Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:23])[C:14]([O:16][CH2:17][CH:18](OC)OC)=[O:15])[CH:7]=[CH:6]2.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.S([O-])([O-])(=O)=O.[Mg+2].[SH:45][CH2:46][C:47]([OH:49])=[O:48]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:23])[C:14]([O:16][CH2:17][C@@H:18]1[S:45][CH2:46][C:47](=[O:49])[O:48]1)=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(O)CS
Reactant: COc1ccc2cc([C@H](C)C(=O)OCC(OC)OC)ccc2c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(Cl)Cl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@H]3OC(=O)CS3)ccc2c1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a round bottom flask is added 2,2-dimethoxyethyl (S)-6-methoxy-α-methyl-2-naphthaleneacetate (13.8 g), dichloroethane (60 mL), camphorsulfonic acid (0.7 g) and magnesium sulfate (1.0 g). The reaction mixture is heated to reflux and a solution of mercaptoacetic acid (13.5 g) in dichloroethane (15 mL) is added dropwise. The mixture is removed from the oil bath and a sample is taken for TLC and NMR analysis. Additional camphorsulfonic acid (0.6 g) is added and the mixture is heated in an oil bath to reflux for 2 hours. The mixture is cooled to room temperature and then shaken with water (50 mL) and saturated sodium bicarbonate (50 mL). The separated lower phase is shaken with saturated sodium bicarbonate (25 mL) and water (50 mL), the phases are separated and the lower cloudy organic phase is vacuum concentrated to give 17.4 g of crude product. The obtained syrup is applied to a silica column and eluted with EtOAc/heptanes (15:85) to provide 8.0 g of product.
Reaction SMILES: [CH2:1](O)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCC/C=C\CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCC/C=C\CCl

Procedure:
By the procedure of example 12, (Z)-2-undecen-1-ol (13 g), 27.8 g of triphenylphosphine in 100 ml of dry CCl4 were reacted under reflux for 6.5 h. Workup as described before as in example 12 gave 12.3 g of (Z)-1-chloro-2-undecene as a colorless oil: bp 65°-66° C./0.2 mmHg.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH2:12](OS(C1C=CC(C)=CC=1)(=O)=O)C>CN(C)C=O.O.CCCCCC>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH3:12]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
1 mol of sodium hydride was added to the solvent dimethylformamide, and 1 mol of hydroxypivalic acid methyl ester was added thereto while the temperature of the solution did not exceed 30° C. The solution was stirred at room temperature for 90 minutes. Then, 1.2 mol of p-toluenesulfonic acid ethyl ester was added to the solution while the temperature of the solution did not exceed 30° C. Then, a water/hexane mixture having the same mass as that of the dimethylformamide was added to and mixed with the solution, after which water was removed therefrom. The resulting organic material was concentrated, and the residue was fractionated under reduced pressure 76-79° C., thereby obtaining the intermediate 3-methoxy-2,2-dimethylpropionic acid methyl ester at a yield of 47%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][C@H:45]([CH3:51])[CH2:46][NH:47][C:48](N)=[O:49])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55]S(O)(=O)=[O:57].CNC>C1COCC1>[CH:48]([OH:49])=[O:57].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][C@H:45]([CH3:51])[CH2:46][N:47]([CH3:48])[CH3:55])[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)O
Reactant: C[C@H](CNC(N)=O)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Agent: CNC
Solvent: C1CCOC1
Product: C[C@H](CN(C)C)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Product: O=CO
Temperature: 60 °C
Reaction time: 42 h
Yield: 34.8 %

