Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].C([O-])(=O)C.[Na+].[Br:32]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Br:32])[C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)C[C@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](Cc1cc(Br)c(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester (7.6 g, 21 mmol) was dissolved in acetic acid (100 mL). Sodium acetate (4.2 g, 51 mmol) was added to the solution. Reaction vessel was placed in a cool water bath to control reaction exotherm. Bromine (1.1 mL, 22 mmol) was added to the mixture in one portion. Reaction stirred at ambient temperature for 10 minutes. Mixture was poured into 1N aqueous sodium thiosulfate solution (400 mL). Material was extracted twice with ethyl acetate. Organic phase was washed successively with water and brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 77% yield as an amber oil. MS m/e (M−H)−=440.0, 442.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C1COCC1>[CH:21]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[O:12][C:11]1[C:10]([Cl:24])=[CH:9][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[Cl:1])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a mixture of methyl 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)-benzoate (1.40 g, 3.37 mmol) in THF (10.0 mL) at 0° C. was added a solution of DIBAL-H (8.12 μL, 8.12 mmol, 1.0 M solution in THF). The reaction mixture was stirred at room temperature for 16 h, quenched with cold 1 N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford 4-(3′-iso-propyl-4′-methoxyphenoxy)-3,5-dichlorobenzyl alcohol as an off-white solid (0.94 g, 100%): 1H NMR (300 MHz, DMSO-d6): δ 7.54 (s, 2 H), 6.81 (m, 2 H), 6.40 (m, 1 H), 5.51 (m, 1 H), 4.54 (d, J=6.0 Hz, 2 H), 3.75 (s, 3 H), 3.21 (m, 1 H), 1.13 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (17:3); Rf=0.27.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19](O)[CH:18]=2)=[CH:13][C:12]=1[C:24]([F:27])([F:26])[F:25])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:3])[CH3:2])=[C:12]([C:24]([F:26])([F:25])[F:27])[CH:13]=2)[N:22]=[CH:21][N:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccccc1Sc1ccc(-c2cc(O)ncn2)cc1C(F)(F)F
Product: CC(C)c1ccccc1Sc1ccc(-c2cc(Cl)ncn2)cc1C(F)(F)F
Yield: 51 %

Procedure:
Then, 4-chloro-6-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyrimidine 47 was prepared as follows. Compound 46 (1.40 g, 3.59 mmol) was treated with POCl3 (30 mL) at 60° C. for an hour. The reaction mixture was concentrated on a rotor-vapor, and the residue was treated with crushed ice (10 g). Water (50 mL) was added. The aqueous solution was then extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography to give a brown oil 47 (0.74 g, 51%). 1H-NMR (CDCl3, 400 MHz) δ 1.19 (d, J=6.7 Hz, 6H), 3.50 (heptet, J=6.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 7.24-7.28 (m, 1H), 7.46-7.50 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.68 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 9.00(s, 1H), MS (DCI) m/z 409, 411 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[N:10]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[OH:11].[Na].[CH2:18](Br)[CH:19]=[CH2:20]>C(O)C>[CH2:20]([O:11][N:10]([C:12]1[NH:16][CH2:15][CH2:14][N:13]=1)[C:4]1[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2])[CH:19]=[CH2:18]
Reactant: ON(C1=NCCN1)c1c(F)cccc1Br
Reactant: C=CCBr
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: C=CCON(C1=NCCN1)c1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 gm (0.016 mol) of 2-[N-(2-bromo-6-fluoro-phenyl)-N-hydroxy-amino]-2-imidazoline hydrochloride and 0.7 gm of sodium were dissolved in 75 cc of absolute ethanol, and then 1.6 ml (about 115% of the stoichiometrically required amount) of allyl bromide were added to the solution. The resulting mixture was stirred for one hour at room temperature, and was then evaporated. The residue was dissolved in dilute (about 1 N) hydrochloric acid, and the resulting solution was extracted with ether (the ethereal extracts were discarded). The acidic aqueous phase was then fractionally extracted with ether at stepwisely increasing pH-values (addition of 2-N-sodium hydroxide), and these ethereal extracts were also discarded. The aqueous phase was now made alkaline with 5 N sodium hydroxide, whereupon a white, amorphous substance precipitated, which was collected by suction filtration, washed with water and dried. 2.95 gm (58.3% of theory) of the compound of the formula ##STR4## were obtained. It had a melting point of 141° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 5.0 g (24.1 mmol) of 1-(4-nitro-phenyl)-piperazine in 100 mL of dichloromethane was added 5.04 mL (28.9 mmol) of diisopropyl-ethylamine. The solution is cooled in an ice-bath, treated with 1.89 mL (26.5 mmol) of acetyl chloride, and stirred at room temperature overnight. The reaction is washed successively with water, 0.5 M HCl, saturated sodium hydrogen carbonate, and brine, and dried over magnesium sulfate, and concentrated to give 5.91 g (98.5%) of the product as a solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)C.[NH3:13]>>[NH2:13][C:4]([CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: N
Reactant: CCOC(=O)Cc1cccnc1
Product: NC(=O)Cc1cccnc1

