Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)[C:2]([N:32]3[CH2:33][CH2:34][C:30]([F:35])([F:29])[CH2:31]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Reactant: FC1(F)CCNC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC(F)(F)C2)c(-c2cncnc2)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 224 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Stage 247.1) and 3,3-difluoropyrrolidine hydrochloride (no extraction with citric acid). After purification by flash chromatography on Silica gel, the residue was suspended in iPr2O (10 mL) and stirred for 30 min. Crystals were filtrated off, washed with iPr2O (10 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=7.198 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=482 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.39 (spt, J=7.14 Hz, 2H) 3.37 (t, J=7.23 Hz, 2H) 3.62 (t, J=12.90 Hz, 2H) 7.36 (d, J=8.21 Hz, 2H) 7.87 (d, J=8.99 Hz, 2H) 8.15 (s, 1H) 8.82 (s, 1H) 8.94 (s, 2H) 9.23 (s, 1H) 10.28 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH2:14]([CH2:21][C:22](=O)[C:23]([OH:25])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].Cl>CO>[C:23]([CH:22]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])[CH2:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:25])=[O:24]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (8.0 g) and benzylpyruvic acid (18.0 g) in methanol (450 ml) was stirred at room temperature under nitrogen for 30 minutes. Sodium cyanoborohydride (4.5 g) was added, and the resulting solution stirred at room temperature for 48 hours. Concentrated hydrochloric acid (7 ml) was added dropwise during 10 minutes and stirring was maintained for an additional 1 hour. The reaction mixture was evaporated to dryness, dichloromethane (150 ml) was added, and the mixture stirred for 30 minutes. The solid was filtered off, stirred with water (100 ml) for 15 minutes, then filtered, washed with water (50 ml), and dried to give 3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 173°-175° as a mixture of isomers.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([C@H:20]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[C:21](O)=[O:22])[CH3:19])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:57]([O:61][C:62]([N:64]([CH3:78])[NH:65][C:66](=[O:77])[C@H:67]([NH:75][CH3:76])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:63])([CH3:60])([CH3:59])[CH3:58].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:57]([O:61][C:62]([N:64]([CH3:78])[NH:65][C:66](=[O:77])[C@H:67]([N:75]([C:21](=[O:22])[C@H:20]([N:18]([C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH3:19])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:76])[CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:63])([CH3:58])([CH3:60])[CH3:59]
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)NN(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of (2R)-2-[N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino]-3-naphthalen-2-ylpropionic acid (0.6 g, 1.33 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.18 g, 1.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.25 g, 1.33 mmol) and the mixture was cooled to 0° C. Then N-methyl-N'-((2R)-2-(methylamino)-3-phenylpropionyl)hydrazinecarboxylic acid tert-butyl ester (0.34 g, 1.11 mmol) and diisopropylethylamine (0.25 ml, 1.44 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The product was chromatographed on silica (40 g) with heptane:ethyl acetate (2:1) to give 0.53 g (64%) of N'-[(2R)-2-(N-((2R)-2-[N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylamino]-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionyl]-N-methylhydrazinecarboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[CH:14](=O)[CH:15]([CH3:17])[CH3:16].C(O)(=O)C>O.CO>[CH3:14][CH:15]([CH:17]=[CH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:16]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CC(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)C=CC(C)C)cc1
Reaction time: 3.5 h

Procedure:
17 g of potassium hydroxide were dissolved in 125 ml of water and 125 ml of methanol, and 150 g of 4-methoxyacetophenone were added. 80 g of isobutyraldehyde were added dropwise (in the course of 1.5 hours) at 50° C. After 3.5 hours, the mixture was cooled to room temperature and neutralized with acetic acid (about 20 ml). The dimeric condensation product was filtered off, washed with methanol and dried in air. Yield: 175 g. The solid was mixed with 5 g of sodium acetate and the mixture was distilled under a waterpump vacuum. 165 g of a yellow oil which solidified at room temperature and was a mixture of 2-methyl-5-oxo-5-(4'-methoxyphenyl)-2-pentene and 2-methyl-5-oxo-5-(4'-methoxyphenyl)-3-pentene were obtained. Boiling point of the isomer mixture=158°-165° C./17 mbars.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10].[CH2:25]([P:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[Br-:1].[CH2:34]([P+:29]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10])[CH2:35][CH2:36][CH3:37]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Reactant: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Product: [Br-]
Reaction time: 3 h
Yield: 97.6 %

