Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH2:23])[CH:18]=3)[C:13]([C:24]#[N:25])=[CH:12]2)=[CH:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][C:38](=[O:40])[CH3:39])[CH:18]=3)[C:13]([C:24]#[N:25])=[CH:12]2)=[CH:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCN)cc32)cc1OCOC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(C)=O)cc32)cc1OCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
To a solution of 4-[6-(2-aminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxy benzoic acid ethyl ester (0.10 g) and triethylamine (0.076 g) in dichloromethane (5 mL) was added acetyl chloride (0.049 g) at room temperature, and this mixture was stirred at room temperature for 12 hours. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane:methanol=10:1) to give the title compound (0.083 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=O.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.CC(O)C>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: [H][H]
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: [Pd]
Agent: CNC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 81 %

Procedure:
25.7 g (0.1 mol) of 2-nitro-2'-hydroxy-5'-methylazobenzene, 0.125 g of palladium carbon, 100 ml of toluene, 50 ml of IPA, 25 ml of water and 7 g of 50% dimethylamine were charged into a 500-ml stainless autoclave with an agitator. After the air in the flask had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. Reaction was then effected in the same way as that employed in Example 1. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 81% of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole. The toluene layer was separated, and most part of toluene was then distilled off from the layer. The residual solid was then crystallized using ethanol and then dried to obtain 15.7 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole (yield, 69.8%; melting point, 128° to 130° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:25][C:26]1[C:34]([O:35][C:36]([C:39]#[N:40])([CH3:38])[CH3:37])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OCC)(=O)C>N1C=CC=CC=1.O>[Cl:25][C:26]1[C:34]([O:35][C:36]([C:39]#[N:40])([CH3:37])[CH3:38])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:21]=[CH:22][C:23]=1[Cl:24])=[O:29]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C#N)Oc1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
N-[5-(3-Amino-4-chlorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.554 mmol) produced in Example C118(ii), 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (199 mg, 0.830 mmol) produced in Example C70(i) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (422 mg, 1.11 mmol) were suspended in pyridine (2 mL), and the suspension was stirred at 60° C. for 16 hr. After cooling to room temperature, ethyl acetate (100 mL) and water (80 mL) were added, and the mixture was partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and dried under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0) and basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and triturated with diisopropyl ether to give the title compound (78 mg, 24%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.O>ClCCl>[CH:4]1([CH:8]=[O:10])[CH2:3][CH2:5][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:8][CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=CC1CCCCCCCCCCCC1
Yield: 60 %

Procedure:
To a stirred mixture of 3 g of zinc dust, 50 ml of anhydrous tetrahydrofuran and 2.66 g of dibromomethane, was added dropwise a solution of 2.13 g of anhydrous titanium tetrachloride in 5 ml of dichloromethane. After 15 minutes, to the resulting solution was added dropwise a solution of 2 g of cyclotridecanone in 8 ml of anhydrous tetrahydrofuran. The mixture was allowed to react at room temperature for 12 hours. The reaction mixture was diluted with 50 ml of pentane, admixed with 100 ml of 1-M hydrochloric acid, and intermixed by shaking. The organic layer was washed successively with water, dilute aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, then dried, and concentrated to yield methylenecyclotridecane. To a solution of this substance in 40 ml of anhydrous dichloromethane, after having been cooled to -15° C., was added dropwise with stirring a solution of 2.64 g of m-chloroperbenzoic acid in 40 ml of anhydrous dichloromethane. After 3 hours of reaction, the organic layer was washed successively with 10-% sodium sulfite solution, 7-% sodium hydrogencarbonate solution, and saturated sodium chloride solution, then dried and concentrated under reduced pressure. The residue was purified by the silica gel chromatography [developed with a petroleum ether-ethyl acetate (20:1) mixture] to yield 2.04 g (95% yield based on the ketone compound) of an epoxide. To a solution of the epoxide in anhydrous dichloromethane, after having been cooled to -18° C., was added dropwise a borontrifluoride-ether complex. After completion of the addition, water was added to the reaction mixture. The organic layer was separated, then concentrated, and purified by the silica gel chromatography to yield oily cyclotridecanecarbaldehyde in a yield of 60-70%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([OH:33])([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=3)[CH:3]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Yield: 33.5 %

Procedure:
Beginning with 5.0 gm (15.9 mMol) 2-bromo-6-benzyloxynaphthalene and 3.34 gm (16.8 mMol) 1-tert-butyloxycarbonyl-4-piperidone, 2.31 gm (33%) of the title compound were recovered as a white solid by the procedure described in Preparation I.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>O1CCOCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: Nc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 100 °C
Yield: 57.8 %

