Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH:15]=[C:14]3[NH:20][C:21]2[C:22]([Cl:28])=[CH:23][N:24]=[CH:25][C:26]=2[Cl:27])[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: C1CNCCNC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCCNCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 1,4-diazepane following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 8 h). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 2H), 7.85 (d, 1H), 7.00 (d, 1H), 4.69 (s, 1H), 3.95 (t, 2H), 3.88 (s, 3H), 2.79 (t, 2H), 2.74 (m, 2H), 2.60-2.52 (m, 4H), 2.40 (t, 2H), 1.74 (m, 2H), 1.63 (m, 2H), 1.39 (m, 4H), 1.30 (m, 2H) [NH's not seen]; MS (ESI): 534.3.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[C:21]([CH2:29][C:30]([O:32]CC)=[O:31])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[C:21]([CH2:29][C:30]([OH:32])=[O:31])=[N:20]2)=[CH:35][CH:36]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccc(F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccc(F)cc12
Yield: 95.4 %

Procedure:
Ethyl 2-[1-[4-(2-naphthamido)benzyl]-5-fluoro-1H-indazol-3-yl]acetate (100 mg, 0.208 mmol) was dissolved in tetrahydrofuran (10 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (44 mg, 1.05 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 90 mg, at a yield of 95.7%.
Reaction SMILES: C(O[C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][NH:18][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: NCc1ccc(F)c(F)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CC(=O)NCc1ccc(F)c(F)c1

Procedure:
A solution of ethyl4,4-dimethyl-3-oxopentanoate (Alfa Aesar, 2.4 g, 14 mmol) and 3,4-difluorobenzylamine (Aldrich, 2.0 g, 14 mmol) in toluene (15 ml) was refluxed for 24 h. The solvent was removed to yield the title compound as an off-white wax. Used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.Br.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31]2.C(N=C=NCCCN(C)C)C>ClCCl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:15])[N:32]3[CH2:31][C:30]4[C:34](=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:38])[F:37])[CH:29]=4)[CH2:33]3)[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Reaction time: 72 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.200 g, 0.604 mmol; Example 58D) and 5-(trifluoromethyl)isoindoline hydrobromide (0.178 g, 0.664 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.160 mL, 0.905 mmol) and the reaction stirred for 3 days. The reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. MS (ESI+) m/z 501.1 (M+H)+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Cl)=[CH:6][CH:5]=1>C(O)C>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCNC(=O)CCCCl)c2c1
Agent: [Na]
Solvent: CCO
Product: COc1ccc2cccc(CCN3CCCC3=O)c2c1

Procedure:
0.01 mol of sodium is dissolved in 50 ml of ethanol, and the N-[2-(7-methoxynaphth-1-yl)ethyl]chloro-4-butyramide obtained in Example 7 is added under magnetic agitation. The agitation is maintained for 20 minutes, and then the mixture is dried and the residue is solubilized in 40 ml of anhydrous dimethylformamide. The solution is heated at boiling point for 7 hours, then evaporated under vaccum and the residue is taken up in ether, then filtered and dried. The residue is recrystallized in petroleum ether.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O:9][B:10](OC)[O:11]C.C([Li])(C)(C)C>C(OCC)C.CCCCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([B:10]([OH:11])[OH:9])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: OB(O)c1cccnc1
Temperature: 25 °C

Procedure:
A solution of 4.0 ml (6.56 g, 42 mmol) of 3-bromopyridine and 9 ml (8 mmol) of trimethylborate in 100 ml of diethyl ether was cooled to -70° C. then treated slowly with 33 ml (83.8 mmol) of a 2.54M tert-butyllithium in pentane solution. After allowing the resulting slurry to warm to room temperature the solvents were evaporated under vacuum. The residual oil was treated carefully with 50 ml of a 1M hydrochloric acid solution. Several milliters of methylene chloride were added and the mixture was stirred until the oil had dissolved. The aqueous layer was washed with fresh methylene chloride. The pH of the aqueous solution was raised to 12 with 5M sodium hydroxide solution and the washing was repeated. The pH of the aqueous solution was then lowered to 6.5 with concentrated hydrochloric acid solution. After chilling, this solution was filtered, saturated with sodium chloride, then extracted several times with a 2:1 mixture of diethyl ether and isopropanol. Evaporation of these extracts produced a colorless solid. This material was further purified by dissolving in methanol, evaporating to a thick paste, adding a few milliters of water, concentrating further under vacuum, then chilling and collecting the crystalline product. Additional product in the aqueous mother liquor was isolated by repeating this process. Thorough drying of this hydrated product at 0.1 mm pressure afforded a fine powder weighing 2.2 g. Elemental analysis and a mass spectrum indicated the product so isolated was primarily the anhydride (tripyridylboroxane).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH:34][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:27][CH:26]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with glycine methyl ester hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a light yellow foam, MS (ESI+): m/z=447.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:10])=[CH:5][CH:4]=1)#[N:2].O[C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22](=[O:27])[CH2:23]S(C)=O.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:21][O:20][C:19]1[C:14]2[O:10][C:9]([CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:23][C:22](=[O:27])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C(=O)CS(C)=O)c1O
Reactant: N#Cc1ccc(C=CC=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cccc2c(=O)cc(C=Cc3ccc(C#N)cc3)oc12

