Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]3[CH:24]=[C:23]([CH3:26])[S:22][C:21]=3[NH:20][C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)[CH2:11]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]1[N:15]([CH3:33])[CH2:14][CH2:13][N:12]([C:16]2[C:25]3[CH:24]=[C:23]([CH3:26])[S:22][C:21]=3[NH:20][C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)[CH2:11]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2Cl)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
Combine 10-((S)-3-[2-(2-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (398.3 mg, 0.91 mmol), formaldehyde (81.4 μL, 1.00 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (289.7 mg, 1.37 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 341.6 mg (83%) of the title compound as a brown foam: mp 72°, dec; mass spectrum (ion spray): m/z=451.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9].BrC1C=CC=CC=1B(O)O.O>C(Cl)Cl>[CH3:3][C:2]1[CH2:1][CH:8]([C:7]([OH:11])=[O:10])[CH2:9][CH2:5][C:4]=1[CH3:6]
Reactant: C=CC(=O)O
Reactant: C=C(C)C(=C)C
Agent: OB(O)c1ccccc1Br
Solvent: ClCCl
Solvent: O
Product: CC1=C(C)CC(C(=O)O)CC1
Yield: 76 %

Procedure:
2,3-Dimethylbuta-1,3-diene (2 equiv.) and acrylic acid (1 equiv.) were combined in the presence of 2-bromophenyl boronic acid (0.2 equiv.) and water (0.1 equiv.) in DCM at room temperature for 28 hours. The product, 3,4-dimethylcyclohex-3-enecarboxylic acid, was isolated in 76% yield. When the reaction was repeated without the addition of water, the yield was 90%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[NH:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:38]Br>C(O)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15]([Br:38])=[CH:14][N:13]=[C:12]([N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:11]=2[NH:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2c(N(Cc3ccccc3)Cc3ccccc3)nccc2n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(N(Cc3ccccc3)Cc3ccccc3)ncc(Br)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.6 %

Procedure:
1-benzyl-4-dibenzylamino-1,3-dihydro-imidazo[4,5,c]pyridine-2-one (1 g, 2.4 mmol) was suspended in 20 mL of acetic acid then sodium acetate (195 mg, 2.4 mmol) was added followed by bromine (456 mg, 2.85 mmol) dropwise. The mixture was stirred at room temperature for 15 minutes. A heavy precipitate was formed. The mixture was diluted in water (50 mL) and the solid was filtered and washed with water. It was then diluted in ethyl acetate (20 mL), dried over magnesium sulfate and the solvent was removed in vacuo to give 1.29 g of the title compound as a light orange solid.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:7][N:6]1[CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:4].O([Si](C)(C)C)[K].CC(C)(C)C(Cl)=O.[CH2:33]([NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:34][CH:35]=[CH2:36].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:33]([N:37]([CH2:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:3]([CH:5]1[CH2:7][N:6]1[CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:4])[CH2:34][CH:35]=[CH2:36]
Reactant: COC(=O)C1CN1C(C)c1cccc2ccccc12
Reactant: C=CCCNCCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)O[K]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: C=CCCN(CCc1ccccc1)C(=O)C1CN1C(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 1 (12.6 g, 49.75 mmol) in THF (200 mL) is added KOTMS (6.38 g, 49.75 mmol). The mixture is stirred overnight at room temperature. The mixture is concentrated and the residue dissolved in dichloromethane (200 mL) and cooled to 0° C. Trimethylacetyl chloride (5.94 g, 49.25 mmol) is added slowly and the mixture is warmed to room temperature over 2 hours. The mixture is cooled to −78° C., 2 (8.63 g, 49.25 mmol) is added and stirring continued at −78° C. for 1.5 h. Saturated sodium bicarbonate (100 mL) is added and the mixture is allowed to warm to rt. The mixture is extracted with EtOAc (4×100 mL) and the organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:8) to provide 15 g (76%) of the title compound as a mixture of two diastereomers in an equimolecular ratio. M+H+=399.37.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)[N:3]=1.[N:16]1[N:17]=[C:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23](O)=[O:24])[NH:19][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][N:12]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:18]4[NH:19][CH:20]=[N:16][N:17]=4)=[O:24])[CH2:13]3)[CH2:9]2)[N:3]=1
Reactant: Cc1ccnc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4nnc[nH]4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 27 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calcd. for C20H21N7O, 375.55; m/z found, 376.2 [M+H]+. 1H NMR (CDCl3): 8.18-8.04 (m, 3H), 7.55-7.42 (m, 2H), 7.39-7.33 (m, 1H), 6.39 (d, J=5.0 Hz, 1H), 3.96-3.79 (m, 2H), 3.77-3.63 (m, 2H), 3.62-3.55 (m, 1H), 3.46-3.37 (m, 2H), 3.15-3.06 (m, 1H), 3.05-2.98 (m, 1H), 2.95-2.90 (m, 1H), 2.33 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][NH:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.CCOCC>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[C:16]([Cl:19])[CH:15]=2)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1NNCc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1c2cc(Cl)ccc2[nH]n1Cc1ccccc1
Yield: 68.5 %