Procedure:
A solution of Intermediate 151e (89 mg, 0.12 mmol) in THF (0.8 mL) was treated with a 2M solution of dimethylamine in THF (1.2 mL, 2.3 mmol) and the mixture was stirred at 60° C. for 42 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown glass. The glass was purified by HPLC (Phenomenex Gemini C18 column, 5-95% MeCN in H2O, 0.1% HCO2H) over 25 mins. Concentration of the fractions in vacuo gave a pale yellow glass. The glass was triturated with ether to give a solid that was filtered off to give the title compound as a fawn coloured solid (16 mg, 19%). LCMS (Method 5): Rt 3.68 min, m/z 720.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.5 Hz), 1.24 (3H, d, J=6.1 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-1.72 (2H, m), 1.74-1.98 (4H, m), 1.99-2.16 (2H, m), 2.17 (6H, s), 2.32-2.39 (1H, m), 2.86-2.95 (1H, m), 3.13-3.19 (1H, m), 3.29-3.34 (1H, m), 4.56-4.65 (1H, m), 4.79-4.86 (1H, m), 5.52 (1H, t, J=4.4 Hz), 6.32 (1H, s), 6.94-6.99 (1H, m), 7.03-7.12 (3H, m), 7.19 (1H, dd, J=9.9, 2.0 Hz), 7.24-7.41 (5H, m), 7.64 (1H, d, J=10.2 Hz), 7.68-7.70 (1H, m), 8.15 (1H, s), 8.20 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([N:16]2[C:20]3[N:21]=[C:22](Cl)[N:23]=[CH:24][C:19]=3[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:17]2[CH3:31])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([N:16]2[C:20]3[N:21]=[CH:22][N:23]=[CH:24][C:19]=3[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:17]2[CH3:31])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2nc(Cl)ncc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ncncc12
Yield: 75 %

Procedure:
A mixture of compound ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (75 mg, 0.16 mmol) and Pd/C (10 mg) in methanol (10 mL) was stirred under 50 psi of hydrogen at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give product ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, yield: 72%). LRMS (M+H+) m/z: calcd 450.2. found 451.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[C:27]([F:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[F:19][C:20]1[C:27]([F:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=Cc1ccc(O)c(F)c1F
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)c(F)c1F)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(2,3-Difluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2,3-difluoro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is crystallized from acetonitrile.
Reaction SMILES: [H-].[Na+].[N+](C(C)C)([O-])=[O:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18]>C(O)C>[Cl:17][C:13]1[C:12]([F:18])=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:4]
Reactant: Fc1c(Cl)cccc1CBr
Reactant: CC(C)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1cccc(Cl)c1F
Reaction time: 0.17 h

Procedure:
Ethanol (100 ml) was added to sodium hydride (content: 60%, 4.7 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. After 2-nitropropane (11 ml) was added to the reaction mixture to stir the mixture for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added to stir the resultant mixture at room temperature for 3.5 hours. Precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was partitioned in diethyl ether and water, and an organic layer was successively washed with a 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:7) to obtain crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oil. Methanol (20 ml) was added to sodium hydride (content: 60%, 1.6 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was cooled to −20° C., and the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and a solution of methyl 2-azidoacetate (5.0 g) in methanol (10 ml) were added within 20 minutes. The temperature of the reaction mixture was raised to 0° C., and after the mixture was stirred for 2.5 hours, water (40 ml) was added thereto. The reaction mixture was concentrated under reduced pressure, the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g). This product was dissolved in xylene (50 ml), and the solution was stirred at 130° C. to 140° C. for 3 hours. The reaction mixture was concentrated, and the resultant residue was purified by column chromatagraphy on silica gel (methylene chloride) and then crystallized from diethyl ether-hexane to obtain the title compound (440 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]([OH:13])=[O:12])[C:8]=1[CH3:9])(=[O:3])[CH3:2].[C:14]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C.CCOCC>CO>[C:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(=O)c1cnn(CC(=O)O)c1C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cn1ncc(C(C)=O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)acetic acid (1.17 g, 6.42 mmol, as a mixture of regioisomers from the previous step) in MeOH (8.8 ml)-Toluene (30.6 ml) was added a 2 M solution of (trimethylsilyl)diazomethane in ether (4.8 ml, 9.6 mmol) dropwise at 0° C. The resulting solution was allowed to warm to rt and stirred for 120 min. The reaction was quenched by addition of AcOH (3 ml) and the solvent was concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give the desired product along with a mixture of regioisomers (>99% yield). 1H NMR (270 MHz, CDCl3) δ 2.45 (3H, s), 2.53 (3H, s), 3.79 (3H, s), 4.90 (2H, s), 7.88 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:15]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[C:16]=[O:17]>>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:12][N:13]([C:16](=[O:17])[NH:15][C:18]34[CH2:19][CH:20]5[CH2:26][CH:24]([CH2:23][CH:22]([CH2:21]5)[CH2:27]3)[CH2:25]4)[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N1CCC12CNC2
Product: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NC13CC4CC(CC(C4)C1)C3)C2