Procedure:
A mixture of ethyl 2-chloropyrimidine-5-carboxylate (0.5 g, 2.68 mmol) and 4-chloroaniline (0.684 g, 5.36 mmol) in dioxane (15 mL) was heated at 100° C. for 8 h, diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 0-30% ethyl acetate in hexanes. The desired fractions were concentrated to give ethyl 2-(4-chlorophenylamino)pyrimidine-5-carboxylate as an orange solid (0.43 g, 58%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.96 (2H, s), 7.57-7.64 (2H, m), 7.45 (1H, br. s.), 7.29-7.36 (2H, m), 4.37 (2H, q, J=7.02 Hz), 1.38 (3H, t, J=7.02 Hz). LCMS: R.T.=4.16 min; [M+H]+=277.96.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]([CH2:43][O:44][P:45]([O:48][CH2:49][CH2:50][NH2:51])([OH:47])=[O:46])[O:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH3:76]/[C:77](/[CH:89]=[CH:90]/[CH:91]=[C:92](\[CH3:104])/[CH:93]=[CH:94]/[C:95]1[C:100]([CH3:102])([CH3:101])[CH2:99][CH2:98][CH2:97][C:96]=1[CH3:103])=[CH:78]\[CH2:79][O:80][C:81](=[O:88])[CH2:82][CH2:83][CH2:84][C:85](O)=[O:86].C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CN(C=O)C>[C:1]([O:20][CH2:21][C@@H:22]([O:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][O:44][P:45]([O:48][CH2:49][CH2:50][NH:51][C:85](=[O:86])[CH2:84][CH2:83][CH2:82][C:81]([O:80][CH2:79]/[CH:78]=[C:77](\[CH3:76])/[CH:89]=[CH:90]/[CH:91]=[C:92](\[CH3:104])/[CH:93]=[CH:94]/[C:95]1[C:100]([CH3:101])([CH3:102])[CH2:99][CH2:98][CH2:97][C:96]=1[CH3:103])=[O:88])([OH:47])=[O:46])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN)OC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/COC(=O)CCCC(=O)O)C(C)(C)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCNC(=O)CCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (500 mg, 0.672 mmol), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (306.5 mg, 0.806 mmol) and 5-(((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-yl)oxy)-5-oxopentanoic acid (269 mg, 0.672 mmol) was dissolved in chloroform/DMF (10 mL, 1:1 mixture) in an amber-colored vial flushed with argon and N,N-Diisopropylethylamine (300 uL, 1.68 mmol) was added. Reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was concentrated and then purified by silica gel chromatography using a dichloromethane/methanol gradient. The fractions were pooled and concentrated to yield yellowish oil (460 mg, 61%). Verified product by NMR. 1H NMR (400 MHz), δH: 8.6 (d, 1H), 8.27 (d, 1H), 6.57-6.61 (dd, 1H), 6.08-6.25 (m, 4H), 5.57 (t, 1H), 5.30-5.34 (m, 4H), 5.18 (m, 1H), 4.68-4.70 (d, 2H), 4.28-4.35 (m, 1H), 4.05-4.15 (m, 1H), 3.81-3.97 (m, 4H), 3.52-3.62 (m, 1H), 3.35-3.45 (m, 2H), 2.95-3.05 (m, 1H), 2.33-2.35 (t, 3H), 2.2-2.3 (m, 7H), 1.9-2.05 (m, 17H), 1.85 (s, 3H), 1.69 (s, 3H), 1.5-1.65 (m, 6H), 1.4-1.5 (m, 2H), 1.18-1.38 (m, ˜40H), 1.01 (s, 3H), 0.84-0.88 (m, 12H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][OH:11].C([OH:15])C>O.C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([OH:15])=[O:11]
Reactant: CC1(C)[C@H]2CC[C@@H](CCO)[C@@H]1C2
Reactant: CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Temperature: 15 °C
Reaction time: 8 h

Procedure:
A solution of chromium trioxide (42.6 g CrO3, 426 mmol) in water (40 mL) was diluted with acetic acid (350 mL). The solution was cooled to 15° C. and the product from Example 4A (27 g, 160 mmol) was added dropwise. The solution was left to stand at room temperature overnight. Ethanol (20 mL) was added to destroy the excess of CrO3. The mixture was heated at 50° C. for 15 minutes and then concentrated under reduced pressure. The residue was suspended in water, acidified to pH 2 and extracted 3 times with ether. The ethereal solution was concentrated and the residue was dissolved in hexanes. The organic solution is decanted from the green tar and concentrated under reduced pressure. The residue was dissolved in 10% aqueous NaOH and neutral impurities were extracted with ether (discarded). The aqueous phase was acidified to pH 2 and extracted with hexanes, dried with Na2SO4, concentrated, cooled and filtered to give 10.9 g of title compound (crystals melting point: 50-53° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:32])C(=O)OC1C=CC=CC=1.[OH-].[Na+]>CCO.O>[CH3:1][NH:2][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:32]
Reactant: CN(CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNCCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C

