Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccnc2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(3,4-dimethoxyphenyl)magnesium bromide (0.5 M in THF, 9.5 mL, 4.75 mmol) was added dropwise by syringe to a solution of nicotinaldehyde (0.88 mL, 9.37 mmol) in dry THF (20 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C., then quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-60% EtOAc-hexanes) to provide the title compound as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH3:19]>C(O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([NH2:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: NC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-Nitrophenoxyacetic acid (10.2 g) was added to thionyl chloride (50 ml) and the mixture was boiled under reflux for 1.5 hours. Excess thionyl chloride was distilled off and the residue was heated with toluene (2×50 ml) and the toluene removed by distillation to leave an oil which solidified on cooling. The acid chloride was added in portions to a stirred mixture of absolute ethanol (50 ml) and concentrated aqueous ammonia (50 ml, SG 0.880) at 10°-15° C. The mixture was stirred for 45 minutes at 10°-15° C. and then allowed to warm up to ambient temperature. The mixture was filtered to give 4-nitrophenoxyacetamide, m.p. 153°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH3:27]OC(C1C=C(OC2C=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC(C)(C)OC=2C=1)=O.C(N)C>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH2:25][CH3:27])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)c(F)c2)c2c(c1)OC(C)(C)C2
Reactant: CNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1
Agent: CCN
Product: CCNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid 66a) (74 mg, 0.22 mmol) and ethyl amine (2.0 M in THF, 1 mL) to give a white solid (28 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=2.78 Hz, 1 H) 8.18 (d, J=8.59 Hz, 1 H) 7.82-7.91 (m, 1 H) 7.34 (dd, J=8.59, 2.78 Hz, 1 H) 7.25 (s, 1 H) 7.19 (d, J=1.01 Hz, 1 H) 3.87 (s, 3 H) 3.52 (dd, J=7.33, 6.06 Hz, 2 H) 2.90 (s, 2 H) 1.49 (s, 6 H) 1.22-1.33 (m, 3 H); LCMS for C20H22N2O5 m/z 371.00 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:18]([O:20]C)=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCc2onc(-c3ccc(Cl)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCc2onc(-c3ccc(Cl)cc3)c2CC1

Procedure:
2.5 of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-6-carboxylate in 20 ml of methanol were treated with 1.5 g of potassium hydroxide in 2 ml water at 20° C. for 16 hours. After removing the methanol by evaporation, the residue was taken up in water. The aqueous-alkaline solution was washed with diethyl ether, acidified with 2N hydrochloric acid and extracted with diethyl ether. After drying over magnesium sulfate and evaporation, there were obtained 1.8 g of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 144°-145° C. after recrystallization from ethyl acetate/hexane.
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]([NH:17][N:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:19]([CH3:22])(=[O:21])=[O:20])=[O:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])=[O:7])(C)(C)C.C(N(CC)CC)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>O1CCOCC1>[C:6]([C@H:8]([C@@H:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]([NH:17][N:18]([CH2:23][CH:24]([CH3:25])[CH3:26])[S:19]([CH3:22])(=[O:21])=[O:20])=[O:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])([OH:7])=[O:5]
Reactant: CC(C)=CC[C@H](C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)=CC[C@H](C(=O)O)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Yield: 99.9 %

Procedure:
A solution of 1.5 g of 2(R)-[1(S)-(tertbutoxycarbonyl)-4-methyl-3-pentenyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide, 0.51 g of triethylamine and 0.93 g trimethylsilyl triflate in 20 ml of 1,4-dioxane was heated at reflux under a nitrogen atmosphere for 4 hours. The mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrochloric acid, water and brine. The ethyl acetate phase was then dried over anhydrous magnesium sulphate and the solvent was evaporated to give 1.31 g of 2(R)-[1(S)-(carboxy)-4-methyl-3-pentenyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a yellow foam.
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:3]=12.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[NH:15]1[CH2:14][CH2:13][CH:12]([N:8]2[C:4]3[C:3](=[N+:2]([O-:1])[CH:7]=[CH:6][CH:5]=3)[NH:10][C:9]2=[O:11])[CH2:17][CH2:16]1.[C:27]([OH:29])([C:26]([F:31])([F:30])[F:25])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c2ccc[n+]3[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2c(ccc[n+]2[O-])n1C1CCNCC1
Reaction time: 3 h

Procedure:
tert-Butyl 4-(4-oxido-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (45 mg, 0.135 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added at room temperature. After 3 h, the volatiles were removed in vacuo to give the title compound as its TFA salt. MS 235.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5](Br)=[C:6]([CH3:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[C:15]1([O-:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[K+]>CN(C)C=O>[N+:1]([C:4]1[C:5]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH3:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: [O-]c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Oc1ccccc1
Temperature: 0 °C
Yield: 17.7 %

