Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[N:10]1[N:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22]Br)=[CH:18][CH:17]=2)[N:12]=[CH:13][CH:14]=1>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:22][CH2:21][O:20][C:19]1[CH:24]=[CH:25][C:16]([CH2:15][N:11]2[N:12]=[CH:13][CH:14]=[N:10]2)=[CH:17][CH:18]=1
Reactant: BrCCOc1ccc(Cn2nccn2)cc1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCCOc2ccc(Cn3nccn3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5 ml of anhydrous N,N-dimethylformamide and 51 mg of sodium hydride (60% oil dispersion) is added dropwise an anhydrous N,N-dimethylformamide (3 ml) solution of 121 mg of 2-hydroxypyridine under stirring over 10 minutes. After stirring at room temperature for 1 hour, the mixture is cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (2 ml) solution of 300 mg of 2-[4-(2-2H-1,2,3-triazolyl)methylphenoxy]ethyl bromide is added dropwise over 30 minutes. The mixture is then stirred at room temperature overnight. The reaction mixture is poured into 50 ml of ice water, which is extracted with twice with 30 ml of toluene. The organic layers are combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, which affords 4-(2-2H-1,2,3-triazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[C:23]([CH3:29])=[N:24][C:25](Cl)=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[C:23]([CH3:29])=[N:24][C:25]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)ccc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Product: Cc1nc(N2CCOCC2)ccc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Yield: 58 %

Procedure:
A solution of 4-[6-(6-chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (613 mg, 1.46 mmol) in 15 mL morpholine was reacted under microwave irradiation at 180° C. for 14 hours. Mixture was concentrated and purified by HPLC to give Compound A91 as a white solid (427 mg, 58%). 1H NMR (MeOH-d4, 400 MHz) δ 1.03-1.05 (d, 6H), 1.51-1.60 (m, 2H), 1.78-1.85 (m, 2H), 1.98 (s, 3H), 2.29 (s, 3H), 3.19-3.25 (m, 2H), 3.54-3.58 (m, 6H), 3.65-3.67 (m, 4H), 4.65-4.70 (m, 1H), 5.20-5.25 (m, 1H), 7.08-7.10 (d, 1H), 7.68-7.71 (d, 1H), 8.07 (s, 1H). Exact mass calculated for C24H34N6O4 470.26, found 471.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[C:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[N:25](COCC[Si](C)(C)C)[C:24]4[C:23](=[O:34])[N:22]([CH2:35][CH2:36][CH3:37])[C:21](=[O:38])[N:20]([CH2:39][CH2:40][CH3:41])[C:19]=4[N:18]=3)[CH:14]=[N:13]2)[CH2:4][CH2:3]1.Cl>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[C:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[NH:25][C:24]4[C:23](=[O:34])[N:22]([CH2:35][CH2:36][CH3:37])[C:21](=[O:38])[N:20]([CH2:39][CH2:40][CH3:41])[C:19]=4[N:18]=3)[CH:14]=[N:13]2)[CH2:4][CH2:3]1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#CCN4CCN(C)CC4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC#CCN4CCN(C)CC4)c3)nc2n(CCC)c1=O
Temperature: 85 °C
Yield: 51.6 %

Procedure:
A mixture of 8-{1-[4-(4-Methyl-piperazin-1-yl)-but-2-ynyl]-1H-pyrazol-4-yl}-1,3-dip ropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.105 g, 0.180 mmol), 2N HCl (2 ml), ethanol (4 ml) was heated at 85° C. for 2 hours. The mixture was cooled and solvent was evaporated. The residue was triturated with diethyl ether and purified by preparative TLC to obtain pure 8-{1-[4-(4-Methyl-piperazin-1-yl)-but-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (0.042 g, 52%).
Reaction SMILES: [OH:1][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][S:18]([O:1][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:8][CH:4]2[CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(O)CC2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(OS(C)(=O)=O)CC2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of the title compound from Step A above (550 mg, 2.4 mmol) and DMAP (296 mg) in DCM (15 mL) was added MsCl (189 μL) at 0° C. The mixture was stirred for 10 min at the same temperature and for an additional hour at RT. The mixture was quenched with ice water and extracted with ethyl acetate (2×50 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue oil was purified via prep-plate purification eluting with 50% ethyl acetate in hexane to afford the title compound (i-39) (555 mg, 75%). ESI-MS calculated for C13H23NO5S: Exact Mass: 305.13. Found 328.14 (MNa)+.
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[S:10][C:9]([CH:11]=[CH:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>CO>[CH3:1][O:15][C:14](=[O:16])[C:13](=[O:17])[CH:12]=[CH:11][C:9]1[S:10][C:6]([Br:5])=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)C(=O)C=Cc1ccc(Br)s1
Solvent: CO
Product: COC(=O)C(=O)C=Cc1ccc(Br)s1
Yield: 81.5 %

