Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:26])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][C:11]#[C:12][C:13]#[C:14][CH2:15][CH2:16][C:17]#[C:18][C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28].O1CC[CH2:34][CH2:33]1>>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30]([O:25][CH2:24][CH3:23])=[O:31])[CH3:28].[CH2:24]([OH:25])[CH2:23][CH2:22][CH2:21][C:20]#[C:19][C:18]#[C:17][CH2:16][CH2:15][C:14]#[C:13][C:12]#[C:11][CH2:10][CH2:9][C:8]#[C:7][C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:26]
Reactant: C1CCOC1
Reactant: CCN=C=O
Agent: OCCCCC#CC#CCCC#CC#CCCC#CC#CCCCCO
Product: CCOC(=O)N(CC)CC

Procedure:
Following the general procedure of Example 1, 1.3 parts CF4 diol, 40 parts tetrahydrofuran, 1.42 parts ethyl isocyanate, 0.2 parts DBTE, and 4 parts TEA were mixed together and allowed to react at room temperature for 11/2 hours. The product was precipitated by the addition of 175 parts n-hexane and was quickly filtered and washed several times with additional n-hexane. After drying, the 2.3 parts of product XLV was obtained representing a 35.8% conversion. The product had a fluffy texture which changes blue very rapidly when exposed to daylight. The product was recrystallized by dissolving in 40 parts hot acetone followed by 20 parts hot petroleum ether. The precipitate turned blue during crystallization at about -8° C. The melting point of the material was 146.4° to 148.8° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.C[C:15](C1C=CC(I)=CC=1)=[O:16].[H-].[Na+].C[C:27]([CH3:35])([CH3:34])[C:28](=O)[CH2:29][C:30](=[O:32])[CH3:31]>C(OCC)(=O)C>[OH:32][C:30]1[CH:29]=[CH:28][C:27](/[CH:34]=[CH:11]/[C:10](=[O:12])[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)=[O:13])=[CH:35][C:31]=1[O:16][CH3:15]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: CC(=O)CC(=O)c1ccc(I)cc1
Reactant: CC(=O)CC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)CC(=O)c2ccc(I)cc2)ccc1O
Yield: 31 %

Procedure:
By a similar procedure as described in Example 1 using 1-(4-iodophenyl)-butane-1,3-dione (prepared by reaction of 4-iodoacetophenone with ethyl acetate in the presence of sodium hydride) in place of 5,5-dimethylhexane-2,4-dione, (E)-5-(4-hydroxy-3-methoxyphenyl)-1-(4-iodophenyl)-pent-4-ene-1,3-dione (0.40 g, 0.95 mmol, 31%) was obtained as a yellow solid: mp 139-141° C.; 1H NMR (400 MHz; CDCl3) δ 3.95 (3H, s, OCH3), 5.87 (1H, s, OH), 6.27 (1H, s, H-2), 6.42 (1H, d, J=16.0 Hz, H-4), 6.87 (1H, d, J=8.4 Hz, H-5′), 6.99 (1H, s, H-2′), 7.06 (1H, d, J=8.4 Hz, H-6′), 7.54-7.60 (3H, m, H-5, H-3″, H-5″), 7.41-7.62 (2H, m, H-2″, H-6″), 16.18 (1H, s, OH) ppm; 13C NMR (100 MHz; CDCl3) δ 187.5, 180.8, 148.1, 146.9, 140.9, 138.0, 135.5, 128.9, 127.6, 123.2, 120.9, 115.1, 109.6, 100.0, 97.1, 56.0 ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.Br[CH2:27][C:28](=[O:38])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.O>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][C:28](=[O:38])[CH2:27][N:3]2[C:2]([CH3:1])=[CH:6][N:5]=[CH:4]2)=[CH:32][CH:33]=1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(CBr)CCc1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Product: Cc1cncn1CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixture of 4-methyl-1-tritylimidazole (12.9 g, 39.8 mmol) and 1-bromo-4-(4-chlorophenyl)butan-2-one (12.5 g, 47.8 mmol, 1.2 equivalents) in CH3CN (~200 mL) was heated at reflux for 16 hours. The reaction mixture was then cooled to room temperature and 2N HCL (30 mL) was added. The reaction mixture was then heated at reflux for 30 minutes, cooled to room temperature and treated with water (~500 mL). The resulting mixture was then washed with ether (~1×100 mL) and the pH adjusted to between 9 and 10 with 2N NaOH. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined extracts were then washed with brine and dried over Na2SO4. After filtration and concentration, the resulting crude product (8.5 g) was purified by silica gel chromotography, eluting with 1-8% methanol in methylene chloride to give 8.2 g of 4-(4-chlorophenyl)-1-(5-methylimidazol-1-yl)butan-2-one (70% yield). The hydrochloride salt was recrystallized from methanol/ethyl acetate with m.p. 227°-228° C.
Reaction SMILES: O=C1NCNC1=O.[N+:8]([C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[CH2:14][N:15]1[C:19](=[O:20])[C:18](=O)[N:17]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=C)([O-:10])=[O:9].[OH-:30].[K+].Cl.[CH3:33]O.O>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[CH2:14][N:15]1[C:19](=[O:20])[C:18](=[CH2:33])[N:17]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=[O:30])([O-:10])=[O:9]
Reactant: [OH-]
Reactant: CO
Reactant: C=C1N(CC(=O)O)C(=O)C(=O)N1Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C1NCNC1=O
Agent: [K+]
Solvent: O
Product: C=C1C(=O)N(Cc2cccc([N+](=O)[O-])c2)C(=O)N1CC(=O)O
Reaction time: 24 h

