Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[N+:20]([O-])([OH:22])=[O:21].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N+:20]([O-:22])=[O:21]
Reactant: CN1CCN(c2ncccc2C(=O)NCCO)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ncccc2C(=O)NCCO[N+](=O)[O-])CC1
Reaction time: 4 h

Procedure:
To a solution of 1.27 g of compound 7 prepared in Examples 2-10 in 13 ml of acetonitrile was added dropwise a mixture of 2.0 g of fuming nitric acid and 1.4 g of acetic anhydride while maintaining the temperature below -10° C. The mixture was stirred for 4 hours, then poured into an aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed twice with water and once with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated to give N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl)nicotinamide (compound 17). The product was dissolved in ethanol, and to the solution was added under ice-cooling hydrogen chloride-saturated ethanol. The hydrochloride thus formed was recrystallized from ethanol to give 1.32 g of N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl) nicotinamide dihydrochloride (compound 18)(yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:24][O:25][CH2:26]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH2:24][O:25][CH3:26])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COCCl
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(COC)c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and chlorodimethyl ether in dimethylformamide there is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methoxymethyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 103°-106° C.,
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[O:25])[C:12](=[O:24])[N:13]3[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[O:25])[C:12](=[O:24])[N:13]3[CH2:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.155 mmol) in DCM (10 ml), TFA (1.716 ml, 23.10 mmol) was added drop wise. The resulting red solution was stirred at room temperature overnight. The volatiles were evaporated under vacuum to afford 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetic acid (0.330 g, 1.137 mmol, 98% yield). MS/ESI+ 291.1 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([CH:29]=O)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:39][CH:40]1[CH2:43][NH:42][CH2:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([CH2:29][N:42]5[CH2:43][CH:40]([F:39])[CH2:41]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C=O)cccc4c3=O)cc2)CCC1
Reactant: FC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CN5CC(F)C5)cccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {1-[4-(8-formyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (81 mg, 0.163 mmol) and 3-fluoroazetidine hydrochloride (23 mg, 0.245 mmol) in dichloroethane (5 mL) was stirred for 10 min. Sodium triacetoxyborohydride (87 mg, 0.409 mmol) was added and the reaction stirred at RT for 18 h. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution, diluted with DCM, filtered through a phase separation cartridge and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 50% EtOAc in DCM) to give the title compound as a gummy solid. LCMS (Method G): RT=2.71 min, [M+H]+=555.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8].C1CCCCC1>C1C(Cl)=CC=C(Cl)C=1>[CH3:1][O:2][C:3]([C:4]1[C:5]([OH:11])=[CH:6][C:7](=[O:8])[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[N:12]=1)=[O:24]
Reactant: COC(=O)CC(=O)C(=NNc1ccc(OC)c(OC)c1)C(=O)OC
Solvent: C1CCCCC1
Solvent: Clc1ccc(Cl)cc1
Product: COC(=O)c1nn(-c2ccc(OC)c(OC)c2)c(=O)cc1O
Yield: 65.2 %

Procedure:
The hydrazone (28) (500 mg) was dissolved in dichlorobenzene and heated to reflux in a sealed tube for 4 hours. The reaction was allowed to cool and cyclohexane was added dropwise to crystallize the desired product. Filtration and drying in vacuo yielded the desired dihydropyridazine ester (29) (295 mg) as a solid. MS+: m/e=307.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([C:6]2[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CO
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)nn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(OC)nn2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(6-methoxy-pyridazin-3-yl)-benzoic acid (5.02 g, 21.8 mmol) (reference example 11f) in methanol (75 mL) is added slowly conc. H2SO4 (3.75 mL). The resulting solution is heated to 50° C. and stirred for 1 hour. The solution is then concentrated to one third volume, cooled to 0°-5° C., adjusted to pH 6 with sat NaHCO3 soln and extracted into ethyl acetate. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 20% ethyl acetate in dichloromethane) to give 4.26 g of title compound as a white crystalline solid. 1H NMR (DMSO) δ 3.90 (s, 3H), 4.10 (s, 3H), 7.38 (d, J=9 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 8.25 (m, 3H). MS (EI) m/z 244 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[ClH:40]>O1CCOCC1>[Cl:40][NH:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NCl)ccc3N2)=C(O)c2ccccc21
Yield: 93 %