Procedure:
16.8 g of ethyl-3-pyridylacetate and 1 l of methanolic ammonia solution are shaken in a pressure vessel at 100° C. for 40 hours. After cooling and concentration, the precipitate is triturated with ether and filtered off with suction. 12.7 g of the 3-(aminocarbonylmethyl)pyridine obtained in this way are hydrogenated with 250 ml of ethanol and 3 g of rhodium/platinum catalyst at 50° C. under a pressure of 3 bar of hydrogen for 2 hours. After cooling, filtration and concentration, the precipitate is triturated with ether and filtered off with suction.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1>>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:25])([F:26])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: c1ccoc1
Product: O=C(c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1)c1ccco1

Procedure:
This compound is prepared by method C using compound 12f and furane
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH:36](=[O:42])/[CH:37]=[CH:38]/[CH:39]=[CH:40]/[CH3:41]>C1COCC1>[CH2:22]([O:21][C:20]1[C:15]2[S:14][C:12]3[N:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:36]([OH:42])/[CH:37]=[CH:38]/[CH:39]=[CH:40]/[CH3:41])=[CH:3][CH:4]=4)[N:9]=[C:10]([CH3:30])[C:11]=3[C:16]=2[N:17]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1)[CH3:23]
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(Br)cc3)nc(C)c12
Reactant: C/C=C/C=C/C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C=C/C=C/C(O)c1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1
Temperature: -10 °C

Procedure:
200 mg (0.4 mmol) 7-(4-bromophenyl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine was mixed at −80° C. in 50 ml THF with 0.48 ml (1.2 mmol) 2.5 M BuLi solution. After 15 min at this temperature, 112 mg (1.2 mmol) (2E,4E) hexadienal was added. Subsequently, the reaction mixture was heated to −10° C. and the reaction was terminated by addition of 10 ml saturated NaHCO3. The organic solvent was removed and the aqueous phase was extracted with CH2Cl2. Following flash chromatographic purification (CH2Cl2/methanol, 8:2) 130 mg (63%) of the title compound was obtained. ESI-MS [m/z]: 503, melting point: 149-150° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[CH:19]=[CH:20][C:21]([CH2:23][OH:24])=[CH:22][C:12]=3[N:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]>CC(C)=O.[O-2].[Mn+4].[O-2]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[CH:19]=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:12]=3[N:11]=2)=[O:8])=[CH:25][CH:26]=1)#[N:2]
Reactant: COCCn1c(NC(=O)c2ccc(C#N)cc2)nc2cc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COCCn1c(NC(=O)c2ccc(C#N)cc2)nc2cc(C=O)ccc21
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 4-cyano-N-[5-hydroxymethyl-1-(2-methoxy-ethyl)-1H-benzimidazol-2-yl]-benzamide (15.4 mg, 0.042 mmol) in acetone (2 mL) was added manganese (IV) oxide (43 mg, 0.42 mmol). After stirring overnight, the black suspension was filtered thru diatomaceous earth and the filtrate concentrated. The filtrate was dissolved in acetone and run through a 2 g SepPak silica gel cartridge to afford 4-cyano-N-[5-formyl-1-(2-methoxy-ethyl)-1H-benzimidazol-2-yl]-benzamide as a white solid (13 mg, 84%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])#[N:4].Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.O>CN(C=O)C>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])#[N:4]
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: C=CCOC(=O)C(CCCCC#N)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCCCC#N)(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 33.9 %