Procedure:
Acetyl chloride (36.4 mL, 515.7 mmol) was slowly added at 0° C. to methanol (200.0 mL) under stirring. A solution of 4-(5-bromo-thiophen-2-yl)-2-oxo-3-butenoic acid (39.6 g, 151.7 mmol) prepared in Step 1 in methanol (20.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 80° C. for 18 hours and then filtered to give 34.0 g of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][N:11]([CH:13]=O)[CH3:12]>>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cccnc1C#N
Product: CN(C)C=Cc1cccnc1C#N
Reaction time: 120 h
Yield: 56 %

Procedure:
A solution of 3-methyl-2-cyanopyridine (20.0 g, 0.17 m), DMF (200 mL) and DMF acetal (30 mL, 0.25 m) was heated at 120° with stirring under N2 for 5 days. Additional acetal was periodically added in 5 mL aliquots (total 45 mL, 0.38 m). The solution was then evaporated to dryness to give a crude oil which solidified on standing. The solid was crystallized from ligroin to yield 16.5 g (56%) of N,N-dimethyl-2-(2-cyano-3-pyridyl)ethenamine. An analytical sample was prepared by recrystallization from ligroin, mp 71.5°-72°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:8]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[NH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C:9]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(CC)NC(C2CCCC2)=C(C(=O)OC)C1c1ccc(F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(CC)nc(C2CCCC2)c(C(=O)OC)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 g (6.98 mmol) of 1,4-dihydro-2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid-3-methylester-5-ethylester is dissolved in 100 ml of absol. methylene chloride, and after addition of 1.6 g (6.98 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), the mixture is stirred for 1 hour at room temperature. After this, it is drawn off by suction over diatomaceous earth and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, d 3.5 cm, mobile solvent ethyl acetate/petroleum ether 5:95).
Reaction SMILES: [OH-:1].[K+].[C:3]([C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][CH2:7][N:8]([CH3:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:4]>O.C(O)C>[C:19]1([C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:6][CH2:7][N:8]([CH3:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]([NH2:4])=[O:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [OH-]
Reactant: CN(CCCc1ccccc1)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(CCCc1ccccc1)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 150 °C

Procedure:
A solution of potassium hydroxide (0.2 g) in water (10 ml) was added to a solution of 1-cyano-1,1-diphenyl-3-[N-methyl-N-(3-phenylprop-1-yl)amino]propane (0.22 g-see Preparation 23) in ethanol (10 ml) and the mixture was heated at 150° C. for 20 hours in a stainless steel pressure vessel then concentrated in vacuo. Water (30 ml) was added to the residue and the mixture was extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a viscous gum, yield, 0.11 g.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CCO.CO.[Cl:12][C:13]1[N:17]([C@@H:18]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C)[C@@H:24]([O:25]C(=O)C)[C@H:19]2[O:20]C(=O)C)[C:16]2[CH:36]=[C:37]([Cl:41])[C:38]([Cl:40])=[CH:39][C:15]=2[N:14]=1>O>[Cl:12][C:13]1[N:17]([C@@H:18]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:24]([OH:25])[C@H:19]2[OH:20])[C:16]2[CH:36]=[C:37]([Cl:41])[C:38]([Cl:40])=[CH:39][C:15]=2[N:14]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of Na2CO3 (23.32 g, 220 mmol) in 440 mL of H2O were added successively 2.0 L of EtOH, 2.0 L of MeOH, and 105.5 g (220 mmol) of 42. The reaction mixture was stirred at room temperature for 2 hr. ACOH (26.44 mL, 462 mmol) was added and stirring was continued at room temperature for 20 min. The reaction mixture was filtered. The solid product was triturated with H2O (800 mL, 20 min), MeOH (500 mL, 30 min), and then recrystallized from EtOH/MeOH (1 L/1 L) to give 52.4 g of 45 as white crystals {2 crops, the 2nd crop (2.8 g) was obtained by evaporation of the mother liquid and recrystallization of the residue two more times from EtOH/MeOH}. Recrystallization was accomplished by dissolving the crude product in a minimum amount of boiling EtOH, diluting it immediately with an equal amount of hot MeOH and allowing it to slowly cool. The filtrate was evaporated and the residue was triturated with H2O (500 mL, 20 min), MeOH (500 mL, 30 min), and then recrystallized twice from EtOH/MeOH to give an additional 15.34 g of 45 {2 crops, the 2nd crop (1.95 g) was obtained by evaporation of the mother liquid and recrystallization of the residue two more times from EtOH/MeOH}. The total of 45 was 67.74 g (87%). MP: 166-168° C.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31](O)=[O:32])[CH:30]=1)[NH:27][CH:26]=[CH:25]2.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:31]([C:29]2[CH:30]=[C:22]([Cl:21])[CH:23]=[C:24]3[C:28]=2[NH:27][CH:26]=[CH:25]3)=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNCCc2ccncc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccncc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Yield: 47.1 %