Procedure:
The above-prepared dioxoimidazolidine product of paragraph (1) (241 mg) and 50.3 mg of potassium hydroxide were suspended in a mixed solution of methanol-water followed by vigorous stirring for 24 hours. The pH of the reaction mixture was adjusted to about 4 using 2N hydrochloric acid and the reaction mixture was concentrated and extracted with ethyl acetate several times. The combined extract was dried over sodium sulfate, concentrated, washed with chloroform and the insoluble matters were filtered off. The filtrate was concentrated in vacuo to give 106 mg of 3-(3-nitrobenzyl)-5-methylidene-2,4-dioxoimidazolidine-1-acetic acid [Compound 13]. The IR and NMR for the compound were:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]=[O:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[F:36][CH:37]([F:48])[O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.COCCOC>O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]([C:42]1[CH:43]=[CH:44][C:39]([O:38][CH:37]([F:48])[F:36])=[CH:40][CH:41]=1)[OH:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(OC(F)F)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: COCCOC
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(OC(F)F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture solution of 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (50 mg) obtained in Example 29-(1), 4-(difluoromethoxy)benzeneboronic acid (55 mg), hydroxyl(1,5-cyclooctadiene)rhodium(I) dimer (1.3 mg) and tri-tert-butylphosphine (0.6 mg) in H2O (1.0 ml)-1,2-dimethoxy-ethane (2.0 ml) was stirred at 80° C. under argon atmosphere for 19 hours. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate (20 ml). The organic layer was filtered through an aminosilane-treated silica gel pad, and the filtrate was evaporated under reduced pressure to give crude 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-(difluoromethoxy)phenyl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[N:5]([CH3:7])[CH3:6].[N:14]1C=CC=C[CH:15]=1.C([Cu])#N.N>O>[CH3:6][N:5]([CH3:7])[C:4]1[CH:3]=[C:2]([CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1)[C:15]#[N:14]
Reactant: CN(C)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: c1ccncc1
Agent: N#C[Cu]
Agent: N
Solvent: O
Product: CN(C)c1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 220 °C
Reaction time: 3.5 h
Yield: 33 %

Procedure:
3-Bromo-N,N-dimethyl-5-nitroaniline (1.73 g, 7.06 mmol) (prepared according to the method described in J. Org. Chem. 60: 5091-5103 (2003)), pyridine (24 mL), and CuCN (1.26 g, 2.14 mmol) were added to a dry sealed tube. The mixture was heated at 220° C. with stirring for 3.5 h. The reaction mixture was allowed to cool to 100° C., poured into a flask containing a mixture of aqueous ammonia (100 mL) and water (100 mL), and extracted with EtOAc (2×100 mL). The EtOAc solution was washed with diluted ammonia solution (100 mL), water (100 mL) and brine (100 mL) successively, dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-(dimethylamino)-5-nitrobenzonitrile (0.44 g, 33%) as an orange solid. 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, 1H, J=2.0, 1.2 Hz), 7.65 (t, 1H, J=2.2 Hz), 7.11 (dd, 1H, J=2.4, 1.2 Hz), 3.10 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2ccccc2F)C(C)C)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)COc2ccccc2F)C(C)C)n(C)c2ccccc12
Yield: 36.4 %

