Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S-])[CH3:2].[Na+].Cl[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]1[N:24]([CH3:25])[C:14]2=[N:15][CH:16]=[C:17]([S:19][C:20]([F:23])([F:22])[F:21])[CH:18]=[C:13]2[N:12]=1.CN1C(=O)CCC1>O>[CH2:1]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]1[N:24]([CH3:25])[C:14]2=[N:15][CH:16]=[C:17]([S:19][C:20]([F:23])([F:22])[F:21])[CH:18]=[C:13]2[N:12]=1)[CH3:2]
Reactant: CC[S-]
Reactant: Cn1c(-c2sccc2Cl)nc2cc(SC(F)(F)F)cnc21
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccsc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
0.32 g of sodium ethanethiolate was added to a mixture of 0.71 g of 2-(3-chloro-thiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5-b]pyridine and 4 ml of NMP, under ice cooling, and the mixture was stirred at 70° C. for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and applied to a silica gel column chromatography to obtain 0.57 g of 2-(3-ethylthiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (3)).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].B(F)(F)F.[CH3:26][CH2:27]OCC.O>C(O)C>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([O:16][CH2:26][CH3:27])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCOCC
Reactant: CCCC1Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Agent: FB(F)F
Solvent: CCO
Solvent: O
Product: CCCC1Cc2c(c(C)c(C)c3oc(C(=O)OCC)cc23)C1=O

Procedure:
To a solution of 4,5-dimethyl-6-oxo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid (8.0 g.) in ethanol (50 ml.) is added borontrifluoride etherate (13 ml.). The reaction mixture is refluxed for 0.5 hour, treated with water and cooled to afford ethyl [4,5-dimethyl-6-oxo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]-furan-2-carboxylate] after filtration and drying.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].[BrH:18]>O.O1CCOCC1.[Cu]Br>[Br:18][C:6]1[CH:8]=[C:2]([F:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc([N+](=O)[O-])c(N)cc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
5-Fluoro-4-methoxy-2-nitroaniline obtained in Reference Example 14 (4.1 g) was dissolved in a mixed solvent of water (20 ml) and 1,4-dioxane (10 ml), 48% hydrobromic acid (12 ml) was added to the solution under refluxing, and then the mixture was refluxed for 15 minutes. The reaction mixture was cooled to 0° C., sodium nitrite was added dropwise thereto, and the mixture was stirred at 0° C. for 15 minutes. The resulting mixture was added dropwise to a solution of copper (I) bromide (3.6 g) in a mixture of water (20 ml) and 48% hydrobromic acid (12 ml) at 0° C. The mixture was stirred at 60° C. for 15 minutes, cooled to room temperature, and further stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (developing solvent:ethyl acetate-hexane=1:8) to obtain the title compound as crystals (5 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1.[Na].[CH3:17]I>CO>[NH2:1][C:2]1[N:6]=[C:5]([N:7]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[CH3:17])[O:4][N:3]=1
Reactant: Nc1noc(Nc2c(Cl)cccc2Cl)n1
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CN(c1nc(N)no1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.0 g (0.012 mole) 3-amino-5-(2,6-dichlorophenylamino)-1,2,4-oxadiazole were added to a solution of 0.6 g (0.025 mole) sodium in 100 ml methanol, and 1.6 ml (0.024 mole) methyl iodide are added in drops and stirred for 24 hours at room temperature. The solvent is distilled off under vacuum, the residue taken up in methylene chloride, extracted with water and, after evaporation of the solvent, 2.8 g of the N-methyl compound, which has an mp. of 177°-178° C. after recrystallization from acetic ester/diisopropyl ether is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](O)=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCOC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.4 %