Procedure:
268 mg (1 mmol) of (4-tert-butyl-benzyl)-(2-pyridin-4-yl-ethyl)-amine, 196 mg (1 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 217 mg (1.1 mmol) of EDC.HCl were stirred over night at rt in 20 ml DCM. The product was purified by column chromatography (silica gel; EtOAc) to yield 210 mg (47%) product as a colorless oil. MS (ISP) 446.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([OH:15])[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH3:14])[CH3:13])[CH:2]=[CH2:3]>[Pd].CCCCCC>[CH2:1]([C:4]1([OH:15])[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH3:14])[CH3:13])[CH2:2][CH3:3]
Reactant: C=CCC1(O)C(C)(C)CCCCC1(C)C
Agent: [Pd]
Solvent: CCCCCC
Product: CCCC1(O)C(C)(C)CCCCC1(C)C
Temperature: 50 °C
Yield: 62.3 %

Procedure:
1-Allyl-2,2,7,7-tetramethylcycloheptan-1-ol (15.00 g, 0.09 moles), 5 wt % Pd/C (1.00g, 0.33 wt % Pd) and n-hexane (20 ml) were added to an autoclave. The air in the autoclave was replaced by nitrogen, followed by applying to a H2 pressure of 50 atm and heating the autoclave to 50° C. under stirring. The reaction was determined as completed at the time when the gas absorption was stopped. It required about 2 hours in this case. The autoclave was cooled down to room temperature and returned to a normal pressure, after which the content was withdrawn. The content was concentrated and subjected to fractionation to obtain 11.90 g (yield 77.6%) of the captioned compound. This compound was a colorless transparent liquid having a woody, earthy and patchuli oil-like odor.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(F)nc1I
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(F)nc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 5 h
Yield: 5.6 %

Procedure:
6-Fluoro-2-iodo-pyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (56 mg), and 4-dimethylaminopyridine (31 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (2 mg, yield 6%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11](N)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[OH:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].N([O-])=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([O:23][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CSc1cccc(-c2nc(N)cc3cccnc23)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 8-(3-methylsulfanyl-phenyl)-[1,7]naphthyridin-6-ylamine (2.05 g, 7.68 mmol) in DMF (30 ml) at 0° C. is added triflic acid (20 ml) slowly. Sodium nitrite (1.06 g) is then added slowly over 15 minutes and the reaction mixture allowed to warm to room temperature. After stirring for 23 hours the reaction is complete by HPLC. The mixture is then diluted with ethyl acetate and washed with water, 2 N sodium carbonate and brine. The organic layer is dried over magnesium sulfate and concentrated. The product is purified by silica gel chromatography, eluting with 30% ethyl acetate in isohexane. The product is obtained as an amorphous solid. MS (ES+) 400.9948
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[CH3:17][N:18]([CH3:32])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([NH2:31])[C:26]([NH2:30])=[CH:27][C:28]=1[F:29]>CO>[F:29][C:28]1[C:23]([O:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:17])[CH3:32])=[CH:24][C:25]2[NH:31][C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:6]=3)=[N:30][C:26]=2[CH:27]=1
Reactant: CN(C)CCCOc1cc(N)c(N)cc1F
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])nc2cc1F
Temperature: 22 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
3.4 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde are added to a solution of 3.5 g of 4-(3-dimethylaminopropoxy)-5-fluorobenzene-1,2-diamine in 150 mL of methanol. The reaction medium is stirred at 22° C. for 18 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-330 cartridge. The elution is carried out in dichloromethane with 10% of methanol. 2.3 g of (3-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yloxy}-propyl)dimethylamine are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.50 to 2.23 (m, 8H); 2.80 (s, 6H); 3.23 (m, 2H); 3.68 (m, 1H); 3.98 (m, 1H); 4.17 (t, J=6.0 Hz, 2H); 5.58 (dd, J=2.5 and 9.5 Hz, 1H); 7.34 (d, J=8.0 Hz, 1H); 7.49 (d, J=11.0 Hz, 1H) 9.11 (s, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][C:6]([NH2:11])([CH3:10])[CH2:5]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([S:27][CH3:28])[C:15]=1[C:16](Cl)=[O:17]>>[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][C:6]([NH:11][C:16](=[O:17])[C:15]2[C:19]([S:27][CH3:28])=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:14]=2[O:13][CH3:12])([CH3:10])[CH2:5]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: CN1CCCC(C)(N)C1
Agent: Cl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(C)CCCN(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-1,3-dimethyl-piperidin-3-ylamine dihydrochloride (Example A.13) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6). MS (m/e): 377.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[N:5]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:23])([CH3:22])[CH2:14]2)=[O:12])[N:3]=1.C(#N)C.[I-].[K+].C[Si](C)(C)Cl>O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:22])([CH3:23])[CH2:14]2)=[O:12])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: COc1cc(Cl)nc(CC(=O)N2CC(C)(C)c3ccccc32)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CN(C(=O)Cc2nc(Cl)cc(=O)[nH]2)c2ccccc21
Yield: 70 %