Procedure:
5.62 g (140 mmol; 60% content) of sodium hydride are added in portions to a solution of 48.64 g (127.73 mmol) of diallyl 2-(4-cyanobutyl)malonate from Example 90A in 160 ml of dry DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 90 min. The reaction solution is then cooled to 0° C. again and, after addition of 45.72 g (153.3 mmol) of methyl 4-(2-bromoethyl)benzoate in 80 ml of dry DMF, stirred at this temperature for 45 min. The mixture is then stirred at room temperature overnight. The reaction mixture is mixed with water and extracted with ethyl acetate. After phase separation, the aqueous phase is extracted three times with 200 ml of ethyl acetate each time. The combined organic phases is washed with saturated sodium chloride solution and dried over sodium sulfate, and then the solvent is stripped off in vacuo. The resulting crude product is purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1→100% ethyl acetate). 18.53 g (43.3 mmol, 34% yield) of a colorless liquid are obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[N:13]=[CH:12][N:11]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][N:35]([Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[C:32]3=[N:33][CH:34]=2)O1.C(=O)([O-])O.[Na+].[I-]>O1CCOCC1.O.CC(=O)OCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:29]3[CH:30]=[C:31]4[CH:37]=[CH:36][N:35]([Si:38]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:39]([CH3:40])[CH3:41])[C:32]4=[N:33][CH:34]=3)[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Ic1ccc2ncnc(N3Cc4ccccc4C3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccc4ncnc(N5Cc6ccccc6C5)c4c3)cnc21
Yield: 34.5 %

Procedure:
0.25 g of 4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline, 0.32 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]-pyridine, 0.16 g of sodium hydrogencarbonate and 0.09 g of PdCl2(PPh3)2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the iodide has reacted completely (HPLC check, about 8 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 30 min), giving 0.12 g of 4-(1,3-dihydroisoindol-2-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline as slightly beige solid (yield 33%, content 95%); MS-FAB (M+H+)=520.0; Rf (polar method): 2.77 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=4[CH3:26])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C)c(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(C)C)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 2,5-dimethylphenylboronic acid in the presence of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′,5′-dimethyl-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 449.2 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[Cl-].[NH4+]>C(O)C.[Fe]>[CH3:1][CH:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cc1
Temperature: 25 °C

Procedure:
To a mixture of (±)-tert-butyl 3-methyl-4-(4-nitrophenyl)piperazine-1-carboxylate (870 mg) and iron powder (378 mg) in ethanol (16 ml) was added an aqueous solution (4 ml) of ammonium chloride (116 mg) at room temperature. The resulting suspension was refluxed for 2 hours with vigorous stirring. The reaction mixture was cooled to room temperature, and the resulting solid was filtered through celite and thoroughly washed with ethyl acetate. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic layers were combined and washed successively with saturated aqueous sodium hydrogencarbonate solution and brine. The solvent was evaporated to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]1[C:7]2[N:8]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2c(n1)sc1cccc(C)c12
Yield: 47.3 %

Procedure:
Ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 4-methyl-2-amino benzothiazole (8.0 g, 48.7 m.mol) and ethyl bromopyruvate (14.0 g, 71.7 mmol), 6.0 g (45% Yield) of ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as a brown solid. (M+H) 261.
Reaction SMILES: [ClH:1].[ClH:2].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[NH:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.OO>Cl.O>[Cl:1][C:10]1[C:9]([Cl:2])=[CH:8][C:7]2[N:3]=[C:4]([NH:12][C:13]3[NH:14][CH2:15][CH2:16][N:17]=3)[NH:5][C:6]=2[CH:11]=1
Reactant: c1ccc2[nH]c(NC3=NCCN3)nc2c1
Reactant: Cl
Agent: OO
Solvent: O
Product: Clc1cc2nc(NC3=NCCN3)[nH]c2cc1Cl
Temperature: 70 °C