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-cabonyl)valinyl]-3-amino-4-oxo-5(2-fluorophenyloxy)-pentanoic acid, tert-butyl ester (76 mg, 0.124 mmol) with TFA as described in Example 80 gave the titled product (25.0 mg, 36%) as a white powder. MS C30H36FN3O6, [M+Na]+=554, [M−=552. TLC (hexane/EtOAc, 50/50) Rf=0.21.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].CCN(C(C)C)C(C)C.O=C1CCC(=O)N1[O:42][C:43](=O)[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Br:52]>C(Cl)Cl>[Br:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[CH2:45][O:44][C:43]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]1[C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:25])=[O:42]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Reactant: O=C(OCc1ccccc1Br)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (836 mg, 2.00 mmol, 1.0 eq.) and DIPEA (0.86 mL, 5.00 mmol, 2.5 eq.) in DCM (30 mL), carbonic acid 2-bromo-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (787 mg, 2.40 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. during 2 hours. The reaction was quenched with 1M aq. citric acid soln. (30 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. To a solution of the previous mixture in EtOH (1.1 mL), conc. H2SO4 (0.10 mL) was added. The solution was stirred at r.t. during 3 hours. Water and 5% aq. NaOH soln. were added and the mixture was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O:10][CH2:11][CH3:12])(=O)C.C(O)(=[O:15])C>[Zn]>[CH:3]12[CH2:4][CH:5]([CH:1]=[CH:2]1)[C:6](=[O:15])[CH2:12][C:11]2=[O:10]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: CC(=O)O
Agent: [Zn]
Product: O=C1CC(=O)C2C=CC1C2
Temperature: 95 °C
Reaction time: 2 h

Procedure:
One-pot process: 100 mg (0.39 mmol) of 3-bromo-4,4-(1′,2′-ethylenedioxy)-bicyclo[3.2.1]-oct-6-en-2-one are taken up in concentrated acetic acid and treated at ambient temperature with 80 mg (1.16 mmol) of zinc powder. The progress of the reaction is monitored by means of thin-layer chromatography (mobile phase: hexane/ethyl acetate 1:1). When after 2 hours brominated starting material can no longer be detected, the reaction mixture is heated continuously at a temperature of 95° C. After a further 2 hours, according to thin-layer chromatography all the reference material 4,4-(1′,2′-ethylenedioxy)-bicyclo[3.2.1]oct-6-en-2-one has reacted. The reaction mixture is filtered and concentrated in vacuo. The residue is treated with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The alkaline aqueous phase is adjusted to pH 3-4 with dilute hydrochloric acid and extracted three times with fresh ethyl acetate. After drying of the organic phase over sodium sulfate and subsequent concentration by evaporation, 45 mg (85% of theory) of technically pure bicyclo[3.2.1]oct-6-ene-2,4-dione are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1(C)[O:17][C:16](=O)[CH:15]=[C:14]([CH3:19])[O:13]1.CC(C)=O>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:17])[CH2:15][C:14](=[O:13])[CH3:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
13.8 g (0.1 mol) of 4-nitroaniline were suspended in 20 ml of dry xylene and 14,22 g (0.1 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one were added. The reaction mixture was heated in an oil-bath at 150° C. for 30 minutes while the acetone formed in the reaction was removed by distillation. The reaction mixture was cooled to room temperature, filtered and the residue was washed thoroughly with ethyl acetate. The filtrate was evaporated to obtain 11.65 g (52%) of N-(4-nitrophenyl)-3-oxobutanamide as a white crystalline solid melting at 119°-21° C. (from ethyl acetate-petroleum ether (40°-60° C.)) (lit.* melting at 120°-122° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[C:25]#[N:26]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:29]=[C:28]([F:30])[CH:27]=[C:24]([C:25]#[N:26])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 3-Bromo-5-fluorobenzonitrile instead of 3-bromopyridineto yield the final compound as a light yellow solid, MS (ISP): m/e=395.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20][CH2:19]2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](CNC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (65 mg, 0.123 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.185 mmol) to afford the crude product (90 mg) as a yellow-green solid: ESI MS m/z 580 [C32H38ClN3O5+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:8](=[O:10])[C:7]5[CH:11]=[CH:12][CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=5)[CH:47]=[CH:46][CH:45]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)Oc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 66.9 %

