Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:16]([O:17][CH3:18])=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=1.C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30](=[O:37])[C@@H:31]1[CH2:35][C:34](=[CH2:36])[CH2:33][NH:32]1.CCN(CC)CC>CN(C=O)C.C1COCC1.O>[CH3:28][O:29][C:30](=[O:37])[C@@H:31]1[CH2:35][C:34](=[CH2:36])[CH2:33][N:32]1[C:12](=[O:14])[C:11]1[CH:15]=[C:16]([O:17][CH3:18])[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:9][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCCCBr
Reactant: C=C1CN[C@H](C(=O)OC)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C=C1C[C@@H](C(=O)OC)N(C(=O)c2cc(OC)c(OCCCCCBr)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of DMF (2 drops) was added to a solution of 4-(5-bromopentyloxy)-5-methoxy-2-nitro-benzoic acid 17 (270 mg, 0.74 mmol) and oxalyl chloride (80 μL, 0.89 mmol) in anhydrous THF (7.5 mL) and the resulting mixture was stirred at rt for an overnight. Excess THF and oxalyl chloride were removed with rotavapor. The acetyl chloride was resuspended in fresh THF (6 mL) and was added dropwise to a solution of 4-methylene-L-proline methyl ester 5 (228 mg, 0.89 mmol), Et3N (0.32 mL, 2.31 mmol), and H2O (0.15 mL) in THF (1.5 mL) at 0° C. under argon atmosphere. The reaction mixture was allowed to warm to rt and stirring was continued for 4 h. After removal of THF, the residue was partitioned between H2O and EtOAc (20/20 mL). The aqueous layer was further extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated. Purification of the residue by flash chromatography (silica gel, 6:4 hexanes/EtOAc) yielded 1-[4-(5-bromopentyloxy)-5-methoxy-2-nitro-benzoyl]-4-methylene-L-proline methyl ester 18 as light yellow oil (rotamers): 1HNMR (300 MHz, CDCl3, rotamers) δ 1.62-1.68 (m, 2H), 1.86-1.98 (m, 4H), 2.64-2.75 (m, 1H), 2.99-3.08 (m, 1H), 3.43 (t, J=5.1 Hz, 2H), 3.59-3.96 (m, 7H), 4.05-4.21 (m, 3H), 4.57-4.61 and 4.90-5.12 (m, 3H), 6.80 and 6.83 (2 s, 1H), 7.64 and 7.67 (2 s, 1H); EIMS m/z 507 and 509 ([M]++Na).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-2-Aminocyclohexanecarboxylic acid (0.150 g, 1.05 mmol) is dissolved in 1.5 ml of water and NaOH (0.09 g, 2.25 mmol) in 1.5 ml of water is added at 0° C. 4-Chlorobenzene sulfonyl chloride (0.243 g, 1.15 mmol) in 1.5 ml of toluene is added. The reaction mixture is stirred at room temperature for 16 hours. The toluene layer is separated and the aqueous layer is washed twice with toluene. The toluene layers are discarded. Ethyl acetate is added to the aqueous layer (15 ml) and 2M HCl until pH<7. The two phases are separated and the aqueous layer is extracted with ethyl acetate (3×15 mL). The combined organic phases are washed with brine (20 ml), dried over MgSO4 and the ethyl acetate is removed under reduced pressure leaving a white solid that is dissolved in toluene (2×10 ml) and concentrated .The product is dried in vacuum.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:14])=[CH:6][CH:5]=1.[OH-].[Li+]>CO>[NH2:1][N:2]=[CH:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCNC(=O)c1cccc(NCc2ccc(C=NN)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NN=Cc1ccc(CNc2cccc(C(=O)NCCC(=O)O)c2)cc1
Yield: 95.3 %

Procedure:
Ethyl β-[[3-[4-(aminoiminomethyl)benzyl]aminobenzoyl]amino]propanoate (75 mg) was treated with 1N lithium hydroxide and methanol (1:1; 20 ml) for 5 min. Methanol was removed under reduced pressure and the residue was purified by HPLC using acetonitrile/water/trifluoroacetic acid system. The desired fractions were collected and lyophilized to give 66 mg of white material. FAB-MS: MH+ =341.2.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:33])([F:35])[F:34])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 9.7 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.52 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as a light yellow solid (0.045 g, 6%). MS (ISN) 484.2 [(M−H)−]; mp 284° C.