Procedure:
A suspension of 2-(2-benzylhydrazino)-5-chlorobenzoic acid (2.5 g) in acetic acid (20 ml) was heated under reflux for 30 minutes. The solution was then cooled and diluted with ether. The solid which formed was recrystallised from ethanol to give 1,2-dihydro-2-benzyl-5-chloro-3H-indazol-3-one as a solid (1.6 g), m.p. 215-225° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[C:21]2[CH:28]([CH3:29])[O:27][C:26](=[O:30])[C:22]=2[CH:23]=[N:24][CH:25]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[C:21]3[CH:28]([CH3:29])[O:27][C:26](=[O:30])[C:22]=3[CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CC1OC(=O)c2cncc(Br)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1OC(=O)c2cncc(-c3ccc(C#N)c(Cl)c3)c21
Temperature: 100 °C
Yield: 15.2 %

Procedure:
To the solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (116 mg, 0.44 mmol), 7-bromo-1-methylfuro[3,4-c]pyridin-3(1H)-one (100 mg, 0.44 mmol) and PdCl2(dppf).CH2Cl2 (28.6 mg, 0.035 mmol) in DMF (5 mL) was added a solution of Na2CO3 (0.44 mL, 2M) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. The mixture was warmed up room temperature, and solvent was removed in vacuo. The residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO 40 g (10% MeOH/DCM, v/v, 0-25%) to give 19 mg of the titled compound. ESI-MS m/z: 284.9 [M+1]+, Retention time 1.32 min; 1H-NMR (MeOD, 400 MHz) δ 1.31 (d, J=6.8 Hz, 3H), 6.23 (q, J=6.8 Hz, 1H), 7.79 (dd, J=8.0, 1.6 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 8.94 (s, 1H), 9.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]1.C([O-])(=O)C.[NH4+:20]>C(O)C>[NH2:20][C:11]1[CH2:12][CH:7]([C:6]2[CH:5]=[C:4]([Cl:15])[S:3][C:2]=2[Cl:1])[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2cc(Cl)sc2Cl)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2cc(Cl)sc2Cl)C1
Yield: 96.3 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (42.0 g) and ammonium acetate (36.9 g) in ethanol (840 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The crystals were filtered, washed with toluene and dried to give 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (40.3 g). To a solution of 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (37.0 g) in ethanol (700 ml) and toluene (1400 ml) were added 3-oxobutylaldehydedimethylacetal (46.6 g) and powdery potassium hydroxide (7.7 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (1.6 g) 30 minutes later; powdery potassium hydroxide (1.6 g) and 3-oxobutylaldehydedimethylacetal (3.7 g) 1 hour later; and powdery potassium hydroxide (1.6 g) 1.5 hours later; and then the mixture was stirred at the same temperature for 2 hours. After the mixture was cooled, the solvent was evaporated under reduced pressure and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the thus obtained oil containing crystals were subjected to silica gel column (EtOAc/hexane) to remove starting materials. The thus obtained crystals were recrystallized from ethyl acetate-hexane to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (32.6 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Br:21]Br>C(O)(=O)C>[Br:21][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:12](=[O:20])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]3)[C:15]=2[CH:16]=1
Reactant: BrBr
Reactant: CCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Solvent: CC(=O)O
Product: CCCCN1CCC(n2c(=O)[nH]c3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(1-butyl-piperidin-4-yl)-1,3-dihydro-benzimidazol-2-one (0.5 g, 1.38 mmol) was suspended in acetic acid (5 ml) and added bromine (0.07 ml, 1.38 ml) in acetic acid (1 ml). The reaction mixture was stirred at room temperature for 90 minutes, then added water (5 ml) and filtrated, the residue was washed with water, then added ethyl acetate (10 ml) and 1 M sodium hydroxide (aq.) (10 ml). The organic phase was dried with magnesium sulphate and evaporated to dryness. The residue was chromatographed on kieselgel 60 and eluted with ethyl acetate/methanol (7/3 (v/v)). The product fractions was evaporated to a foam. Yield 40 mg (0.1 mmol, 8%). M.p. 179-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:34][CH2:33][CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCCc1cccc(F)c1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCCc4cccc(F)c4)=NC3=O)cc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
The suspension of 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14 g) (71 mg, 0.2 mmol), m-fluorophenylethylamine (28 ul, 0.22 mmol) and DIEA (diisopropylethylamine) (0.11 mL, 0.44 mmol) in acetonitrile (2 mL) was stirred under at 80° C. for 4 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 4-ethoxy-6-[2-[2-(3-fluoro-phenyl)-ethylamino]-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (60 mg, 67%) as a light yellow solid: LC-MS m/e 447 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:21])[C:13]3([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]3)[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[F:9][C:7]1[CH:6]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:21])[C:13]3([CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27]3)[N:12]([CH3:28])[CH2:11]2)[CH:4]=[C:3]([F:2])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C)C[C@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
0.10 g (0.25 mmol) (R)-methyl 2-(3-(3,5-difluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)acetate hydrochloride in 20 ml acetonitrile were combined with 83 mg (0.60 mmol) potassium carbonate and with 0.04 ml (0.60 mmol) methyl iodide. The reaction mixture was stirred for 5 days at RT. Then the reaction was evaporated down and reacted without any further purification.
Reaction SMILES: C(O[C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[CH3:6])C.C([Li])CCC.[CH:21]1([NH:26][C:27]2[C:32]([CH:33]=O)=[CH:31][N:30]=[C:29]([S:35][CH3:36])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:21]1([N:26]2[C:27]3[N:28]=[C:29]([S:35][CH3:36])[N:30]=[CH:31][C:32]=3[CH:33]=[C:5]([CH3:6])[C:4]2=[O:15])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Temperature: -40 °C
Yield: 36.5 %