Procedure:
A mixture of 6 gm of 3,5-dinitro-2-bromotoluene and 3 gm of potassium phenolate in 20 ml of dimethyl formamide was boiled under reflux for 20 hours. Subsequently, the solution was poured on 200 gm of ice and the precipitate was filtered off. After recrystallization from ethanol, there was obtained 1.1 gm of yellow crystals with a melting point of 103° C. The mass spectrum showed a molecular mass of 274 (calculated 274).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[S:5][C:6]=1[C:7]([OH:9])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C>[O:58]1[CH2:59][CH2:60][CH:55]([NH:54][C:7]([C:6]2[S:5][C:4]([CH2:10][CH2:11][C:12]3[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:14][O:15][CH:16]=3)=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:56][CH2:57]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)NC1CCOCC1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 4-methyl-2-[2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (70 mg, 0.22 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (79 mg, 0.24 mmol), N,N-diisopropyl ethyl amine (190 μL, 1.11 mmol) and 4-aminotetrahydropyran (25 mg, 0.24 mmol). The resulting reaction mixture was stirred overnight and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (84 mg, 95%) as a white solid. S: m/e=399.2 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][C:38](=O)[CH3:39])=[CH:32][CH:31]=1>>[CH3:39]/[C:38](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:37]/[C:36](=[O:41])[C:33]1[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:42])[F:43])=[CH:31][CH:32]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Product: C/C(=C/C(=O)c1ccc(C(F)(F)F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 290 mg (0.76 mmol) of Intermediate 47 and 150 mg (0.76 mmol) of Intermediate 24 to yield 140 mg (31% yield) of Example 10: TLC (DCM/MeOH, 4/1): Rf=0.47; 1H NMR (DMSO-d6, 300 MHz) δ11.52 (d, 1H, J=8.9), 7.96 (d, 2H, J=8.1), 7.80 (m, 2H), 7.72 (d, 2H, J=8.4 ), 7.42 (m, 3H), 7.10 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4), 5.61 (s, 1H), 4.20 (t, 2H, J=6.6), 4.15 (m, 1H), 3.17 (m, 1H), 3.05 (t, 2H, J=6.5), 2.77 (dd, 1H, J=13.6, 8.6), 2.41 (s, 3H), 1.69 (s, 3H); low resolution MS (ES+)m/e 595.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.C(N(CC)CC)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>C(Cl)Cl>[CH2:37]([NH:39][C:40]([N:17]1[CH2:18][CH2:19][C:20]2[N:12]([C@@H:6]3[C:7]4[C:3](=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=4)[CH2:4][C@H:5]3[OH:29])[N:13]=[C:14]([C:21]3[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=3)[C:15]=2[CH2:16]1)=[O:41])[CH3:38]
Reactant: CCN=C=O
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(Cl)cc(Cl)c4C[C@H]3O)c3c2CNCC3)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(Cl)cc(Cl)c3C[C@H]2O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
According to Scheme 17: To a solution of 3-[1-((1R,2R)-4,6-dichloro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13e) (0.03 g, 0.071 mmol) in dry CH2Cl2 at 0° C. triethylamine (57 mg, 0.564 mmol) and ethylisocyanate (5.5 mg, 0.077 mmol) was added. The mixture was stirred for 1 h at room temperature and purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 31 mg of 3-(3-cyano-phenyl)-1-((1R,2R)-4,6-dichloro-2-hydroxy-indan-1-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamide (22a)
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.O.[OH-].[Li+]>O>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH:21]3[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCC(Oc2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nnc(Cc2ccccc2)s1)c1ccc(OC2CCC(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
0.128 g of methyl 4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate (0.28 mmol, 1 eq.) is placed in 2 mL of a mixture of tetrahydrofuran and water at room temperature. 0.024 g of lithium hydroxide monohydrate (0.57 mmol, 2 eq.) in 1 mL of water is added. After stirring for 2 hours at room temperature, the tetrahydrofuran is evaporated off and water is added. The aqueous phase is washed with dichloromethane. The aqueous phase is cooled to a temperature of 4° C. in an ice bath and acidified with 1N hydrochloric acid solution. The solid is filtered off and washed successively with water, with ethanol and then with diethyl ether to give 0.069 g of 4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH2:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: NCC(O)CO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCC(O)CO
Yield: 85.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 1.9 g of 3-amino-1,2-propanediol were used as the starting materials. 6.5 g (86%) of the title compound was obtained as a white wax.
Reaction SMILES: [OH:1][C:2]1([CH3:19])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:4][CH2:3]1>CO.[Pd]>[OH:1][C:2]1([CH3:19])[CH2:3][CH2:4][N:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CC1(O)CCN(CC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of compound benzyl 2-(4-hydroxy-4-methylpiperidin-1-yl)acetate (400 mg, 1.61 mmol) in methanol (10 mL) was added Pd/C (10%, 100 mg) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 1 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to afford 2-(4-hydroxy-4-methylpiperidin-1-yl)acetic acid (250 mg, quantitative) as a colorless solid, which was used directly without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([CH2:57][OH:58])[CH:53]=[C:54]([NH2:56])[CH:55]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1>>[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:55]=[C:54]([NH:56][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:53]=[C:52]([CH2:57][OH:58])[CH:51]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 66.8 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,4,5-trimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:32][CH2:33][CH3:34])[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7](=[O:16])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:2].I[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH3:36][C:37]([CH3:40])([CH3:39])[CH2:38][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:16])[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:5]([CH2:32][CH2:33][CH3:34])=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:14][CH:13]=1
Reactant: CC(C)(C)CI
Reactant: CCCc1nc(CC)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OCC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
A mixture of 4′-{[4-ethyl-5-(4-hydroxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.52 g), 1-iodo-2,2-dimethylpropane (0.29 g), cesium carbonate (0.45 g) and dimethylformamide (10 mL) were stirred at 80° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.37 g, 62%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:1]1([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:30]4[CH2:31][CH2:32][CH:27]([CH2:26][OH:25])[CH2:28][CH2:29]4)=[CH:15][C:14]=3[C:21]([F:22])([F:23])[F:24])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCC1CCNCC1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(C(F)(F)F)c1
Product: OCC1CCN(Cc2ccc(N3CCC(CN4CCCC4)CC3)c(C(F)(F)F)c2)CC1