Procedure:
4-(2-Carboxyphenyl)piperidine-1-carboxylic acid t-butyl ester (5.0 g, 160 mmol, 1.0 eq.) and THF (100 mL, 1.0 mol) were combined at room temperature under nitrogen. 1.0M Borane-THF complex in THF (32.7 mL, 32.7 mmol, 2.0 eq.) was added dropwise over 10 minutes (5° C. exotherm, gas evolution). The mixture was stirred at room temperature for 5 minutes, then heated at 50° C. for 1 hour. The mixture was cooled to room temperature, and the reaction was quenched slowly with MeOH (30 mL) (mild exotherm, significant gas evolution), then concentrated by rotary evaporation. The material was azeotroped with MeOH (2×50 mL). The crude product was dissolved in EtOAc (100 mL, 1 mol), washed with NaHCO3 (50 mL), then saturated aqueous NaCl (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield 4-(2-hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (4.4 g) as a clear, light yellow oil that solidified upon sitting.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:19]/[C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: Cc1ccc2c(c1)O/C(=C\c1ccc(F)cc1)C(=O)/C(=C/c1ccc(F)cc1)O2

Procedure:
Calone is reacted with 4-fluorobenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(4-fluorophenyl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][OH:43])([CH2:12][O:13]2)[C:10]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(N(CC)CC)C>ClCCl>[C:45]([O:43][CH2:42][C@:11]12[O:24][C@:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=4)[CH:26]=3)([O:13][CH2:12]1)[C@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]2=[O:44])(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of (1S,3R,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-2-one 28g (13.4 g, 21.8 mmol) in dichloromethane (40 mL) were added acetic anhydride (3.0 mL, 32.7 mmol) and triethylamine (6.0 mL, 43.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours and quenched with water (100 mL). The resulting mixture was extracted with dichloromethane (100 mL×2). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 28h as a pale yellow solid (12.1 g, 84.6%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ (ppm): 7.29 (m, 4H), 7.24 (m, 3H), 7.19 (s, 1H), 7.12 (d, 1H), 7.07 (m, 2H), 6.99 (d, 2H), 6.76 (m, 2H), 6.68 (d, 2H), 4.94 (d, 1H), 4.58 (d, 1H), 4.47 (d, 1H), 4.37 (d, 1H), 4.31 (m, 2H), 4.07 (d, 1H), 3.95 (m, 3H), 3.88 (m, 5H), 1.97 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[N:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][C:8]2=[O:20])[CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][C:38]1[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=[C:30]([C:28]([C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:11]5[CH:12]=[N:13][C:14]6[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=6[C:10]=5[NH:9][C:8]4=[O:20])[CH2:5][CH2:6]3)[CH:23]=2)=[O:29])[CH:39]=1
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5c6ccccc6ncc54)CC3)ncn2)cc2oc(=O)[nH]c12

Procedure:
134 mg (0.500 mmol) 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one, 145 mg (0.500 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.174 mL (1.00 mmol) DIPEA were stirred overnight in 5 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with a 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: CO[C:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH2:14]1COCC1>>[CH3:14][O:11][CH2:10][CH:9]1[CH2:12][CH2:13][CH:6]([CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8]1
Reactant: COC(C)(C)c1ccc(C=O)cc1
Reactant: C1CCOC1
Product: COCC1CCC(C(C)C)CC1

Procedure:
In an autoclave, 405 g (2.5 moles) of the 4-(1-methoxy-1-methylethyl)-benzaldehyde obtained according to A, in 200 ml of THF, were flushed several times with nitrogen and hydrogen in the presence of 1 g of ruthenium hydroxide and then hydrogenated at 150° C. and under a hydrogen pressure of 300 bar until the pressure remained constant.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([F:35])=[CH:31][C:32]([F:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([F:35])=[CH:31][C:32]([F:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(F)cc(F)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(F)cc(F)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,7-difluoro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[C:14]2[NH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH3:4].ClCCl.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(N(CC)CC)C>[CH:27]([C:26]([NH:1][CH2:2][C:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[NH:11][C:10]=2[CH:14]=1)([CH3:4])[CH3:5])=[O:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(-c2nc3cccc(C(C)(C)CN)c3[nH]2)cc1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc3ccc(C(C)(C)CNC(=O)C(C)C)cc3[nH]2)cc1
Reaction time: 10 h