Procedure:
2-(Diethoxy-phosphoryl)-propionic acid ethyl ester (15.24 g, 64 mmol) was dissolved in tetrahydrofuran (100 mL) to which n-butyl lithium (47.7 mL, 119 mmol, 2.5 M in hexanes) was slowly added at −70° C. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (15 g, 63 mmol) was dissolved in tetrahydrofuran (70 mL) then added to the reaction mixture allowing the reaction to warm to −40° C. After 3 hours the reaction was warmed to room temperature, poured into cold 1 N citric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a yellow oil which was purified by silica gel chromatography. The resulting oil was dissolved to 1,8-diazabicyclo[5.4.0]undec-7-ene (75 mL) and heated to 150° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (350 mL), washed with 5% HCl and brine, dried over MgSO4, then filtered and concentrated in vacuo The remaining residue was diluted with diethyl ether and the precipitated solid was filtered off to give 8-cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (6.33 g, 31.3%). 1H NMR δ(400 MHz, CDCl3) 8.52 (s, 1H), 7.39 (d, J=1.2 Hz, 1H), 5.96, (m, 1H), 2.59 (s, 3H), 2.30 (m, 2H), 2.19 (d, J=1.2 Hz, 3H), 2.07 (m, 2H), 1.86 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:17]([C:16]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:15]=3[O:14][CH3:13])[NH:10][C:5]=2[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ccc(C(F)(F)F)cc2[nH]1

Procedure:
Prepared analogously to Example 14 from 4-trifluoromethyl-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[CH:2]=1.[CH3:18][C:19]([CH:22]=[O:23])([CH3:21])[CH3:20].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([CH:22]1[O:17][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[O:23]1)([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)C=O
Reactant: OC(O)(Cc1ccccc1Br)c1cccnc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)C1OC(c2cccnc2)C(c2ccccc2Br)O1
Reaction time: 8 h

Procedure:
8 g (0.027 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-ethanediol and 4.5 g (0.0525 mol) of pivaldehyde were dissolved in 100 ml of methylene chloride. This was achieved by adding 4.35 ml (0.0525 mol) of boron trifluoride etherate dropwise at room temperature and stirring overnight. Thereafter, the mixture was poured onto ice water and was neutralized with NaHCO3 solution. The organic phase was washed with water, dried over Na2SO4 and filtered, and the filtrate was evaporated down. The crude product was purified by chromatography.
Reaction SMILES: [C:1]1([OH:14])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:15]=[O:16].[NH2:17]C1C=CC=CC=1>O1CCOCC1.C(OCC)C>[O:16]1[C:15]2[CH:1]=[CH:2][CH:3]=[CH:4][C:7]=2[CH2:8][CH2:9][NH:17]1.[C:10]1([OH:13])[CH:9]=[CH:8][C:7]([C:4]2[CH:5]=[CH:6][C:1]([OH:14])=[CH:2][CH:3]=2)=[CH:12][CH:11]=1
Reactant: C=O
Reactant: Nc1ccccc1
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCNO2
Temperature: 25 °C

