Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]#[N:11])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[C:10]([CH:9]([C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:11]
Reactant: COc1ccc([N+](=O)[O-])c(CC#N)n1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC(C#N)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under argon, 2-(6-methoxy-3-nitropyridin-2-yl)acetonitrile (500 mg, 2.59 mmol) was dissolved in acetonitrile (11 mL) in a flame dried round-bottom flask. Two equivalents of anhydrous potassium carbonate (0.72 g, 5.18 mmol) were added to this solution, and methyl 2-bromoacetate (245 μL, 2.59 mmol) was introduced dropwise. The reaction mixture was stirred at room temperature until the starting materials were consumed, approximately four hours. The crude material was combined with CH2Cl2 and inorganic debris was filtered off using a phase separator syringe equipped with a sodium sulfate drying cartridge. The filter cake was washed with small quantities of CH2Cl2 and all organic filtrates were collected and combined. The organic solvents were evaporated in vacuo at 40° C. and the resulting viscous dark brownish oil either directly used in the next reaction step or purified by flash chromatography on a short silica-gel column (ethyl acetate/hexane gradient) prior to its further chemical reaction. C11H11N3O5, Mr=265.22; 1H NMR (400 MHz, DMSO-d6) d: 3.15-3.29 (m, 2H), 3.64 (s, 3H), 3.99 (s, 3H), 5.22 (t, J=7.2 Hz, 1H), 7.08 (d, J=9.2 Hz, 1H), 8.48 (d, J=8.8 Hz, 1H); LCMS (ESI) tR: 1.98 min (96-100%, UV220, UV254, ELSD), m/z: 266.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[C:27](=[O:29])=[O:28].Cl>O1CCCC1>[CH2:1]([O:5][C:6]1[C:7]([F:15])=[C:8]([F:14])[C:9]([C:27]([OH:29])=[O:28])=[C:10]([F:13])[C:11]=1[F:12])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=O
Reactant: CCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
24.4 g of the compound (2) dissolved in 250 mL of tetrahydrofuran (THF) were cooled at −78° C. in an argon atmosphere; thereto were then dripped 82 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 14.6 g (54.8 mmol) of 4-butoxy-2,3,5,6-tetrafluorobenzoic acid (3).
Reaction SMILES: CC(O)(C#C)C.[CH3:7][C:8]([OH:17])([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])C#C.[OH-].[K+]>>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][CH2:11][C:8](=[O:17])[CH3:7]
Reactant: C#CC(C)(O)CCC=C(C)C
Agent: C#CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)CCC=C(C)C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
A 100 ml-four-necked flask equipped with a thermometer, a reflux condenser, and a stirrer was charged with 8.61 g (102) mmol 2-methyl-3-butin-2-ol (MBI) and 15.58 g (102) mmol 3,7-dimethyl-6-octen-1-in-3-ol (DLL) stirred with 750 rpm and heated up to reflux temperature. After 5 min an internal temperature of 93° C. was reached, and 2 ml KOH (41.42% in H2O, 20.53 mmol) were added. The reaction was controlled by GC (samples were taken after 60 min, 155 min and 385 min). The ketones were separated by distillation. Yield acetone 5.7 g, (95.8%), yield 6-methyl-5-hepten-2-on (MH) 12.3 g, (95.2%), not optimized.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:27]=[CH:28]/[O:29]C)[C:5]([O:25][CH3:26])=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH:20]=3)[C:18]#[N:19])=[N:10][N:9]=2)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:27][CH:28]=[O:29])[C:5]([O:25][CH3:26])=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH:20]=3)[C:18]#[N:19])=[N:10][N:9]=2)[CH:7]=1
Reactant: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(CC(C)C)c(C#N)c3)s2)c1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
To a solution of 5-(5-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D36) (130 mg) and sodium iodide (92 mg) in acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.078 mL) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product 5-{5-[5-fluoro-2-(methyloxy)-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D37) (75 mg) as a yellow oil. MS (ES): C22H20FN3O2S requires 409. found 410.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#N)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