Procedure:
N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (55.3 g) and toluene (500.0 mL) were added to a reactor. The reaction mixture was cooled to 0˜5° C. and then tributylphosphine (35.0 mL) was added thereto. The temperature of the reaction mixture was raised to 10˜20° C. The reaction mixture was stirred at the same temperature for 3 hours and then filtered under reduced pressure. The resulting white solid was washed with toluene (331.0 mL) and then dried under reduced pressure to obtain tributyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphonium bromide as a white solid (80.1 g, yield 97.6%).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH:18]=[CH:17][C:16]([C:21](=[O:30])[CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([CH3:20])[CH2:15][C:14]=3[CH:13]=[N:12]2)=[CH:7][CH:6]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH:18]=[CH:17][C:16]([C:21]([OH:30])([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:1])([CH3:20])[CH2:15][C:14]=3[CH:13]=[N:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C(=O)CCc2ccccc2)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(CCc1ccccc1)C1(C)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Reaction time: 2.5 h
Yield: 82 %

Procedure:
A 3 M THF solution of methylmagnesium bromide (0.15 mL, 5.4 eq) was added to a THF (1 mL) solution of Example 202 (30 mg, 0.083 mmol) at room temperature. After 2.5 h, the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The EtOAc layer was concentrated and purified by flash column chromatography (4 g ISCO silica gel cartridge, 0 to 50% EtOAc-hexanes) to give the title compound (25.7 mg, 82%) as a 1:1 mixture of two isomers. MS found: (M+H)+=377.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][CH2:19]Cl)=[C:12]([CH:16]=1)[C:13]([O-:15])=[O:14]>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH:18]=[CH2:19])=[C:12]([CH:16]=1)[C:13]([O:15][CH3:1])=[O:14]
Reactant: O=C([O-])c1cc(Cl)ccc1OCCCl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1ccc(Cl)cc1C(=O)OC
Reaction time: 1 h
Yield: 34.5 %

Procedure:
Potassium tert-butoxide (40.4 g, 0.36 mol) was added portionwise to a solution of 5-chloro-2-(2-chloroethoxy)benzoate (76 g, 0.3 mol) in 600 mL of THF at 0° C. After stirring at that temperature for 1 hour, TLC showed complete consumption of starting material and the mixture was poured into ice water. The aqueous layer was extracted twice with EtOAc (200 mL), and the combined organics were evaporated to dryness. The residue was purified by silica gel column chromatography (Hexanes/EtOAc=50:1-30:1) to afford 22 g (34%) of methyl 5-chloro-2-(vinyloxy)benzoate. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, 1H), 7.38 (dd, 1H), 7.00 (d, 1H), 6.52 (dd, 1H), 4.67 (dd, 1H), 4.44 (dd, 1H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>N1C=CC=CC=1>[CH2:27]([NH:29][C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([O:14][CH3:15])[N:13]=2)[CH:3]=1)=[O:31])[CH3:28]
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
To a solution of [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine (184 mg, 0.45 mmol, Example 2) in pyridine (1.5 mL) is added ethyl isocyanate (43 μL, 0.54 mmol). The reaction mixture is stirred for 18 hours at ambient temperature, quenched with the addition of water (25 mL), and extracted four times with EtOAc (25 mL). The combined extracts and washed four times with aqueous copper sulfate solution (25 mL), with water (25 mL), with brine (25 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica (4.5 g) eluting with 20 to 40% EtOAc in heptane to afford 1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-urea [98.3 mg, 52%, Example 41]. LCMS: RT=2.68 minutes, MS: 422 (M+H). 1H NMR (300 MHz, CDCl3), δ 8.11 (1H, d, J=0.17 Hz), 7.88 (2H, s), 7.62 (1H, d, J=0.026 Hz), 7.49 (1H, d, J=0.026 Hz), 7.18 (4H, m), 6.81 (2H, m), 6.22 (1H, d, J=0.08 Hz), 5.83 (1H, s), 5.35 (1H, s), 3.93 (3H, d, J=0.04 Hz), 3.73 (3H, d, J=0.012 Hz), 3.55 (2H, m), 3.19 (2H, q, J=0.022 Hz), 2.81 (2H, m), 2.13 (1H, s), 1.04 (2H, t, J=0.022 Hz). IC50=7.6 nM
Reaction SMILES: C(N[C:5]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:6]=1OCC1OC1)(=O)C>C(O)C.Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C([N+]([O-])=O)C=1NC(=O)C>[NH2:16][CH:15]1[CH2:14][CH2:13][C:12]2[C:6](=[CH:15][CH:5]=[CH:6][CH:12]=2)[CH2:5]1
Reactant: CC(=O)Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Agent: CC(=O)Nc1c(OCC(O)CNC2CCc3ccccc3C2)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1
Yield: 202.9 %