Procedure:
27.9 g of 4,4′-biphenol and 48.6 g of aqueous formaldehyde (37%) were added into a 4-neck reactor equipped with a stirrer, temperature controller, and condenser, and then 80 ml of 1,4-dioxane was added as a solvent. The mixture was stirred at room temperature, and to the resulting solution 27.9 g aniline in 30 ml 1,4-dioxane was dripped at a rate of one drop per second while stirring. Upon completion of the dripping the solution was heated and reacted under refluxing for 10 hours. The reaction mixture was dried in a rotary evaporator under vacuum to obtain a pale orange solid. The pale orange solid was dissolved in ethyl ether and washed with 3N NaOH aqueous three times, followed by 1 N aqueous HCl solution several times and pure water several times, before removing the solvent in vacuo to obtain pale orange 4,4′-biphenol dihydrobenzoxazine solid. m.p. 170° C. EA: Calcd.: C: 80.00%; H: 5.71%; N: 6.66%. Found: C: 80.30%; H: 5.73%; N: 6.56%.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.[CH2:34]([O:52][CH2:53][CH:54]([CH2:74]O)[O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]/[CH:64]=[CH:65]\[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>C(Cl)Cl>[CH3:6][N:7]([CH2:8][C:9]([O:11][CH2:74][CH:54]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]/[CH:64]=[CH:65]\[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:53][O:52][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:10])[CH3:12]
Reactant: CN(C)CC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COC(=O)CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
In a solvent mixture of 22 ml N,N-dimethylformamide and 11 ml methylene chloride was suspended 572 mg (5.547 mmol) of N,N-dimethylglycine followed by addition of 1736 mg (8.414 mmol) of N,N'-dicyclohexylcarbodiimide and the mixture was stirred at ambient temperature overnight. The solvent was then distilled off under reduced pressure and the residue was dissolved in 12 ml of pyridine containing 327 mg (0.551 mmol) of dissolved 1,2-O-dioleylglycerol. Then, 80 mg (0.388 mmol) of N,N'-dicyclohexylcarbodiimide (DCC) was added and the reaction was conducted at 50° C. overnight. After completion of the reaction, the solvent was distilled off and the residue was dissolved in methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, dried, and concentrated. The residue was subjected to column chromatography (silica gel/ethyl acetate-n-hexane) to provide 251 mg (67.2%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH3:32])[NH:5][C:6](=[O:31])[CH:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]=[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:30])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)[CH3:8].[OH-].[Na+:35]>C1COCC1>[Na+:35].[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[CH:20][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH:7]([CH3:8])[C:6]([NH:5][C@H:4]([C:3]([O-:33])=[O:2])[CH3:32])=[O:31])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[C:22]1=[O:30]
Reactant: COC(=O)[C@H](C)NC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12)C(=O)N[C@@H](C)C(=O)[O-]

Procedure:
To a solution of N-{2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy]propionyl} alanine methyl ester (50 mg, 0.11 mmol) in THF (10 ml) was added dropwise 2N sodium hydroxide (0.1 ml) at 0-50° C. After 4h stirring at room temperature THF (100 ml) was added, the organic layer washed 3 times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The residue was taken up in 5% sodium bicarbonate (10 ml) and chromatographed on a LoBar RP18 column using as eluant water/methanol (7:3) to give pure title compound in 84-yield (42 mg).
Reaction SMILES: C(O)=O.[CH3:4][N:5]([CH3:36])[C:6](=[O:35])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:10][CH:9]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:64][C@H:63]([CH2:62][O:61][C:58]1[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=1)[CH2:65][NH:34][CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH:22]2[CH2:21][CH2:20][N:19]([C:17]([NH:16][CH2:15][CH2:14][C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6](=[O:35])[N:5]([CH3:4])[CH3:36])=[CH:13][CH:12]=3)=[O:18])[CH2:24][CH2:23]2)=[CH:31][CH:30]=1
Reactant: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 27.2 %

Procedure:
4-{2-[({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)amino]ethyl}phenyl dimethylcarbamate formate (0.47 g, 0.94 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.40 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.22 g, 0.256 mmol).