Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](Cl)=[CH:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[C:31]([O:33][CH3:34])=[O:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=3)[N:27]=[CH:26][CH:25]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
After dissolving 4-amino-3-chlorophenol (2.22 g, 15.45 mmol) in dimethylsulfoxide (40 ml), sodium hydride (618 mg, 15.45 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. Methyl 7-(benzyloxy)-4-chloro-6-quinolinecarboxylate (4.05 g, 12.36 mmol) was added, and the mixture was heated at 100° C. for 2 hours while stirring. Upon cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (3.938 g, 9.06 mmol, 73.3%) as light brown crystals.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.CCOCC>[CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Pregna-4,20-dien-3-one (1, 1.19 g. 3.99 mmol) was refluxed for 24 h with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.72 g, 12.1 mmol) in 40 ml of benzene under Argon. The cooled suspension was diluted with ether and washed with two 100 ml portions of 5% (w/w) sodium hydroxide, two 100 ml portions of water and once with 100 ml of brine. Ether (100 ml) was added to the resulting emulsion, which was dried over sodium sulfate and then filtered through a column of sodium sulfate (20 g). After washing the residue twice with 50 ml portions of ether the combined filtrates were concentrated under reduced pressure and then flash chromatographed (25% ethyl acetate/hexanes on silica gel) to give a slightly yellow crystalline solid (0.26 g, 0.88 mmol, 226).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Li]CCCC.B(OC(C)C)(OC(C)C)OC(C)C.Cl>C1COCC1>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:14]([S:11]([NH2:10])(=[O:13])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCc1ccc(NS(=O)(=O)C(C)(C)C)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(N)(=O)=O
Product: CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-n-propylphenyl-t-butylsulfonamide (2.85 g, 11.2 mmoL) in anhydrous THF (20 mL) cooled to -40° C. under N2 was added 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to rt and stirred for 2 h. To the mixture, containing the bright red dianion at 0° C., was added B(OiPr)3 (3.9 mL, 1.5 equiv). The next day 2N HCl (3 mL) was added and the mixture was stirred for 1 h. The solvent was removed under reduced pressure and the residue was extracted with EtOAc. The organic was washed with 2N HCl, H2O and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. Rf=0.5 (1:1 EtOAc/Hex). The crude material was used in subsequent steps without further purification.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3OC3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1)C1OC1.C(O)(=O)C=C.C(C1CC(=O)OC1=O)=CCCCCCC>>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: C=CC(=O)O
Agent: CCCCCCC=CC1CC(=O)OC1=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 80 °C

Procedure:
10.54 g of bisphenol A diglycidyl ether was heated to 70° C. under stirring and then 4.46 g acrylic acid was added slowly under nitrogen atmosphere. After maintaining the reaction at 70° C. for 2 hours, 13.0 g of 2-octen-1-ylsuccinic anhydride was added and then the temperature was raised to 80° C. under mechanical stirring. The reactants are stirred at 80° C. for 2-3 hours to complete the reaction.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3C=C2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ICC.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([C:2]1[N:15]([S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:1]=1)[CH3:4]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
n-Butyllithium (2.03 mL, 3.25 mmol, 1.6M in hexanes) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.60 g, 2.32 mmol) in THF (9.0 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then iodoethane (0.557 mL, 6.97 mmol) was added. The reaction mixture was warmed up to 0° C. and stirred for 2 hours, after which more iodoethane (0.278 mL, 3.48 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. Saturated aqueous ammonium chloride and ethyl acetate were then added, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.25 g, 23% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:41])[CH2:37][C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:38](=[O:39])[CH2:37][C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: COCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 95 (136 mg, 0.37 mmol) in dry DMF (7 ml) was added the acid 27 (300 mg, 3.0 eq, 1.1 mmol), HOBT (74 mg, 1.5 eq, 0.55 mmol) and EDC (210 mg, 3.0 eq, 1.1 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and sat NaHCO3 soln, the organic phase was collected, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was triturated with Et2O to afford title compound 92 (150 mg, 72% yield). 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 9.62 (s, 1H), 8.43 (d, J=5.48 Hz, 1H), 8.06 (m, 2H), 7.93 (m, 1H), 7.85 (m, 1H), 7.76 (s, 1H), 7.45 (m, 2H), 7.05 (m, 2H), 6.90 (m, 1H), 6.58 (m, 1H), 5.35 (s, 2H), 3.84 (m, 3H), 3.63 (s, 2H), 3.25 (s, 3H). MS (m/z): 562.1 (M+H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.O=P(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36]>ClCCCl>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cccc2c(=O)[nH]cnc12
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ncnc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a suspension of methyl 4-oxo-3,4-dihydroquinazoline-8-carboxylate (150 mg, 0.73 mmol) in 4 mL of anhydrous DCE, POCl3 (80 μL, 0.87 mmol, 1.2 equiv.) was added followed by DIPEA (630 μL, 3.6 mmol, 5.0 equiv.). The resulting mixture was stirred at 90° C. for 1-2 h. After cooling down to rt, 3-(trifluoromethyl)benzylamine (97 μL, 0.81 mmol, 1.1 equiv.) was added. The reaction mixture was stirred at 80° C. for 2-4-h. After work-up, the crude was purified by chromatography to yield the title compound in 66% yield. 1HNMR (in CDCl3): 3.19 (s, 3H), 4.90 (s, 2H), 7.41-7.45 (m, 2H), 7.53 (t, J=8.9 Hz, 2H), 7.58 (s, 1H), 7.97 (dd, J=1.5 and 8.4 Hz, 1H), 8.04 (dd, J=1.5 and 7.3 Hz, 1H). Mass: M+H+: 362.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.O1[CH2:15][CH2:14]OC(O)C1O.[CH:18]([CH:20]=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][CH:20]=[CH:18][N:9]=2)=[CH:4][N:3]=1
Reactant: OC1OCCOC1O
Reactant: O=CC=O
Reactant: N#Cc1ccc(Cl)nc1
Product: Clc1ccc(-c2ccccn2)cn1
Yield: 82.5 %