Procedure:
2-(2-Benzimidazolyl) amino-2-imidazoline dihydrochloride (13.7g, 0.05 mol) was dissolved in concentrated hydrochloric acid (100 ml) and water (100 ml). The solution was stirred and heated to 70°C. A 10% solution of hydrogen peroxide (27 ml) was added dropwise over 10 minutes resulting in precipitation of a white solid. Water (100 ml) was added to cool the reaction mixture to 60°C. A further quantity of 10% hydrogen peroxide (10.5 ml; 10% excess in all) was added. The reaction mixture was heated to 80°C for 15 minutes, and filtered whilst hot to give a solid m.p. 265°-272°C. The filtrate was cooled to give more solid m.p. 285°-292°C. Finally evaporation of the mother liquors in vacuo yielded a third quantity. All 3 solids were combined and recrystallised twice from water to yield 2-(5,6-Dichloro-2-benzimidazolyl) amino-2-imidazoline hydrochloride (7.86g; 53%) as colourless microcrystals m.p. 279° -281°C.
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH2:10][C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(CC3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.[Li+].CC([N-]C(C)C)C.I[CH2:88][CH2:89][CH2:90][C:91]([O:93]C)=[O:92].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO.O>[C:1]([C:3]1[CH:39]=[CH:38][C:6]2[NH:7][C:8]([CH:10]([C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][NH:15]4)[CH2:88][CH2:89][CH2:90][C:91]([OH:93])=[O:92])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Reactant: COC(=O)CCCI
Agent: CC(C)[N-]C(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(CCCC(=O)O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 145-A) (510 mg, 0.93 mmol) in THF (10 mL) was stirred at −78° C. and then LDA (2.0M in heptane/THF/ethylbenzene, 0.47 mL, 0.93 mmol) was added and the reaction was stirred for 10 minutes. At this point, methyl 4-iodobutanoate (0.5 mL, 3.7 mmol) was added and the dry ice bath was removed and the reaction was stirred for 2.5 hours at rt. The reaction was diluted with ethyl acetate (100 mL) and poured into saturated aq. solution of sodium chloride. The layers were separated and the organic layer was dried over Na2SO4, concentrated and absorbed onto silica to purify via FCC (0-20% EtOAc:hexanes). The resulting residue was deprotected of the SEM and Boc group using the conditions shown in Example 142-C. The resulting residue (170 mg, 0.408 mmol) was dissolved in MeOH (5 mL) and was added potassium carbonate (180 mg, 1.3 mmol), the reaction was heated at 65° C. overnight. The mixture was then poured into water (50 mL) and the pH was adjusted to −1 with 3 M HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate, dried over Na2SO4, and purified by reverse-phase FCC (0-50%) ACN:water to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04-12.24 (m, 1H) 11.86-12.03 (m, 1H) 10.88 (s, 1H) 7.93-8.22 (m, 1H) 7.63-7.83 (m, 1H) 7.36-7.52 (m, 1H) 7.12 (t, J=2.81 Hz, 1H) 6.79 (s, 1H) 6.05 (br. s., 1H) 4.87 (dd, J=9.41, 5.62 Hz, 1H) 3.76 (s, 3H) 2.52-2.59 (m, 1H) 2.45 (s, 3H) 2.03-2.30 (m, 3H) 1.48-1.64 (m, 1H) 1.30-1.46 (m, 1H). HRMS calcd. for C23H22N4O3 (M+H)+ 403.1770. found 403.1758.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH:12]1([C:15]([CH3:17])=[O:16])[CH2:14][CH2:13]1>>[CH:12]1([C:15]([CH:17]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])=[O:16])[CH2:14][CH2:13]1
Reactant: CC(=O)C1CC1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: O=C(C=Cc1ccccc1[N+](=O)[O-])C1CC1

Procedure:
2-Nitrobenzaldehyde is condensed with methyl cyclopropyl ketone to give 2-(2-nitrophenyl)vinyl cyclopropyl ketone. The latter is reduced selectively with hydroxylamine and hydroxylamine O-sulfonic acid in dilute sodium hydroxide solution to yield 2-(2-nitrophenyl)ethyl cyclopropyl ketone, which is then reduced with sodium borohydride to 2-(2-nitrophenyl)ethyl cyclopropyl carbinol. The carbinol is treated in the usual way with phosphorus tribromide and zinc bromide to afford 4-[6-(2-nitrophenyl)-3-hexenyl] bromide. The latter is reacted with potassium iodide, potassium carbonate and 3,5-heptanedione to produce 4-[6-(2-nitrophenyl)-3-hexenyl]-3,5-heptanedione which is selectively reduced with hydroxylamine and hydroxylamine O-sulfonic acid to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:20]([O:22]C)=[O:21])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.CO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:20]([OH:22])=[O:21])[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c(OCc3ccccc3)cc(OC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc(OCc2ccccc2)c2cc(C(=O)O)[nH]c2c1

Procedure:
0.11 g of methyl 4-benzyloxy-6-methoxy-1H-indole-2-carboxylate is dissolved in 3 ml of acetone and 2 ml of methanol. 6 ml of 1N sodium hydroxide are then added. This mixture is left to react for 4 hours at room temperature. The medium is concentrated on a rotary evaporator and diluted with 20 ml of water. The resulting mixture is acidified to pH=2 with concentrated hydrochloric acid. A light brown solid is obtained. The recovered mass is 700 mg, which corresponds to a yield of 67%.