Reaction SMILES: [C:1]([C:3]1[CH:46]=[CH:45][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:16]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4S(C3C=CC(C)=CC=3)(=O)=O)[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(C)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)NS(C)(=O)=O)N(COCC[Si](C)(C)C)C=2C=1)#N>>[C:1]([C:3]1[CH:46]=[CH:45][C:6]2[NH:7][C:8]([CH:10]([C:16]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(NS(C)(=O)=O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(NS(C)(=O)=O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Product: Cc1cc(C)c2[nH]ccc2c1C(NS(C)(=O)=O)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)methanesulfonamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)methanesulfonamide as described in Example 64-B and 64-C. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (s, 1H) 7.97 (br. s, 1H) 7.58-7.60 (m, 1H) 7.49 (m, 1H) 7.18 (t, J=2.78 Hz, 1H) 6.78 (s, 1H) 6.35-6.37 (m, 2H) 2.82 (s, 3H) 2.44 (s, 3H) 2.42 (s, 3H). HRMS calcd. for C20H19N6O2S (M+H)+ 394.1332. found 394.1332.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[N+:20]([O-])=O)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.[Ni]>[NH2:20][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1

Procedure:
A solution of 5.6 g (18.7 mmol) (4-isopropyl-phenyl)-(5-methoxy-2-nitro-phenyl)-methanone in 100 ml methanol is hydrogenated in the presence of 2 g Raney nickel at 5 bar for 5 h. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in ether and the product is precipitated by the addition of gaseous hydrochloric acid as its hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)[C:9]=2[CH:18]=1)=[O:4].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:34])[F:19])[CH:22]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:18]=1)=[O:4]
Reactant: COC(=O)c1ccc2nnn(CCCCCl)c2c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
6-methoxycarbonyl-1-(4-chlorobutyl)-1H-benzotriazole (9.61 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.8 g compound (I-56) with a yield of 63.4%. ESI-MS [M+H]+: m/z 461.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16](=[O:23])[C:17]([C:19]([F:22])([F:21])[F:20])=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:13][C@H:17]([C:16]([O:15][CH3:14])=[O:23])[C:19]([F:22])([F:21])[F:20])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: COC(=O)C(=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H](Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Reaction time: 0.25 h
Yield: 43 %

Procedure:
4-(4-Bromophenyl)-1,3-thiazol-2-ylamine (510 mg, 2.0 mmol) and methyl-3,3,3-trifluoropyruvate (0.10 mL, 1.0 mmol) were dissolved in 50 mL methylene chloride. Titanium (IV) chloride (1M in toluene, 1.6 mL, 1.6 mmol) was added dropwise to give an orange-brown suspension. The mixture was stirred for 15 min and then added by cannula to a solution of sodium cyanoborohydride (0.26 g, 3.0 mmol) in 50 mL of methanol. The mixture was stirred for 15 min and then quenched by the addition of H2O and saturated aqueous sodium bicarbonate. The mixture was extracted three times with methylene chloride. The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (100% methylene chloride) afforded methyl N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-3,3,3-trifluoroalaninate (0.17 g, 44%) as a white solid. MS (ES) m/z 392.8.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH2:20][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
tert-Butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(tritylamino)propylcarbamate (6.19 g, 11.3 mmol) was dissolved in 115 mL of anhydrous CH2Cl2 and 18.2 mL of glacial acetic acid. The reaction mixture was cooled to 0° C. under an atmosphere of N2 and boron trifluoride diethyl etherate (1.51 mL, 11.9 mmol) was added dropwise over several minutes. After stirring for 5 hours, the reaction mixture was treated with 183 mL of cold, aqueous 10% NaOH solution. The reaction mixture was extracted into 200 mL of a 3:1 chloroform/2-propanol mixture and the layers were separated. The aqueous portion was extracted with two additional portions of the chloroform/2-propanol mixture. The organic phases were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5%-10% methanol/CHCl3) gave tert-butyl (2S)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (3.43 g) as a colorless syrup.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[C:35]([CH:36]=O)=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[N:31]=1.C([BH3-])#N.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:36][C:35]4[C:30]([O:29][CH3:28])=[N:31][C:32]([O:38][CH3:39])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: COc1ccc(C=O)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)c(OC)n1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (120, 60.0 mg, 0.150 mmol) in 2.0 mL of ethanol and 0.1 mL of acetic acid, 2,6-dimethoxy-pyridine-3-carbaldehyde (121, 120 mg, 0.75 mmol) and silica supported cyanoborohydride (0.40 g, 0.484 mmol) were added. The reaction was heated to 100° C. for 18 minutes at 300 Watts in microwave, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (122, 60 mg).