Procedure:
A mixture of 7.85 g of 4-cyanocinnamaldehyde (U.S. Pat. No. 2,993,834), 11.4 g of 2'-hydroxy-3'-methoxy-2-(methylsulfinyl)acetophenone, 250 ml of toluene, and 0.5 ml of piperidine was refluxed for 3 hrs. The mixture was chilled, and the crystalline ppt. filtered, and recrystallized from toluene, mp. 274°-75°; yield 7 g (46%); λ max mμ (ε) 222 (20,600), 328 (42,500); ν max 745 (m), 845 (m), 1060 (m), 1275 (m), 1570 (m), 1595 (m), 1655 (ms), 2230 (m) cm-1.
Reaction SMILES: [Sn](Cl)Cl.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[NH:13][C:14]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1>C(O)(=O)C.C(OCC)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[NH:13][C:14]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:24]=2)=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1
Reactant: O=[N+]([O-])c1ccc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)cc1NCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)cc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
Add tin(II) chloride (0.11 g, 0.6 mmol) to a solution of 2-(2,6-difluorophenyl)-4-phenyl-5-(3-(benzyl)amino-4-nitrophenyl)imidazole (0.09 g, 0.2 mmol) in 10 mL acetic acid. Bubble nitrogen through the solution for 15 minutes and then heat at 90° C. for 1 hour under a nitrogen atmosphere. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and then wash sequentially with 3:1 ammonium hydroxide:saturated aqueous ammonium chloride, saturated aqueous sodium chloride, and water. Dry the organic phase over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5:1 dichloromethane:acetonitrile to provide the title compound (0.05 g, 59%).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH3:28])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].O[Li].O.Cl>O1CCCC1.O>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH3:28])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4cnn(C)c4c3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2cnn(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-6-yl)quinoxaline-6-carboxylate (70 mg, 0.18 mmol) in tetrahydrofuran (20 mL) was added LiOH.H2O (9.0 mg, 0.36 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (30 mL), adjusted the pH to 6 with hydrochloric acid (3N), and filtered to give 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-6-yl)quinoxaline-6-carboxylic acid as a light yellow solid (20.5 mg, 30%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([C:14]([O:16]CC)=O)=[C:10]([OH:13])[C:11](=[O:12])[N:6]2[CH2:5][C:4](=[O:19])[N:3]1[CH3:20].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:9]2[N:8]=[C:7]3[N:6]([C:11](=[O:12])[C:10]=2[OH:13])[CH2:5][C:4](=[O:19])[N:3]([CH3:20])[N:2]3[CH3:1])=[O:16])=[CH:24][CH:23]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Product: CN1C(=O)Cn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)N1C
Yield: 79.7 %

Procedure:
Reaction of intermediate 22, ethyl 1,2-dimethyl-7-hydroxy-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.050 g, 0.177 mmol) with 4-fluorobenzylamine (0.11 g, 0.87 mmol) as described in the preparation of example 1 gave 0.051 g (80% yield) of the title amide as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.27 (3H, s, NCH3), 3.30 (3H, s, NCH3), 4.61 (2H, d, J=6.3 Hz, NCH2), 4.67 (2H, s, CH2), 7.08 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.74 (1H, broad t, NH), 12.0 (1H, s, OH). MS (ESI+) m/z 362 [M+H+].
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])=[C:8](/[CH:10]=[CH:11]/[CH:12]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[CH:9]=1.Cl>C1COCC1.O>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH:12](/[CH:11]=[CH:10]/[C:8]2[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1)([OH:21])=[O:20]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
18 mg (0.75 mmol) of lithium hydroxide are added to a solution of 150 mg (0.25 mmol) of methyl 4-[(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-{2-[4-(methoxycarbonyl)-phenyl]ethyl}pent-4-en-1-yl]benzoate in 10 ml of THF and 10 ml of water, and the mixture is stirred at 50° C. for 12 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and concentrated. The residue obtained is purified directly by preparative HPLC. This gives 130 mg (content 96%, 0.22 mmol, 87% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[O:25])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(N)c2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Reaction time: 1 h

