was placed 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone (168 mg, 5 mmol) in THF under anhydrous conditions. The solution of the prepared cyclohexylmagnesium bromide (5 mL) was added dropwise. After addition, the mixture was allowed to come to RT and stirred at RT for 2 h. The reaction was monitored by TLC and NMR. The reaction was quenched with ice water and the product extracted into EtOAc. The organic extracts were concentrated and the residue purified by silica gel column chromatography (#100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified by HPLC. 1HNMR (CD3OD, TFA salt) d (ppm): 7.25 (m, 2H), 7.10 (d, 1H), 6.92 (m, 1H), 6.80 (m, 3H), 4.60 (m, 1H), 4.65 (m, 1H), 4.22 (m, 2H), 3.70 (m, 1H), 3.40 (m, 1H), 3.20 (m, 2H), 3.0 (s, 3H), 2.70 (m, 1H), 2.38 (s, 3H), 2.20 (m, 2H), 1.80 (m, 2H), 1.70 (m, 3H), 1.50-1.20 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:24]=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:7][C:6]=4[CH:19]=3)[N:26]=2)[CH2:32][CH2:31]1
Reactant: Nc1ccc2sc(NC(=O)c3ccccc3)nc2c1
Reactant: CN1CCN(c2ccnc(Cl)n2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2ccnc(Nc3ccc4sc(NC(=O)c5ccccc5)nc4c3)n2)CC1

Procedure:
N-{5-[4-(4-Methylpiperazin-1-yl)pyrimidin-2-ylamino]benzothiazol-2-yl}benzamide was prepared by heating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and 2-chloro-4-(4-methylpiperazin1-yl)pyrimidine (IM 10, 40 mg, 0.186 mmol) in ethanol (3 mL) to 80° C. for 4 days. Brine (25 mL) and saturated sodium hydrogencarbonate solution (25 mL) were, added and the product was extracted with chloroform (3×40 mL) and ethyl acetate (40 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed. The residue was purified by pTLC (dichloromethane:methanol=4:1) to yield a solid (44 mg, 99 μmol, 53%). LC/ESI-MS: m/z=446 [M+H]+; m/z=444 [M−H]−; Rt=2.38 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C@H:15]1[CH2:20][C:19]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:21]2[C:19]3[CH2:20][C@H:15]([NH:14][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)[CH2:16][O:17][C:18]=3[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CO3)CC1
Temperature: 50 °C
Yield: 54.9 %

Procedure:
A mixture of 4-trifluoromethylbenzoic acid (195 mg, 1.02 mmol) in thionyl chloride (5 mL) was heated at 50° C. for 20 min and then to reflux for 10 min. The mixture was allowed to cool after which the excess of thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to an ice-cooled solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230 mg, 0.930 mmol) and triethylamine (194 μL, 1.39 mmol) in anhydrous methylene chloride (20 mL) with stirring. The reaction mixture was allowed to reach room temperature and was washed with a saturated NaHCO3 solution. After drying (MgSO4) and evaporation of the solvent in vacuo, a crude product was obtained which was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH3). This procedure gave 214 mg (55% yield) of the title compound as a white solid: mp 212–214° C.; [α]22D−73° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 419 (100, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19](F)[CH:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[C:19]([N:25]([CH3:26])[CH3:24])[CH:18]=[N:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(F)c1
Reactant: CNC
Agent: Cl
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(N(C)C)c1

Procedure:
The title compound, MS: m/e=337.3 (M+), was prepared in accordance with the general method of example 27 from 3-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-5-fluoro-pyridine and dimethylamine hydrochloride.