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[CH3:30][O:31][C:32](Cl)=[O:33].Cl>O1CCCC1>[CH3:30][O:31][C:32]([O:1][C@H:2]1[C@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:33]
Reactant: COCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1OC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
A suspension of 2 g of (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in 30 ml of dry tetrahydrofuran is treated in small portions with 0.34 g of sodium hydride suspension (80% strength in paraffin) and stirred at room temperature for 30 minutes, then 0.66 g of methylchloroformate is added dropwise and the mixture is stirred for 3 h. It is then poured onto ice water, neutralized with semiconcentrated aqueous hydrochloric acid and extracted three times with a little ethyl acetate, and the collected organic phases are washed with a little water and dried over potassium carbonate. The volatile components are stripped off in vacuo and the solid residue is purified on silica gel (eluent: diethyl ether). 1.2 g of the title compound of melting point 176–77° C. (diethyl ether) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:13]2[C:14]([NH2:21])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Na+].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][C:13]3[C:14](=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=3)[NH:21][C:24]2=[O:25])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(NCc2cnc(SC)nc2N)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2Cc3cnc(SC)nc3NC2=O)c1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
Into a solution of 5.0 g (16.3 mmol) of 5-[(3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-ylamine in 55 mL of dimethylformamide cooled to 5° C., was added 1.63 g (40.8 mmol) of sodium hydride as a 60% mineral oil suspension. The ice bath was removed, and the reaction was stirred for 1 hour. To the reaction was then added 7.94 g (48.9 mmol) of 1,1′-carbonyldiimidazole. After stirring the mixture a further 2.5 hours, the mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and a saturated solution of ammonium chloride. The dichloromethane layer was washed twice with each of saturated ammonium chloride, water, and a saturated solution of sodium chloride. The dichloromethane solution was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with chloroform/methanol (10:0.25 v/v), to give 3.24 g (60%) of the title compound.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>BrCC1C=CC=CC=1>[CH2:18]([O:11][C:3]1[C:2]([I:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: Cc1ccccc1
Agent: BrCc1ccccc1
Product: O=[N+]([O-])c1cnc(OCc2ccccc2)c(I)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 3-iodo-5-nitropyridin-2-ol (0.011 mol, 3 g) in 30 ml of toluene, 2.5 ml of (bromomethyl)benzene and 5.1 g of Ag2CO3 was added. The mixture was stirred at 70° C. for 6 h. The crude was filtered through Celite and washed with ethyl acetate. The solvent was evaporated affording 3.6 g (yield 90%) of the expected product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]([O:38][CH2:39][CH2:40][OH:41])=[C:27]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[CH:26]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:26]=[C:27]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=3)[C:28]([O:38][CH2:39][CH2:40][OH:41])=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a flamed dried round bottom flask with 8-phenyloctyl amine (0.484 mL, 2.43 mmol) and THF (5 mL) cooled to 0° C. was added n-BuLi (0.972 mL, 2.5 M in hexane, 2.43 mmol) dropwise over a 5 min. period. The resulting solution was allowed to stir 5 min. and then warmed to room temperature for 30 min. This solution was then added dropwise to a solution of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.300 g, 0.696 mmol) in THF (15 mL) at −20° C. This final mixture was stirred at −20° C. for 15 min and then warmed to room temperature for 15 min. At this point, the reaction mixture was quenched with H2O (10 mL) and diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (20 to 40% EtOAc/petroleum ether gradient) to afford the product (0.267 g, 65%) as a clear oil; 1H NMR (CDCl3) δ 1.09-1.48 (m, 9H), 1.48-1.72 (m, 4H), 2.58 (t, J=6.8 Hz, 2H), 3.30-3.35 (m, 2H), 3.35-3.41 (m, 2H), 3.46 (dd, J=6.8, 13.0 Hz, 2H), 6.07-6.18 (m, 1H), 7.11-7.19 (m, 3H), 7.21-7.31 (m, 2H), 7.35-7.44 (m, 4H), 7.44-7.57 (m, 2H), 7.63 (s, 2H), 7.77 (s, 2H); mass spectrum [(+) ESI], m/z 590 (M)+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[F:21][C:22]1[CH:23]=[C:24]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.35 min; [M+H]+=494.1.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[CH3:8][N:9]1[C:13]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=[N:10]1.CI>O>[CH3:3][N:14]([C:13]1[N:9]([CH3:8])[N:10]=[CH:11][CH:12]=1)[C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=1
Reactant: CN(C)C=O
Reactant: Cn1nccc1NC(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(C(=O)c1ccc(C(F)(F)F)cc1)c1ccnn1C
Reaction time: 0.33 h

Procedure:
Under cooling in an ice bath, 60% sodium hydride (39 mg) was added to a dimethylformamide (2.1 mL) solution of N-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)benzamide (200 mg), and the obtained solution was then stirred for 20 minutes. Thereafter, methyl iodide (51 μL) was added to the reaction solution, and the obtained solution was then stirred for 1.5 hours, and then at a room temperature for 17 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=70:30 to 50:50), so as to obtain the title compound (141 mg) in the form of a colorless oily substance. 1H NMR (200 MHz, CHLOROFORM-d) δ ppm 3.41 (s, 3H) 3.60 (s, 3H) 6.01 (d, J=1.76 Hz, 1H) 7.36 (d, J=1.76 Hz, 1H) 7.43 (d, J=8.79 Hz, 2H) 7.52 (d, J=8.35 Hz, 2H)