The ester from Step 2 (0.51 g 1.5 mmol) was dissolved in THF (5 mL) and ethanol (5 mL), treated with 2.5N sodium hydroxide (1.2 mL, 3.0 mmol), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl, extracted with ethyl acetate, washed with water, brine, dried over MgSO4, concentrated in vacuo, and recrystallized from diethyl ether/hexane to give a white powder (0.10 g, 21%): mp 238.1–239.7° C. 1H NMR (acetone-d6/300 MHz) 7.97 (s, 1H), 7.92 (d, 1H, J=2.4 Hz), 7.89 (d, 1H, J=2.4 Hz), 6.14 (q, 1H, J=6.6 Hz). FABLRMS m/z 302 (M−H). ESHRMS m/z 301.9819 (M−H, Calc'd 301.9832). Anal. Calc'd for C12H5ClF3NO3: C, 47.47; H, 1.66; N, 4.61. Found: C, 47.41; H, 1.70; N, 4.55.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:17][CH2:16][C:15](=O)[CH2:14]1.N1CCCC1.Cl>CO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH2:17][CH:13]([CH3:12])[CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC1CCC(=O)C1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: CO
Solvent: C1CCNC1
Solvent: O
Product: CC1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (2.193 g, 10.2 mmol), 3-methylcyclopentanone (2 g, 20.4 mmol) and pyrrolidine (1.67 mL, 19.43 mmol) in MeOH (42 mL) was stirred at room temperature overnight, followed by reflux for 2 days. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromo-3′-methylspiro[chroman-2,1′-cyclopentan]-4-one, which was purified by chromatography (PE:EA 300:1-200:1) (2.3 g, 76%). 1H NMR (CDCl3): 7.94 (d, 1H), 7.52-7.49 (m, 1H), 6.83-6.79 (m, 1H), 2.79 (m, 2H), 2.39-2.22 (m, 0.5H), 2.21-1.95 (m, 3H), 1.91-1.75 (m, 1H), 1.67-1.57 (m, 1H), 1.51-1.41 (m, 0.5H), 1.31-1.15 (m, 1H), 1.08-0.98 (m, 3H).
Reaction SMILES: C([NH:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)C1C=CC=CC=1>C(O)=O.[OH-].[Pd+2].[OH-].[C]>[NH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:8])[C:18]=2[N:19]=[CH:20]1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: NCCCCn1cnc2c(N)nc3ccccc3c21
Yield: 36.5 %

Procedure:
67 mg (0.150 mmol) of 4-Benzylamino-1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline was dissolved in 5 ml of formic acid. 0.15 g of 20% palladium hydroxide-carbon was added thereto and the mixture was refluxed for 2 days under heating. The reaction mixture was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:32% acetic acid=6:3:1 (v/v)) to obtain the acetic acid salt of the object. The product was treated with alkali and the solid was collected by filtration to obtain 14 mg (0.0548 mmol) of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinoline-4-amine shown below as faint brown powder. ##STR47## The physicochemical properties of this compound was in agreement with those of the compound of Example 17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=O)=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:18]([CH2:17][C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Product: Clc1ccc(Cc2nc3cc(Cl)ccc3[nH]2)cc1
Temperature: 200 °C

Procedure:
142.5 g (1 mol) of 4-chloro-o-phenylenediamine, 170.5 g (1 mol) of 4-chlorophenylacetic acid, and 190 g (1 mol) of p-toluene sulfonic acid monohydrate (hereinafter called PTS) were thoroughly blended and heated using a mantle heater while stirring. The temperature was raised to 200° C. in 30 minutes, then the mixture was heated at 200° to 220° C. for 3 hours until almost all steam was evaporated. The reaction mixture thus obtained was poured into aqueous ammonia and stirred to solidify. The solid was washed with water and dried to produce a purple powder. This powder was recrystallized with a solvent to obtain 0.5 g of white, needle-shaped crystals of 6-chloro-2-(4-chlorophenylmethyl)benzimidazole. The compound was dissolved in as much an amount of acetic acid as can dissolve this compound. The solution thus obtained was added to 100 ml of water containing 0.04 g of cupric chloride to obtain the composition of the present invention.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24]C)=[S:16])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:10]([C:8]1[S:7]/[C:6](=[N:14]\[C:15](=[S:16])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])/[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:9]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=S)c1cc(Cl)ccc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=S)c1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