Procedure:
A solution of Example 42E (1.91 g, 3.45 mmol) in 4 M hydrochloric acid in 1,4-dioxane (30 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 1.58 g (93%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.38 (td, J=12.87, 3.68 Hz, 1 H) 0.78 m, 10 H) 1.59 (s, 3 H) 2.08 m, 1 H) 2.23 (td, J=12.78, 4.60 Hz, 1 H) 7.07 m, 2 H) 7.53 m, 2 H) 7.77 (m, 2 H) 8.16 (d, J=7.72 Hz, 1 H) 13.58 (s, 1 H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH:24][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC1(C(=O)OCc2ccccc2)CCCCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
1.21 g (12 mmol) of triethylamine was added to a solution of 2.33 g (10 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in 100 ml of tetrahydrofuran, 1.55 g (10 mmol) of phenylacetyl chloride was added dropwise thereto under ice-cooling, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 3.21 g (91%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([OH:22])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9].Br[CH2:28][CH2:29][OH:30]>>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([O:22][CH2:28][CH2:29][OH:30])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Reactant: OCCBr
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCO)c1OCCC(C)c1ccc(F)cc1
Yield: 67 %

Procedure:
Example 7c (93 mg, 0.24 mmol) was reacted with 2-bromoethanol (1.5 eq.) as described under General Procedure F and the crude mixture was purified by flash chromatography (silica gel, Et2O/hexane 70:30) to afford the title compound (68 mg, 67%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.13-4.11 (m, 2H), 3.95 (d, J=6.8 Hz, 2H), 3.84 (s, 3H), 3.76-3.70 (m, 2H), 3.00 (m, 1H), 2.80 (t, J=6.5 Hz, 1H), 2.50 (s, 3H), 2.20 (s, 3H), 2.06-1.98 (m, 2H), 1.29 (d, J=6.9 Hz, 3H). MS (ES+) m/z 425.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[CH3:12][NH2:13].CCO>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:13][CH3:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: CN
Solvent: CCO
Product: CNC(=O)Cc1cncc(Br)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 103 using (5-bromo-pyridin-3-yl)-acetic acid (ABCR, Karlsruhe, Germany, 1.815 mmol) and 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 7.26 mmol) to give the title compound as an off-white solid. (HPLC: tR 1.74 min (Method A); M+H=229, 231 MS-ES)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Cl:13]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCc1cc(Br)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml), and pyridine (2 drops), and the mixture was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was used in the subsequent step without further purification. (2) The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0° C. Added thereto was tetraethylammonium cyanide (8.8 g), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was used in the subsequent step without further purification. (3) The above 5-bromo-2-chlorophenylacetonitrile was added to water (90 ml)-sulfuric acid (75 ml), and the mixture was stirred under heating at 160° C. overnight. The mixture was further diluted with water, and cooled to 0° C. The solvent was removed by decant, and the residue was dissolved in diethyl ether. The solution was washed with water and brine, and extracted with 10% sodium hydroxide. To the extract was added concentrated hydrochloric acid to make the solution acidic. The precipitates were collected by filtration, and purified by silica gel column chromatography (chloroform) to give 5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M−H). (4) The above 5-bromo-2-chlorophenylacetic acid was treated in a manner similar to Reference Example 118-(4) and (5) to give the desired 5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a pale yellow solid. APCI-Mass m/Z 377/379 (M+H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[Cl:45][C:46]1[N:51]=[CH:50][C:49]([CH:52]([NH2:54])[CH3:53])=[CH:48][CH:47]=1>O1CCCC1>[Cl:45][C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:54][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=4)[N:22]([S:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=4)(=[O:35])=[O:34])[CH:21]=3)[C:17]([C:43]#[N:44])=[CH:16][N:15]=2)[CH3:53])=[CH:48][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: CC(N)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)c4ccc(Cl)nc4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 110 °C
Yield: 58 %

Procedure:
Diisopropylethylamine (730 μl, 4.2 mmol) was added to a mixture of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (330 mg, 2.1 mmol) and 1-(6-chloropyridin-3-yl)ethanamine (described in the literature: EP 375907 (B1))(500 mg, 1 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 15 minutes. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a wax (345 mg, 58% yield).
Reaction SMILES: [C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](N(C)OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][Mg]Cl)=[CH:23][CH:22]=1>C1COCC1>[C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](=[O:10])[CH2:25][C:24]1[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COc1ccc(C[Mg]Cl)cc1
Reactant: CCCCC#Cc1ccccc1C(=O)N(C)OC
Solvent: C1CCOC1
Product: CCCCC#Cc1ccccc1C(=O)Cc1ccc(OC)cc1
Yield: 69 %