Procedure:
Phenyl methyl(2-(2-oxo-6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)ethyl)carbamate (700 mg, 1.56 mmol) was stirred in EtOH (20 mL). To this suspension was added solid NaOH (624 mg, 15.6 mmol), followed by water (10 mL). The flask was then fitted with a condenser and was heated to reflux for 2 h. When TLC analysis showed that the reaction was complete, the mixture was cooled to room temperature and diluted with water. The product was extracted with dichloromethane (3×) and the combined organics were dried, filtered and concentrated, then chromatographed in EtOAc, followed by 10% 2M NH3/MeOH in dichloromethane. The isolated spot was then triturated with methanol and ether. Yield (223 mg, 43%). 1H NMR (DMSO-d6) δ 7.73 (d, 1H, J=3.6 Hz), 7.59 (d, 1H, J=5.4 Hz), 7.10 (m, 2H), 6.73 (m, 2H), 6.45 (brs, 2H), 3.91 (t, 1H, J=7.2 Hz), 2.81 (t, 1H, J=7.2 Hz), 2.65 (t, 1H, J=7.2 Hz), 2.50 (t, 1H, J=7.2 Hz); ESI-MS (m/z, %): 329 (MH+, 70), 149 (100), 141 (80), 127 (96).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])#[N:20]
Reactant: CC(C)(C)CC(C)(N)C#N
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Product: CC(C)(C)CC(C)(C#N)NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-amino-2,4,4-trimethylpentanenitrile (CAN 65260-84-6) as starting materials and isolated (643 mg, 87%) as a yellow oil; MS (ESI, m/z): 378.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2
Reactant: NCCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3-[2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (12.3 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 12.5 g (80%) of 3-[2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>[NH4+].[OH-]>[Cl:15][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccc2cccc(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Oc1cccc2ccc(Cl)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 2,8-dihydroxyquinoline (4 g, 24.8 mmol, Fluka) and phosphorus oxychloride (20 mL, Aldrich) was stirred at 100° C. for 1 h. The clear solution was cooled to room temperature and poured slowly with stirring into a mixture of NH4OH (150 mL) and crushed ice (200 g). The white solid that precipitated was filtered, dissolved in concentrated HCl (200 mL) and stirred at 100° C. for 1 h. Neutralization of the cooled to room temperature acid solution with NH4OH afforded white precipitate, which was filtered, washed with water and dried to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 180 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH:33]=O>>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:33][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 416.86 g/mol.
Reaction SMILES: CC([O-:5])(C)C.[K+].[OH2:7].[ClH:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C:34]([CH2:43][O:44][C:45](NCC)=[O:46])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=[CH:14][C:15]=1[Cl:16].O.O.[Cl:52][C:53]1[CH:54]=[C:55]([CH:60]([CH2:72][CH2:73][N:74]2[CH2:79][CH2:78][C:77]([C:87]3[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=3)([CH2:80][O:81][C:82](NCC)=[O:83])[CH2:76][CH2:75]2)[CH2:61][N:62]([CH3:71])[C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:56]=[CH:57][C:58]=1[Cl:59].Cl.Cl>CN(C=O)C>[OH2:5].[ClH:9].[C:45]([CH2:80][C:77]1([C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)[CH2:78][CH2:79][N:74]([CH2:73][CH2:72][CH:60]([C:55]2[CH:56]=[CH:57][C:58]([Cl:59])=[C:53]([Cl:52])[CH:54]=2)[CH2:61][N:62]([CH3:71])[C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:75][CH2:76]1)([OH:46])=[O:44].[OH2:27].[OH2:7].[C:82]([CH2:43][C:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:36][CH2:35]1)([OH:83])=[O:81].[ClH:8]
Reactant: CCNC(=O)OCC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(CCN1CCC(CC(=O)O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: 80 °C
Yield: 136.9 %

Procedure:
1.8 g of potassium tert-butylate and then 1.5 g of the compound obtained in step C of EXAMPLE 15 are added to a solution of 2.3 g of the compound obtained in PREPARATION 1.22 in 20 ml of DMF, and the reaction mixture is heated to 80° C. for 2 hours. It is concentrated under vacuum, the residue is taken up in water, the mixture is neutralized to pH 7 by adding concentrated HCl solution, the product is extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/MeOH (95:5; v/v) mixture. The product obtained is taken up with ethereal hydrogen chloride and the solvent is evaporated off under vacuum. 0.96 g of the expected product is obtained after crystallization in iso ether.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[N:14]=[C:15]([NH:18][CH:19]([CH3:21])[CH3:20])[S:16][CH:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].CC(O)=O>C1(C)C=CC=CC=1.O>[Cl:22][C:8]1[C:7]([O:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[N:14]=[C:15]([NH:18][CH:19]([CH3:21])[CH3:20])[S:16][CH:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1Cl)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1Cl)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
2-Isopropylamino-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (18 g, 40.7 mmol) was suspended in toluene (400 ml). NaH (2.4 g, 61 mmol) was added to the vigorously stirred mixture while monitoring H2 evolution. The mixture became a clear solution during heating to reflux. After refluxing for 3 h, the mixture was cooled to room temperature. A solution of AcOH (69.2 mmol) in H2O (3 vol) was added to the mixture. After vigorous agitation for 1 h at 0° C., the solids were collected by filtration and rinsed with H2O. The wet cake was dried under high vacuum to a constant weight to provide 8-chloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-ol (15 g, 86% yield).