To a solution of Example 6C (212 mg, 0.534 mmol) in CH2Cl2 (20 mL) at 0° C. was added IM BBr3 in CH2Cl2 (1.6 mL, 1.6 mmol) and the reaction was allowed to warm to room temperature for 3 h. Saturated sodium bicarbonate was added, and the organic layer was separated, washed with brine, dried with anhydrous MgSO4 and concentrated under reduced pressure to provide quantitatively of the title compound. 1H NMR (300 MHz-DMSO-d6) δ: 0.95 (t, J=7 Hz, 4H), 1.37 (s+m, 11H), 1.82 (m, 2H), 4.30 (t, J=7 Hz, 2H), 6.95 (d, J=9 Hz, 1H), 7.40 (d-d, J=9 Hz, 3 Hz, 1H), 7.80 (s, 1H), 8.37 (d, J=3 Hz, 1H), 13.62 (s, 1H); MS (DCI/NH3) m/z 383 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1.[Cl-].[Na+].O>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]([CH:22]=[O:23])[C:3]2[CH:4]=[CH:5][NH:6][C:7]=2[CH:8]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(C(F)(F)F)cc2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-bromo-6-(trifluoromethyl)-1H-indole (5.23 g, 19.81 mmol) in tetrahydrofuran (20 ml) was cooled to −78 ° C. and treated slowly with n-butyllithium (1.6 M solution in hexanes, 39.6 ml, 63.4 mmol). The solution was stirred for 15 min at −78 ° C., and then treated with dimethylformamide (7.67 ml, 99 mmol), and stirred for 30 minutes more, allowing the reaction to warm to ambient temperature. The resulting solution was poured into brine and extracted with ethyl acetate. The pooled organics were dried over sodium sulfate and concentrated to give an amber oil. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 1.17 g, (32%). 1H-NMR (CDCl3, 500 MHz) δ ppm 10.28 (s, 1H), 8.72 (br s, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H). Mass spec.: 214.14 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.O>[CH2:22]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH:21]=[CH2:20]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
Potassium carbonate (28.0 g.) was added to a stirred solution of t-butyl ethyl malonate (37.6 g.) in dry N,N-dimethylformamide (DMF) (100 ml.). After 1 hour allyl bromide (34 ml.) was added. The mixture was heated at 70° C. for 66 hours, cooled to room temperature and diluted with water (900 ml.). The mixture obtained was extracted with ethyl acetate (3×200 ml.). The extracts were dried (MgSO4) and evaporated. The oil obtained was purified by flash column chromatography eluting with 1:15 v/v ethyl acetate/petroleum ether (b.p. 60°-80° C.) to give t-butyl ethyl 2-allylmalonate as a colourless oil (15.6 g.), b.p. 70°-72° C. at 0.2 mmHg; NMR: 1.21 (3H,t), 1.42 (9H,s), 2.66 (2H,m), 3.28 (1H,m), 4.16 (2H,q), 5.06 (2H,m) and 5.76 (1H,m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:19]=[CH:18][C:12]4C(C)CN[O:16][C:11]=4[CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH3:7][N:6]1[CH2:5][CH2:4][O:16][C:11]2[CH:10]=[C:9]([C:7]3[NH:6][C:5]4[CH:20]=[CH:21][C:2]([NH:1][C:32](=[O:34])[C:31]5[CH:30]=[CH:29][C:28]([N:25]6[CH2:24][CH2:23][O:22][CH2:27][CH2:26]6)=[CH:36][CH:35]=5)=[CH:3][C:4]=4[N:8]=3)[CH:19]=[CH:18][C:12]1=2
Reactant: CC1CNOc2cc(-c3nc4ccc(N)cc4[nH]3)ccc21
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Product: CN1CCOc2cc(-c3nc4cc(NC(=O)c5ccc(N6CCOCC6)cc5)ccc4[nH]3)ccc21

Procedure:
Compound 169 was prepared according to the procedure similar to that described in Scheme III from 5-amino-2-(4-methyl-3,4-dihydrobenzoxazin-7-yl)benzimidazole and 4-morpholinobenzoic acid. [M+H]+ calcd for C27H27N5O3: 470.21; found: 496.96.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[C:19]([NH:21][CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[CH:22]1([NH:21][C:19]([C:18]2[CH:17]=[C:16]([CH:28]=[CH:27][CH:26]=2)[CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:20])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(NC1CCC1)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC3CCC3)c2)CC1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
A stirred suspension of tert-butyl piperazine-1-carboxylate (8.94 mmol, 1.665 g), 3-(chloromethyl)-N-cyclobutylbenzamide (8.94 mmol, 2 g), potassium carbonate (17.88 mmol, 2.471 g) and sodium iodide (0.894 mmol, 0.134 g) in acetonitrile (50 ml) was heated at 80° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (3.3 g). MS (ESI) m/z 374.4 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOCCCc1ccc(OB(O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(3-ethoxypropyl)phenylboric acid (0.65 g), cupric acetate (0.27 g) and molecular sieves 4A (0.8 g) suspended in dichloromethane (15 ml) was added triethylamine (1.0 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)n(CCCCC(C)O)c(=O)n2C

Procedure:
To 11.8 g of 7-allyl-3-methyl-1-(5-oxyhexyl)-xanthine (prepared by alkylation of 7-allyl-3-methylxanthine with 1-chlorohexan-5-one in dimethylformamide in the presence of potassium carbonate at 100° C. for 5 hours; melting point: 71° C.), dissolved in 200 ml of ethanol, 1.5 g of sodium borohydride was added slowly under stirring at a temperature of max. 30° C. After stirring at room temperature for 6 hours the mixture was evaporated under reduced pressure. The residue was extractively worked up with dilute sodium hydroxide solution and with methylene chloride. The combined methylene chloride phases were washed with water, dried and evaporated under reduced pressure. The residue was purified by means of chromatography on silica gel (mobile phase: methylene chloride/ethanol/ammonia-solution (28%), volume ratio 8:2:0.2) and by recrystallization from methylene chloride/diethylether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:18]=3[CH:36]=2)=[CH:4][CH:3]=1.[OH:37]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:18]=3[CH:36]=2)=[O:37])=[CH:6][CH:7]=1
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C)cc3)cc21
Reactant: OO
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(C)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1B(O)O.Br[C:19]1[S:23][C:22]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1[C:19]1[S:23][C:22]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:21][N:20]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1c(B(O)O)c(=O)n(C)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2nnc(N(C)C3CC(C)(C)NC(C)(C)C3)s2)c(=O)n(C)c2ccccc12
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A degassed reaction mixture of (4-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (500 mg, 2.15 mmol), 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (858 mg, 2.57 mmol), tetrakis(triphenylphosphine)palladium(0) (248 mg, 0.215 mmol) and Na2CO3 (682 mg, 6.44 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated via microwave irradiation at 100° C. for 1 h. After cooling to room temperature, the mixture was filtered through celite, washed with MeOH then the filtrate was concentrated. The residue was purified by silica gel chromatography (2%˜10% 2M NH3 in MeOH/DCM) to give 4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one (240 mg, MS: 442.1 [M+H+].) (4 mg, MS: 442.0 [M+H+], LCMS Rt=1.25 min (LCMS method D); 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.55 (s, 1H), 8.14 (dd, J=8.08, 1.52 Hz, 1H), 7.72-7.81 (m, 1H), 7.61-7.69 (m, 1H), 7.33-7.45 (m, 1H), 4.61 (br. s., 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.11 (s, 3H), 1.95 (d, J=12.13 Hz, 2H), 1.79 (br. s., 2H), 1.50 (s, 6H), 1.39 (br. s., 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4C(F)(F)F)cc23)CC1
Yield: 90.3 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.0 mg (0.062 mMol) 2-trifluoromethylbenzoyl chloride, 20.3 mg (89%) of the title compound were recovered.