Procedure:
1.9 g. 4-(2-Aminomethylpropan-2-yl)-2-(4-methoxyphenyl)-benzimidazole (obtained in Example 6) in 200 ml. dichloromethane are reacted with 2.5 ml. triethylamine and 0.82 g. isobutyric acid chloride at ambient temperature. After 10 hours, the solvent is removed in a vacuum and the residue is digested with water and 2N aqueous ammonia solution. The reaction mixture is extracted 4 times with dichloromethane and the organic phase is dried over anhydrous sodium sulphate, filtered and evaporated. Ethyl acetate is added thereto, a part thereof is distilled off with the dichloromethane and left to crystallise and the product is filtered with suction. The product is recrystallised from ethyl acetate to give 0.6 g. of the title compound; m.p. 218°-220° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:29])[CH2:4][CH2:5][N:6]1[C:26](=[O:27])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:15]4[C:16]5[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:17]=5[CH:18]=[CH:19][C:20]=4[N:8]([C:9]=23)[C:7]1=[O:28]>O.CO.Cl.[C].[Pd]>[CH3:2][N:3]([CH3:29])[CH2:4][CH2:5][N:6]1[C:26](=[O:27])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:15]4[C:16]5[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[C:17]=5[CH:18]=[CH:19][C:20]=4[N:8]([C:9]=23)[C:7]1=[O:28]
Reactant: CN(C)CCn1c(=O)c2cccc3c4c5c(ccc4n(c1=O)c23)C(=O)CCC5
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C)CCn1c(=O)c2cccc3c4c5c(ccc4n(c1=O)c23)C(O)CCC5
Yield: 77.3 %

Procedure:
0.5 g (1.2 mmol) of the compound of Example 4 was dissolved in a mixture of water (50 ml) with methanol (25 ml) and 1.2 ml of 1 N hydrochloric acid was added thereto. Next, hydrogenation was effected in the presence of palladium-carbon under a hydrogen pressure of about 4.5 kg/cm2. After confirming the completion of the reaction by thin layer chromatography, the catalyst was filtered off and the residue was concentrated to about 2/3. After adding 50 ml of water and 5 ml of conc. aqueous ammonia thereto, the obtained mixture was extracted with ethyl acetate. The organic layer was taken up, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to thereby give 0.35 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+](C1C=C(S(O[CH2:26][C@@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1OC[C@@H]1CO1
Yield: 72 %

Procedure:
A solution of methyl 2-hydroxy-5-methylbenzoate (0.166 g, 1 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.26 g, 1 mmol) and caesium carbonate (0.39 g, 1.2 mmol) in dimethylformamide (5 mL) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by flash chromatoghrphy on silica gel (eluent:ethyl acetate/n-heptane), yielding the titled compound (0.16 g, 72%) as colourless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (90 mg, 99%), MS (ISP) m/z=366.4 [(M+H)+], mp 329° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9]Cl)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClCCN1CCOCC1.[N:20]1[N:24]2[C:25]3[C:33]4[CH:34]=[N:35][NH:36][C:32]=4[N:31]=[CH:30][C:26]=3[C:27](=[O:29])[NH:28][C:23]2=[N:22][CH:21]=1>>[N:1]1([CH2:7][CH2:8][CH2:9][N:28]2[C:27](=[O:29])[C:26]3[CH:30]=[N:31][C:32]4[NH:36][N:35]=[CH:34][C:33]=4[C:25]=3[N:24]3[N:20]=[CH:21][N:22]=[C:23]23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ncnn2c2c1cnc1[nH]ncc12
Reactant: ClCCCN1CCNCC1
Agent: ClCCN1CCOCC1
Product: O=c1c2cnc3[nH]ncc3c2n2ncnc2n1CCCN1CCNCC1