Procedure:
Following the procedure of Example 27, but starting from 1-(2-acetamido-3-nitrophenoxy)-2,3-epoxypropane (5 g) and 2-aminotetralin (2.96 g) in absolute ethanol (80 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-acetamido-3-nitrophenoxy)propanamine hydrochloride is obtained ((iA): R=H, E=acetamido, G=nitro, and the chain is attached to position 2 of the tetralin moiety) (Ex. 89). A mixture of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-acetamido-3-nitrophenoxy)propanamine hydrochloride (4 g) and 97% formic acid (19 ml) is charged in a hydrogenation vessel and freezed. The air contained in the reaction vessel is replaced by nitrogen and 10% Pd/C (0.25 g) is rapidly introduced therein. Hydrogenation is carried out at room temperature and 2.5 bar until the theoretical amount of hydrogen has been consumed. The reaction mixture is then heated, at atmospheric pressure, for 2 hours by means of a boiling water-bath. The catalyst is filtered off, the filtrate is evaporated to dryness and the obtained residue is taken up in hydrogen chloride saturated-isopropanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)O)[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(OCC)(=O)C>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: CC1(C)COc2c(C(O)C3CCCCC3)cc(Br)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)COc2c(CC3CCCCC3)cc(Br)cc21

Procedure:
Following General Procedure J and using (5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-cyclohexyl-methanol (Intermediate 45, 0.62 g, 1.94 mmol), trifluoroacetic acid (4 mL, 52 mmol) and triethyl silane (1.5 mL, 9.4 mmol) followed by flash column chromatography using 3% ethyl acetate in hexane as the eluent, the title compound was obtained (0.58 g, 92%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([NH:34][C:35](=[O:38])[CH2:36][Cl:37])=[N:26]1>C(#N)C>[Cl-:37].[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([NH:34][C:35]([CH2:36][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:38])=[N:26]1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(CCl)Nc1noc2ccccc12
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1noc2ccccc12
Product: [Cl-]
Yield: 64.1 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 1e) (114 mg) and N-benzo[d]isoxazol-3-yl-2-chloro-acetamide (Example 4a) (89 mg) were dissolved in acetonitrile (10 mL) and left for one week. The resulting crystals were filtered off and washed with diethyl ether (3×10 mL) to afford the titled compound as a solid (120 mg).
Reaction SMILES: [C:1]([NH:4][CH:5](Br)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].CCN(CC)CC.[CH3:24][N:25]([CH3:34])[S:26]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)(=[O:28])=[O:27].[Li]CCCC.[NH4+].[Cl-]>O.C1COCC1>[C:1]([NH:4][CH:5]([C:32]1[N:31]=[CH:30][N:29]([S:26](=[O:28])(=[O:27])[N:25]([CH3:34])[CH3:24])[CH:33]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC(C(=O)NCc1ccccc1)c1cn(S(=O)(=O)N(C)C)cn1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a cooled (-78° C.) THF solution (150 mL) of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and BBr3 (1M solution in CH2Cl2, 9.0 mL, 9.0 mmol)) was added Et3N (1.62 g, 16.0 mmol), and then a THF solution of the 2-lithio salt of N,N-dimethylimidazole-1-sulfonamide (generated by the addition of n-BuLi (2.5M in hexane, 3.9 mL, 9.68 mmol) into a cooled (-78° C.) THF solution (25 mL) of N,N-dimethylimidazole-1-sulfonamide (1.54 g, 8.8 mmol)) was added during a 15 min interval. The reaction mixture was stirred at this temperature (30 min) and then at room temperature (45 min). A saturated aqueous NH4Cl solution (50 mL) and H2O (50 mL) were then sucessively added to the reaction, and the aqueous mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4), and the volatile materials were removed by distillation in vacuo. The residue was purified by flash column chromatography on SiO2 gel (4% MeOH/CHCl3) to give 0.50 g (17%) of the desired product: mp 145°-147° C. (recrystallized from EtOAc/hexane); Rf 0.35 (4% MeOH/CHCl3); IR (KBr) 3400, 1640, 1530, 1380, 720 cm-1 ; 1H NMR (DMSO-d6) δ 1.96 (s, C(O)CH3), 2.77 (s, N(CH3)2), 4.25 (dd, J=6.0, 15.5 Hz, CHH), 4.34 (dd, J=6.0, 15.5 Hz, CHH), 5.43 (d, J=8.0, Hz, CH), 7.19-7.30 (m, 5 PhH), 7.40 (s, C5H), 8.17 (s, C2H), 8.42 (d, J=8.0 Hz, NH), 8.67 (t, J=6.0 Hz, NH); 13C NMR (DMSO-d6) 22.42 (C(O)CH3), 37.80 (N(CH3)2), 42.11 (CH2), 51.40 (CH), 115.50 (C5), 126.64 (C4'), 126.94 (2C2' or 2C3'), 128.12 (2C2' or 2C3'), 136.70 (C2), 139.17 (C1'), 140.26 (C4), 168.93 (C(O)NH), 169.09 (C(O)CH3) ppm; mass spectrum (FD) 380 (M+ +1, 34), 248 (13), 247 (100), 108 (64).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].ClC1C=C(C=CC=1)C(OO)=[O:15]>ClCCl>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][O:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)CCCC1CO1