Procedure:
Using 3-(isopropoxy)benzoic acid (56 mg, 0.31 mmol), oxalyl chloride (33 μL, 0.39 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol) and N,N-dimethylacetamide (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (82 mg, 67%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:15]([N:1]([C@@H:2]([CH2:3][CH2:4][CH3:5])[C:6]([O:8][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)=[O:7])[CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CCC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 9 h
Yield: 70.6 %

Procedure:
To a solution of L-norvaline (685 mg, 5.85 mmol) in MeCN (15 mL), BnBr (3.48 mL, 29.24 mmol) and K2CO3 (4.04 g, 29.24 mmol) were added. The mixture was stirred at 60° C. for 9 h, and then cooled down to room temperature and filtered, washing the solid with EtOAc. The filtrates were concentrated in vacuo and the residue purified by column chromatography on silica (100% hexane to hexane/EtOAc 5:1) to obtain benzyl ester 9 as a colorless oil (1.6 g, 71% yield).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].O.CCOCC>C(Cl)Cl>[N:7]([C:1]1([O:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: ON=C1CCCCC1
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: O=NC1(OCc2ccc([N+](=O)[O-])cc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of cyclohexanone oxime (2.66 g, 23.51 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (10.42 g, 23.51 mmol) and 4-nitrobenzoic acid (39.29 g, 235.1 mmol) in methylene chloride (300 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL) and 3% sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was recrystalized in diethyl ether/petroleum, ether (1:1) in a −5° C. freezer to give 1-Nitroso-1-para-nitrobenzoxycyclohexane as bright blue crystals (20-25% yield): Rf 0.55 (pentane/ethyl acetate=20:1); 1H NMR (300 MHz, Benzene-d6) δ 1.17-2.04 (m, 10H), 7.38-7.98 (d, 4H); 13C NMR (300 MHz, Benzene-d6) δ 22.1 (2CH2), 25.0 (CH2), 29.7 (2CH2), 123.8 (2Ph-CH), 125.3 (O—C—N), 131.1 (2Ph-CH), 135.3 (Ph-C), 151.1 (Ph-C), 162.6 (C═O).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:33])=[O:32]>>[ClH:1].[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:40][CH:41]=1)(=[O:32])=[O:33]
Reactant: CN(c1ccc2c(c1)nc(NCCc1ccccc1)n2C)c1ccnc(Cl)n1
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Product: CNS(=O)(=O)CCc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCCc3ccccc3)n4C)n2)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-phenethyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 2-(4-amino-phenyl)-ethanesulfonic acid methylamide (54 mg, 0.25 mmol) as a white solid (100 mg, 66%). 1H NMR (300 MHz, d6-DMSO) δ 9.30 (s, 1H), 7.82 (d, J=6.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.20-7.33 (m, 5H), 7.06-7.14 (m, 3H), 6.98 (q, J=6.2 Hz, 1H), 5.70 (d, J=6.0 Hz, 1H), 3.65 (m, 2H), 3.60 (s, 3H), 3.45 (s, 3H), 3.21-3.26 (m, 2H), 2.95-3.00 (M, 2H), 2.84-2.90 (m, 2H), 2.59 (d, J=5.1 Hz, 3H) ppm. MS (ESI) m/z=571 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1CCCCC1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.[F:70]C1C=C(O)C=CC=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:70])[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Oc1cccc(F)c1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: C[C@H](Oc1cccc(F)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 3-fluoro-phenol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 547.4 [(M+H)+].