Procedure:
Prepared from the product of Example 63 and 4-hydroxymethylpiperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([NH:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
80 mg (0.29 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.26 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 0.15 mL (0.87 mmol) DIPEA in 1.5 mL DMF were stirred at 150° C. After the reaction of the reactants the reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down. The residue was dried.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]2[O:16][CH3:17])=O.[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[NH:27][C:28]2[S:29][CH2:30][C:31](=[O:33])[N:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:17][O:16][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3](/[CH:1]=[C:30]3/[C:31](=[O:33])[N:32]=[C:28]([NH:27][C@@H:25]4[CH2:26][C@H:24]4[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:29]/3)[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:13]([NH2:15])=[O:14]
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Reactant: COc1c(C(N)=O)cnc2ccc(C=O)cc12
Product: COc1c(C(N)=O)cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-quinoline-3-carboxylic acid amide (example 2b) and 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f) to give 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid amide. LC-MS m/e 445 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([F:23])([F:22])[C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])=[CH:13][N:12]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([F:22])([F:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][N:12]=1
Reactant: COC/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of (E)-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-methoxyprop-1-en-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (48; 80 mg, 0.18 mmol) in EtOH (10 mL) was added 10% Pd/C (8 mg), and the mixture was stirred under hydrogen atmosphere for 1 h. The reaction mixture was filtered through a pad of Celite®, the Celite® cake was washed thoroughly with EtOAc (3×30 mL) and then the filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 45-50% EtOAc/hexanes) afforded 50 (65 mg, 0.14 mmol, 77%) as a semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.36 (s, 1H), 7.87 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.38-7.33 (m, 1H), 6.77-6.73 (m, 1H), 6.67-6.63 (m, 1H), 5.56 (d, J=14.5 Hz, 1H), 5.09 (d, J=14.5 Hz, 1H), 3.37-3.34 (m, 2H), 3.33 (s, 3H), 2.75 (t, J=7.0 Hz, 2H), 1.90-1.85 (m, 2H). MS (ESI): m/z 426 (M+H)+. HPLC: 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)=[O:7])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: COc1cccc(C2CCCN2CCNC(=O)c2ccc(Cl)cc2)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C(NCCN1CCCC1c1cccc(O)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 4-chloro-N-{2-[2-(3-methoxyphenyl)-1-pyrrolidinyl]ethyl }benzamide (0.58 g) in chloroform (30 ml) was added boron tribromide (99.0%, 0.61 ml) at -10° C., under nitrogen. The cooling bath was removed after 15 rains, and the reaction mixture was allowed to warm to ambient temperature. Crushed ice was added followed by 5:1-chloroform/2-propanol. The layers were separated, and the aqueous phase was extracted with 5:1 chloroform/2-propanol (2 times). The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to afford 0.29 g (52%) of 4-chloro-N-{2-[2-(3-hydroxyphenyl)-1-pyrrolidinyl]ethyl}benzamide.