Procedure:
After dissolving 0.53 g of 2-amino-4-(4-aminophenoxy)pyridine in a mixture of 20 ml of tetrahydrofuran and 10 ml of dimethylformamide, 0.36 ml of p-fluorophenyl isocyanate was added and the mixture was stirred for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (chloroform:methanol=20:1, followed by 10:1). The solvent was distilled off under reduced pressure to obtain 610 mg of the target substance as a white powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH:8]2[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=4)[N:13]=[CH:12][C:11]=3[O:10][CH2:9]2)[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1>>[OH:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][C:34]([C:31]4[CH:32]=[CH:33][C:27]5[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=5[CH:30]=4)=[O:35])[CH2:7][CH2:6]3)[CH2:21][C:20]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: N[C@H]1CC[C@H](C2COc3cnc4ccc(O)cc4c3C2)CC1
Product: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](C4COc5cnc6ccc(O)cc6c5C4)CC3)cc2N1

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using 3-(trans-4-amino-cyclohexyl)-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-6-ol and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH3:22])[CH:21]=[C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:9]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of benzyl 4-chlorophenyl ketone (10.0 g, 43.3 mmol) and dimethylformamide dimethylacetal (23 mL, 173 mmol) in DMF (125 mL) was heated at 75° C. for 20 h. The volatiles were removed in vacuo to provide 3-dimethylamino-1-(4-chlorophenyl)-2-(phenyl)prop-2-en-1-one (43.3 mmol assumed) which was used directly in the next step. 1HNMR (CDCl3): δ 2.76 (s, 6H), 7.15 (m, 2H), 7.16-7.3 (m, 5H), 7.36 (m, 2H), 7.41 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)[CH:8]=O)=[CH:4][C:3]=1[Cl:37].Cl.Cl.Cl.[CH3:41][N:42]([CH3:56])[CH2:43][C:44]([CH3:55])([CH3:54])[CH2:45][NH:46][C:47]1[C:48]([NH2:53])=[CH:49][CH:50]=[CH:51][CH:52]=1>CN(C=O)C>[NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([C:8]2[N:46]([CH2:45][C:44]([CH3:55])([CH3:54])[CH2:43][N:42]([CH3:41])[CH3:56])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[N:53]=2)[CH2:10][C:11]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:16][CH2:17]2)=[O:30])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1c(Cl)cc(CC(C=O)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Reactant: CN(C)CC(C)(C)CNc1ccccc1N
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CC(C)(C)Cn1c(C(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)Cc2cc(Cl)c(N)c(C(F)(F)F)c2)nc2ccccc21
Reaction time: 16 h

Procedure:
To a solution of 320 mg (0.596 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde (Intermediate product 36) in 7 mL DMF was added 230 mg (0.695 mmol) N-(3-dimethylamino-2,2-dimethyl-propyl)-benzene-1,2-diamine-trihydrochloride (Intermediate product 37) and the mixture was stirred for 16 hours in an atmosphere of air. The reaction mixture was evaporated down i. vac. and the residue combined with EtOAc. The org. phase was washed with sat. aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated i. vac. The crude product was purified by column chromatography (silica gel, gradient dichloromethane/MeOH 20/1→10/1 v/v) then (Alox, neutral, activity II-III, gradient EtOAc/MeOH 100/0→40/1) and HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: [I-]
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCCCI)cc1
Reaction time: 8 h

Procedure:
To a solution of 32.7 g (146 mmol) of 4-(5-chloropentoxy) benzonitrile in 350 mL acetone is added 38.3 g (150 mmol) of sodium iodide in 230 mL of acetone. The reaction is heated to reflux and stirred overnight. The acetone is removed under reduced pressure and the residue partitioned between water and ether. The ethereal layer is dried, filtered and evaporated to give 4-(5-iodopentoxy) benzonitrile, m.p. 51°-54° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH:37]([NH:41][CH2:42][CH2:43][OH:44])[CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][CH2:42][CH2:43][OH:44])[CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: OCCNC1CCCNC1
Product: O=C1N=C(N2CCC[C@H](NCCO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{(3S)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(Piperidin-3-ylamino)-ethanol following General Procedure C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:17][CH:16]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[C:19](=[O:20])[C@H:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[C@H:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17]1
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2F)C(=O)[C@@H]1NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-naphthoyl chloride (178 mg, 0.934 mmol) in CH2Cl2 (3 ml) was added a solution of aminopyrrolidinone of Example W (250 mg, 0.849 mmol) and triethylamine (146 mg, 1.44 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred at room temperature for 18 h. The solvent was then removed in vacuo and the resulting foam was purified by radial chromatography on a silica gel plate (4 mm) eluting with 2/98 EtOH/CH2Cl2 to give the title compound (380 mg, 100%) as a colorless foam. MS M+1 calcd for C26H25N2O4F 449, found 449. DSC =142.2°-151.5° C.@55.9 J/g.