Procedure:
The same synthesis procedures as in Example 1 were conducted except for using 2-chloro-5-cyanopyridine and 1,4-dioxane-2,3-diol in place of 4-cyanopyridine and a 40% glyoxal aqueous solution, respectively, and, after completion of the reaction, the organic layer was distilled under reduced pressure of 3.0 to 3.1 Torr to obtain a 150 to 152° C. fraction. Thus, there was obtained 151.0 g (yield: 82.5%) of the end product as pale yellow crystals. HPLC analysis revealed that purity of the product was 99.1%.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][CH:17]([NH2:19])[CH3:18]>C1COCC1>[CH:17]([NH:19][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)([CH3:18])[CH3:16]
Reactant: CC(C)N
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(NC(C)C)c(C=O)cc2c1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added propan-2-amine (5.76 mL, 67.7 mmol) and the reaction mixture was stirred for 12.5 h at 160° C. and finally 45 min at 180° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 2-(isopropylamino)-6-methoxyquinoline-3-carbaldehyde SLA 28186 as an orange solid (1.64 g, 99% yield).
Reaction SMILES: C([N:5]1[CH2:8][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:6]1)(C)(C)C.[N+:15](C1([N+]([O-])=O)CNC1)([O-:17])=[O:16].B(F)(F)F.CCOCC.C(OC(=O)C)(=O)C.[N+]([O-])(O)=O>>[CH2:6]1[N:5]([N+:15]([O-:17])=[O:16])[CH2:8][C:7]1([N+:9]([O-:11])=[O:10])[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Reactant: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Agent: FB(F)F
Solvent: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Yield: 90 %