Procedure:
2-(1-Hexyn-1-yl)-N-methyl-N-(methyloxy)benzamide (158) (0.50 g, 2.04 mmol) was treated with 4-methoxy benzylmagnesium chloride in THF at 40° C. to give 0.43 g (69%) of the title compound (159) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.2 Hz, 3H), 1.40-1.53 (m, 2H), 1.56-1.65 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 3.78 (s, 3H), 4.36 (s, 2H), 6.83 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 7.26-7.30 (m, 1H), 7.33-7.39 (m, 1H), 7.44-7.50 (m, 2H). LCMS (ESI): m/z 307 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[Br:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:30]([C:28]2[S:29][C:25]([Br:24])=[CH:26][CH:27]=2)=[O:31])[S:3][CH:4]=1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Reactant: O=C(O)c1ccc(Br)s1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Br)s1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 5-bromothiophene-2-carboxylic acid, using general method D, to give 5-bromo-thiophene-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Light yellow solid. MS 528.1 ([M+H]+)
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[N:4]=1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:27]=[CH:26]2>O1CCOCC1.ClCCl.CN(C)C1C=CN=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[N:4]=[C:3]([CH3:2])[O:7][N:6]=4)=[CH:9][CH:10]=3)=[O:15])[CH2:17][CH2:18]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2
Reactant: Cc1nc(-c2ccc(C(=O)N3CCNCC3)cc2)no1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The BOC group is cleaved off using 4N HCl in dioxane. A solution of 100 mg of the resulting [4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]piperazin-1-ylmethanone (“A”) and 120 mg of 6-chloronaphthalene-2-sulphonyl chloride in 5 ml of dichloromethane is admixed with 400 mg of 4-dimethylaminopyridine on polystyrene, and the mixture is stirred at room temperature For 18 hours. Filtration and removal of the solvent gives [4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl][4-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]methanone, FAB 497.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:23])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:38])=[CH:18][C:17]=3[F:23])[CH:14]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)cc3F)ncn2)cc1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of N-(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine (88 mg, 0.26 mmol) in THF (2 mL) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.72 mL, 0.26 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated with isopropyl ether to give the title compound (125 mg, 93%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.50 (s, 1H), 8.09 (s, 1H), 7.85 (br s, 0.5H), 7.66 (d, 1H, J=12.6 Hz), 7.36-7.15 (m, 9.5H), 6.88 (d, 1H, J=8.1 Hz), 5.91 (s, 1H), 4.42 (br s, 2H), 3.72 (s, 2H), 3.71 (s, 3H); MS (ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:29][NH:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]([CH3:31])([CH3:30])[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]([CH3:33])([CH3:32])[CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]([CH3:35])([CH3:34])[CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[N:37]([CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[C:38]=[O:39]>O1CCCC1>[CH3:1][C:2]1([CH3:36])[CH2:3][N:4]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:5][CH2:6][N:7]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:8][C:9]([CH3:35])([CH3:34])[CH2:10][N:11]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:12][CH2:13][N:14]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:15][C:16]([CH3:33])([CH3:32])[CH2:17][N:18]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:19][CH2:20][N:21]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:22][C:23]([CH3:31])([CH3:30])[CH2:24][N:25]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:50][CH2:51][CH3:52])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[O:39])[CH2:26][CH2:27][N:28]([C:38]([NH:37][CH2:40][CH2:41][CH2:42][Si:43]([O:44][CH2:45][CH3:46])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])=[O:39])[CH2:29]1
Reactant: CC1(C)CNCCNCC(C)(C)CNCCNCC(C)(C)CNCCNCC(C)(C)CNCCNC1
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCO[Si](CCCNC(=O)N1CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)CN(C(=O)NCCC[Si](OCC)(OCC)OCC)CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)CN(C(=O)NCCC[Si](OCC)(OCC)OCC)CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)CN(C(=O)NCCC[Si](OCC)(OCC)OCC)CCN(C(=O)NCCC[Si](OCC)(OCC)OCC)CC(C)(C)C1)(OCC)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
0.69 g (1.35 mmol) of 6,6,13,13,20,20,27,27-octamethyl-1,4,8,11,15,18,22,25-octaazacyclooctacosane is dissolved in 20 cm3 of anhydrous tetrahydrofuran (THF) in a 200 cm3 Schlenk tube. 3.2 g (12.9 mmol) of (3-isocyanatopropyl) triethoxysilane are rapidly added. The reaction mixture is stirred at room temperature for 12 hours. After evaporating the solvent, the solid obtained is washed twice with 50 cm3 of anhydrous pentahe. 1.97 g of the expected compound are obtained in the form of a white powder.