Procedure:
In analogy to the experimental procedure of example 8) 1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of 1-benzyl-1,6-diaza-spiro[3.3]heptane was converted using 1-isocyanato-adamantane instead of (3-isocyanato-propyl)-benzene into the title compound which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)[CH3:2].Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=2)[NH:26][CH:25]=[C:24]3[CH:33]2[CH2:34][CH2:35][N:36]([S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])[CH2:37][CH2:38]2)[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCNCc1cncc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 36 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of ethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.3 mg of the title compound (36%).
Reaction SMILES: [F:1][C:2]([F:18])([S:14](F)(=[O:16])=[O:15])[C:3]([F:13])([F:12])[O:4][C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7].C[Si](C)(C)[O-:21].[K+:24].O1CCCC1>OCC(CO)O>[F:1][C:2]([F:18])([S:14]([O-:21])(=[O:16])=[O:15])[C:3]([F:13])([F:12])[O:4][C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7].[K+:24]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Yield: 65 %

Procedure:
The procedure of Example 1 was followed using perfluoro-3-oxapentanesulfonyl fluoride (7.95 g, 25 mmol), potassium trimethylsilanolate (3.2 g, 25 mmol) and dry tetrahydrofuran (100 mL) while heating at reflux for 1.5 h. Potassium perfluoro-3-oxapentanesulfonate (3.79 g initially and 1.74 g by concentrating the filtrate under vacuum; total 5.53 g, 65% yield) was isolated as a white solid: 19F NMR (fluorotrichloromethane) δ -79.4 (m, CF2, 2F), -83.2 (s, CF3, 3F), -84.9 (m, CF2, 2F), -115.0 ppm (m, CF2, 2F); Positive ion Fast Atom Bombardment MS (Glycerol matrix, Cs⊕ ion bombardment) m/e 393, 747, 1101, 1455, 1809 for M+K⊕ to M5 +K⊕.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]3)[N:11]([CH2:26][C:27]3[CH:40]=[CH:39][C:30]([C:31](NC4NN=NN=4)=[O:32])=[CH:29][CH:28]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)(C)[CH:43]=[O:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH2:18][CH2:19]3)[N:11]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:44][CH3:43])=[O:32])=[CH:39][CH:40]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)C(=O)N1CCC(c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)CC1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCN(CC(C)(C)C)CC2)cc1