Procedure:
106 mg of 2-(4-chloro-6-methoxypyrimidin-2-yl)-1-(3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone and 4 ml of acetonitrile are placed in a reactor suitable for microwave irradiation and then 0.45 g of potassium iodide and 347 μl of trimethylchlorosilane are added. The orangey-colored heterogeneous solution is stirred and irradiated at 100° C. for 1 hour. The resulting product is taken up in 25 ml of water and stirred, extraction is carried out with 3 times approximately 25 ml of EtOAc, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtered through a VF filter and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel, elution being carried out with methanol/dichloromethane (2.5/97.5). The fractions containing the expected compound are combined and evaporated under reduced pressure. 6-Chloro-2-[2-(3,3-dimethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one is isolated and characterized: 0.20 g in the form of a yellow solid; yield 70% (LCMS ES+ retention time Tr (min)=1.19; [M+H]+: m/z 318).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22](=[O:27])[CH:23]([NH2:26])[CH2:24][OH:25].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16]([NH:26][C@H:23]([C:22]([O:21][CH3:20])=[O:27])[CH2:24][OH:25])(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: COC(=O)C(N)CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in a mixture of DCM/DMF (1/1, 10 ml). 2-Amino-3-hydroxy-propionic acid methyl ester (0.2 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in ACN, affording after filtration, Compound (15) as a white powder (54 mg; 39%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(Nc2c(Cl)c(F)nc(F)c2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
3,5-Dichloro-2,4,6-trifluoro-pyridine (136) (1 g, 4.95 mmol) and N-(4-Amino-phenyl)-acetamide (137) (0.743 g, 4.95 mmol) were dissolved in NMP (12 mL), iPr2EtN (9.9 mmol) was added and the mixture was shaken at room temperature for 5 hours. TLC and LC-MS indicated complete reaction at this point. The mixture was diluted with EtOAc (50 mL), washed with NaHCO3 (aqueous sat., 50 mL) and passed through a plug of silica gel to remove any baseline impurities. Upon concentration, the desired product (138) precipitated as a beige/pink powder that was collected by filtration under reduced pressure followed by drying under high vacuum for 16 h (1.43 g, 2.88 mmol, 58% yield). LC-MS (ESI): (exact mass: 331.01) m/e=332.1 [M+1]+ (100%), 664.9 [2M+1]+ (30%), 996.2 [3M+1]+ (10%). 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 6.99 (d, 2H, J=7.2 Hz), 7.49 (d, 2H, J=6.8 Hz), 9.00 (s, 1H), 9.89 (s, 1H). 19F NMR (400 MHz, DMSO-d6): δ−76.55 (TFA reference), −75.89 (s, 2F).
Reaction SMILES: CO[C:3]([CH3:5])=[CH2:4].[C:6]([O:10][C:11]([NH:13][C@H:14]([CH2:21][OH:22])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])([CH3:9])([CH3:8])[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[C@@H:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:21][O:22][C:3]1([CH3:5])[CH3:4])=[O:12])([CH3:7])([CH3:9])[CH3:8]
Reactant: C=C(C)OC
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
120 ml of isopropenyl methyl ether are added to a solution of 159.5 g of methyl 4(S)-tert-butoxycarbonylamino-5-hydroxyvalerate and 3 g of p-toluenesulfonic acid hydrate in 500 ml of methylene chloride at 0° C. The reaction mixture is stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction solution is washed with 100 ml of saturated sodium bicarbonate solution and evaporated. The title compound is obtained by FC (800 g of silica gel, mobile phase E): [α]D =+20.5 (c=0.8 in CHCl3); Rf (D)=0.24; MS: (M)+ =287.