Procedure:
The upper reaction scheme is the conversion of the N-tertiarybutyl,3,3 dinitroazetidine to the N-acetyl, 3,3 dinitroazetidine. The reaction conditions are a catalytic amount of boron trifluoride etherate as the Lewis acid and acetic anhydride as the solvent-reactant. The temperature is 125 degrees C. As shown there was about a 90% yield. The compound is nitrated with 70% nitric acid and heated to give TNAZ.
Reaction SMILES: [C:1]([O:11][Si](C)(C)C)(=O)[CH2:2][C:3]([O:5][Si](C)(C)C)=[O:4].C([Li])CCC.[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH2:25]C.C(=O)(O)[O-].[Na+]>C(OCC)C>[O:11]=[C:1]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCCCCC(=O)Cl
Reactant: C[Si](C)(C)OC(=O)CC(=O)O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCC(=O)CC(=O)O
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A stirred solution of bis-trimethylsilyl malonate (21.6 g, 71.5 mmol) in 100 mL of anhydrous diethyl ether was cooled to −78° C. To this solution, n-butyl lithium (1.6 M in ether, 44.7 mL, 71.5 mmol) was added slowly, keeping the temperature below −60° C. Upon completion of addition, the reaction was allowed to warm to −10° C., at which time hexanoyl chloride (5 mL, 35.75 mmol) was added quickly and allowed to stir for 30 minutes. Next, 150 mL of a cold, aq. 5% sodium bicarbonate solution was added, and the resulting solution was stirred vigorously for 30 minutes. The aq. layer was separated out and acidified with cold 4N sulfuric acid until pH=2. The aq. layer was then extracted 2×50 mL with diethyl ether, dried over MgSO4, and concentrated down in vacuo to afford a white solid. This solid could be further purified by recrystallization from hexane, if necessary. 4.9 g, 87% yield. 1H NMR (300 MHz, CDCl3) δ=3.49 (s, 2H, CH2), 2.59 (t, 2H, J=7.3 Hz, CH2), 1.64 (p, 2H, J=7.4 Hz, CH2), 1.34 (m, 4H, CH2CH2), 0.92 (t, 3H, J=6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ=204.4, 182.8, 87.9, 48.1, 43.4, 31.3, 23.5, 14.1 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:19][C:18](I)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>CN(C=O)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:19][C:18]([C:26]#[C:25][CH2:24][OH:27])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(I)cc21
Reactant: C#CCO
Agent: Cl[Pd]Cl
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C#CCO)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-iodo-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (0.20 g, 0.44 mmol), Pd(PhCN)2Cl2 (10 mg) CuI (7 mg) Et3N (1 mL) and propargyl alcohol (0.036 g, 0.66 mmol) in DMF was stirred at ambient temperature overnight. The solvent was removed and the residue partitioned between H2O and CH2Cl2 (100 mL each). The layers were shaken, the organic layer separated and dried over MgSO4. The solvents were removed in vacuo and the residue purified via flash column chromatography (eluant 5% MeOH/CH2Cl2) to afford 0.117 g title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH3:38])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([N:37]([CH2:35][CH3:36])[CH3:38])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCNC
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.019 ml (0.22 mmol) of N-ethylmethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 63 mg (99% of theory) of the desired target compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:23][CH2:22][C:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[Si]([Cl:38])(C)(C)C>C(OCC)(=O)C>[ClH:38].[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:19][CH2:20][C:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:24]([CH3:26])[CH3:25])[CH2:22][CH2:23]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)OCCCCc1c(C2CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
4-(2-(4-Benzyl-4-(dimethylamino)cyclohexyl)-1H-indol-3-yl)butyl acetate (less polar diastereomer) (120 mg, 0.27 mmol) was dissolved in ethyl acetate (10 ml), and Me3SiCl (68 μl, 0.54 mmol) was added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 174 (117 mg, m.p. 187-191° C., 90%) was obtained as a white solid
Reaction SMILES: C[O:2][C:3]1[S:4][C:5]2[C:10]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[N:9][C:8]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:7][C:6]=2[N:25]=1.O>O1CCOCC1.Cl>[OH:14][CH2:13][C:12]([NH:11][C:10]1[C:5]2[S:4][C:3](=[O:2])[NH:25][C:6]=2[N:7]=[C:8]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:9]=1)([CH3:15])[CH3:16]
Reactant: COc1nc2nc(SCc3ccccc3)nc(NC(C)(C)CO)c2s1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2[nH]c(=O)sc12
Temperature: 45 °C

Procedure:
To a solution of the product from example 1 step f) (0.21 g) in 1,4-dioxane (5 ml) was added water (0.1 ml) and concentrated hydrochloric acid (1 drop). The mixture heated at 45° C. for 3 hours then evaporated to dryness. Recrystallisation (acetonitrile) gave the title compound (0.110 g).
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].Cl>CN(C=O)C.CN(C=O)C.C1CN2C(=NCCC2)C1>[C:16]([CH2:15][N:14]1[CH2:21][C:19](=[O:20])[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:2](=[O:3])[CH2:1][N:8]([CH2:7][C:5]([OH:6])=[O:4])[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)([OH:18])=[O:17]
Reactant: NCCCCN
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NCCCCNC(=O)CN(CC(=O)O)CC1
Reaction time: 8 h

Procedure:
A 1 L three-neck flask was charged with 340 mL of dry DMF. Two syringes were charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (3.00 g, 8.40 mmol) in 100 mL of DMF and 1,4-diaminobutane (0.740 g, 8.40 mmol) in DMF/DBN, (96 mL/4 mL). The solutions were added simultaneously at ambient temperature to the flask at a rate of 30 mL/hour. After the addition was complete, the reaction mixture was allowed to stir overnight, stripped to dryness, and 1N HCl added to adjust the pH to 10.4. The solution was applied to AG1-X8 (100-200 mesh, OAc-) resin and eluted with 0.5N acetic acid to yield 0.52 g (13.6%) as a white solid, after removal of acetic acid and lyophilization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: OC1CCNCC1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(N2CCC(O)CC2)c1

Procedure:
Analogously to the process described in Example 3, 125 mg (0.248 mmol) of the compound from Example 2A and 50 mg (0.497 mmol) of 4-hydroxypiperidine were used to obtain 20 mg (16% of theory) of the title compound. The first component step of the process was effected here at a reaction temperature of 130° C. The preparative HPLC purification was performed by method 11
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([CH3:26])[CH:31]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)no4)cc3)c2cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(3-methylisoxazol-5-yl)carbamate (81 mg) were added to toluene (5 ml), then diisopropylethylamine (0.88 ml) was added and the mixture was heated and stirred at 100° C. for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate: toluene (1:1) mixed solvent to obtain the title compound (102 mg).