Procedure:
To a solution of the intermediate from Example 142 step F (100 mg, 0.225 mmol) in 1,2-dichloroethane (3 mL) was added trimethyl acetaldehyde (29 mg, 0.337 mmol) and sodium triacetoxy borohydride (71 mg, 0.337 mmol). After 16 hours the reaction was diluted with DCM (10 mL) and washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This material was used in the next step without any further purification. LC-MS: 3.44 min; (M+H)=514.2.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:21])([F:20])[CH2:15][CH2:16][C:17](Cl)=[O:18].Cl>C(OCC)C.C(O)C.C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([C:17](=[O:18])[CH2:16][CH2:15][C:14]([F:21])([F:20])[F:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: O=C(Cl)CCC(F)(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(C(=O)CCC(F)(F)F)C(=O)OCC
Temperature: 55 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 20.35 g of magnesium (turning) and 148 ml of ethanol, 0.1 ml of carbon tetrachloride was added and heated to 55° C. To the mixture, a mixed solution of 197 ml of ethanol, 700 ml of diethyl ether and 168 g of diethyl malonate was added dropwise over one hour. After 2 hours, the reaction solution was cooled to -5° C. under a nitrogen flow and 112 g of 4,4,4-trifluorobutyryl chloride was added. After the temperature was returned to ambient temperature over one hour, the reaction was further conducted for 12 hours. The reaction solution was poured into an aqueous 5% ice-cooled hydrochloric acid, and extracted three times with diethyl ether. The layers were combined and the combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 179 g of 4,4,4-trifluorobutyryl-malonic acid diethyl ester (b.p.: 125°-134° C., 15 mmHg) (yield: 90%).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[CH3:24][C:25]([CH3:32])([CH2:29][CH2:30][CH3:31])[C:26](Cl)=[O:27].Cl>C(OCC)C>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:26](=[O:27])[C:25]([CH3:32])([CH3:24])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC(C)(C)C(=O)Cl
Reactant: CCCCCCNCc1ccc(F)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCN(Cc1ccc(F)cc1F)C(=O)C(C)(C)CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
22.7 g (0.10 mol) of N-hexyl-2,4-difluorobenzylamine and 24.3 g (0.24 mol) of triethylamine are dissolved in 150 ml of diethyl ether. A solution of 17.8 g (0.12 mol) of 2,2-dimethylpentanoyl chloride in 50 ml of diethyl ether is added dropwise at room temperature over the course of 30 minutes. The mixture is stirred for a further 18 hours at room temperature until the reaction is complete (GC check). For work-up, the resultant suspension is adjusted to pH 7 using 70 ml of 2N hydrochloric acid. Everything dissolves, and two phases form, which are separated. The organic phase is washed with 50 ml of water, dried using magnesium sulfate, filtered and evaporated on a vacuum rotary evaporator. 37.8 g of a pale yellow liquid, which is subjected to fractional distillation, are obtained. 21.4 g (63% of theory) of a colourless oil which boils at 126°-127° C. and 0.4 mbar are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[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:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=4[O:2][CH3:1])[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: COc1ccc(C(=O)O)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)N[C@@H]2COc3cccc(N4CCN(C)CC4)c3C2)c(OC)c1
Yield: 70.8 %

Procedure:
A solution of 2,4-dimethoxybenzoic acid (185 mg, 1.01 mmol) in thionyl chloride (5 mL) was heated at 55° C. for 15 min. 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 (228 mg, 0.920 mmol) in anhydrous methylene chloride (20 mL) with stirring. The precipitated product was dissolved by the addition of triethylamine (193 μL, 1.38 mmol) to give a clear light yellow solution. The ice-bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The mixture was washed with a saturated NaHCO3 solution, dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 268 mg (71% yield) of the title compound as an oil: [α]21D−91° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 411 (4, M+). The base (238 mg, 0.578 mmol) was dissolved in anhydrous diethyl ether (10 mL) under nitrogen and was cooled on an ice-bath. A solution of HCl in diethyl ether (3 M, 0.5 mL), diluted with diethyl ether (5 mL), was added dropwise with stirring. The HCl salt was filtered, washed with diethyl ether, and dried in vacuo affording 187 mg (69% yield) of the product as a white powder: mp sinters >44° C.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.O=[C:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20](O)=[O:21]>>[CH2:16]1[C:15]2[C:20](=[O:21])[O:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][C:2]=3[C:14]=2[CH2:19][CH2:18][NH:17]1
Reactant: O=C(O)C1CNCCC1=O
Reactant: Oc1cccc2ccccc12
Agent: Cl
Product: O=c1oc2c(ccc3ccccc32)c2c1CNCC2
Yield: 29.4 %

Procedure:
Prepared by the method described in Example 1 from 1-napthol (10.0 g, 0.069 moles) and 4-oxo-3-piperidinecarboxylate hydrochloride (9.6 g, 0.05 moles). Recrystallization from 2-propanol/N,N-dimethylformamide yielded the product (3.7 g), mp 227°-230° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15]Br)[C:7](=[O:17])[C:6]=2[CH:18]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[S:9]2(=[O:11])=[O:10])[CH2:27][CH2:26]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of 5-fluoro-2-(4-bromobutyl)-1,2-benz-isothiazol-3(2H)one 1,1-dioxide and 0.02 mol of 1-(2-pyrimidinyl)piperazine are stirred with 0.02 mol of K2CO3 in 150 ml of absolute DMF at 100° C. for 1 hour. The mixture is then evaporated. Water is added and the organic substance is taken up in methylene chloride. The dried CH2Cl2 phase is applied to asiatic gel column and eluted with CH2Cl2 /CH3OH (95:5).