Procedure:
By substituting 3-piperazinopropyl chloride for the 1-chloro-2-morpholinoethane in the procedure of Example 8 and utilizing the 4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one product of Example 11, 4-(3-piperazino)propyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]CC)[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as an opaque oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.[BH4-].[Na+]>CO>[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH:2][CH2:3][CH:4]([OH:15])[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)[N:24]=1)(=[O:18])[CH3:17]
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: CC(=O)Nc1nc(C=O)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(O)CNCc2csc(NC(C)=O)n2)cc1OC
Yield: 82 %

Procedure:
α-(Aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride (2.88 g) and 2-acetamido-4-formyl-thiazole (2.1 g) were suspended in 14 ml methanol, and 1.8 ml triethylamine was added dropwise to this suspension with stirring. The resulting solution was heated under reflux for 30 minutes, and 0.70 g sodium borohydride was added in small portions with stirring under ice cooling. The crystals which separated out were collected by filtration, washed with water and methanol in that order and vacuum-dried, giving 3.55 g of α-[[[(2-acetamido-4-thiazolyl)methyl]amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 204°-206° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[CH:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([S:33]([NH:36][C:37]2[S:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])[CH:27]=1.N1C=CC=CC=1>C(Cl)Cl>[S:41]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:36][S:33]([C:28]1[CH:27]=[CH:26][C:31]([NH:32][C:15](=[O:17])[CH2:14][O:13][C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)=[CH:30][CH:29]=1)(=[O:35])=[O:34]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C(O)COc1ccnc2c(C(F)(F)F)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(COc1ccnc2c(C(F)(F)F)cccc12)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
(8-Trifluoromethylquinolin-4-yloxy)-acetic acid (0.50 g, 1.84 mmol) was suspended in 20 mL DCM with rapid stirring. At rt, oxalyl chloride (0.19 mL, 1.2 equiv) was added dropwise and stirring continued for 4 h. Solvent and excess oxalyl chloride were removed in vacuo, the white residue was re-suspended in DCM, and the mixture cooled to 0° C. N′-(2-thiazolyl)sulfanilamide (0.47 g, 1.0 equiv) was added followed by pyridine (0.30 mL, 2.0 equiv). The mixture was allowed to warm to rt overnight. The solid was collected and rinsed with fresh DCM. Further purification was effected by suspending the solid in 20 mL methanol, stirring vigorously for 4 h, and filtration. After drying under vacuum, white solid 0.65 g (69%) was obtained. 1H-NMR (DMSO-d6) 5.11 (s, 2H), 6.79 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.22 (d, J=4.8 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.85 (d, J=5.2 Hz, 1H); 13C-NMR (DMSO-d6) 68.0, 103.6, 108.8, 120.0, 122.0, 124.8 (q, J=270 Hz), 125.1, 125.4, 126.4 (q, J=33 Hz), 127.7, 127.8, 129.2, 137.7, 142.1, 145.6, 153.2, 161.2, 166.5, 169.4 LC/MS (10-99%) M/Z: M+1 obs=509.5; tR=3.13 min.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].O.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]=2)[C:15](=[O:16])[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:7]1)[CH3:27]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2cc(C3CCCCC3)ccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(C3CCCCC3)ccc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 32.7 g of 3 -carboethoxy-4-hydroxy-7-cyclohexyl-quinoline and 7.1 g of sodium hydride (50% strength in mineral oil) in 400 ml of absolute dimethylformamide is stirred for 45 minutes at room temperature with exclusion of water. In the course thereof, the temperature of the reaction mixture rises to 35°C and a homogeneous solution is produced. 39 g of ethyl iodide are added dropwise to this solution over the course of 10 minutes whilst stirring and the mixture is stirred for a further 21/2hours at 55°C. It is then cooled to room temperature and 500 ml of water are added slowly, whilst stirring. The resulting precipitate is filtered off, well washed with water and recrystallised from ethanol-ether. 1-Ethyl-3-carboethoxy-4-oxo-7-cyclohexyl-1,4 -dihydroquinoline, thus obtained, melts at 176°-178°C.