Procedure:
A solution of 6,6-dimethyl-1-heptene (5.33 g, 0.0423 mol) and m-chloroperoxybenzoic acid (9.5 g of 85%, 0.048 mol) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. The resulting solution was washed and aqueous sodium hydroxide (3×50 ml of 2M) and dried over sodium sulfate. The solvent was distilled off at atmospheric pressure to yield (4,4-dimethylpentyl)oxirane as a residue, having the following structural characteristics:
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]5([CH2:36][CH3:37])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])CC1.Cl.Cl.CNC(C1C2C=C(C3C([Cl:59])=CN=C(NCCCC4(CC)CCNCC4)N=3)SC=2C=CC=1)=O>>[ClH:24].[ClH:59].[CH3:3][NH:6][C:7]([C:9]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]4([CH2:36][CH3:37])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[N:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CCNCC1
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C)CC1
Agent: Cl
Product: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CCN(C)CC1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-ethyl-1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-{5-chloro-2-[3-(4-ethylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide di-hydrochloride and isolated as a yellow solid. ES+(m/z) 486 (35Cl) and 488 (37Cl) [M(free base)+H].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=1.CCN(CC)CC.[CH2:30]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41](=[O:53])[C@@H:42]([NH2:52])[CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:37][CH2:36]1)=[O:34])[CH3:31]>C(#N)C.O>[CH2:30]([O:32][C:33]([N:35]1[CH2:36][CH2:37][N:38]([C:41](=[O:53])[C@@H:42]([NH:52][C:20]([C:10]2[CH:9]=[C:8]([Cl:7])[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:22])[CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:39][CH2:40]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(Cl)nc(-c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, oxalyl chloride (0.843 ml) was added to a solution of 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid (1.17 g) in acetonitrile (50 ml) and it was refluxed for 3 h. The reaction mixture was cooled down to 0° C. and NEt3 (2.07 ml) was added, followed by 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester (1.7 g) in 10 ml acetonitrile. It was stirred at RT under argon for 1 h. Water was added and the reaction mixture was extracted with EA. The org. layers were dried (Na2SO4) and evaporated off. Purification by column chromatography (EA/Hept 1/3 to 1/2) offered 1.61 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.BrN1C(=[O:19])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)C>C(Cl)(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([CH:1]=[O:19])=[CH:7][CH:6]=1
Reactant: Cc1ccc(-c2ncco2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: O=Cc1ccc(-c2ncco2)cc1
Temperature: 100 °C

Procedure:
To 2-(4-methylphenyl)oxazole (6.41 g, 40.3 mmol) and N-bromosuccinimide (14.7 g, 82.6 mmol) in carbon tetrachloride (300 mL) was added 2,2′-azobisisobutyronitrile (500 mg, 3.1 mmol) and the reaction mixture was heated at 100° C. for 12 h. The reaction mixture was cooled to 0° C., filtered through a fritted funnel, and concentrated in vacuo. To this crude reaction mixture was added 95% ethanol (300 mL) and silver nitrate (15.1 g, 88.8 mmol), and the reaction mixture was refluxed for 4 h, cooled to room temperature, filtered through a fritted funnel, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 10:1 hexanes/ethyl acetate) gave 880 mg (13%, 2 steps) of the title compound. MS 174 (M+H)+.
Reaction SMILES: C(OC([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:30]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([OH:21])=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCCN(CCc2ccccc2)C(=O)OC(C)(C)C)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(SCCCNCCc2ccccc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl {2-[3-(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor J-01b, 5.5 mg, 0.015 mmol) is dissolved in TFA/dichloromethane (1:1, 1.5 ml) and stirred at rt for 1.5 h. The solvents are evaporated under reduced pressure and the residue is dried under high vacuum, yielding the pure title compound: tR=1.51 min (LC-2), ESI-MS (pos.): m/z 370.39 [M+H]+; ESI-MS (neg.): m/z 368.42 [M−H]+.