Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:25][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:24][CH2:23]3)=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:26][C:27]1([CH3:39])[NH:36][C:35]([CH3:38])([CH3:37])[CH2:34][C:29]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:28]1>C(O)(C)(C)C>[OH:1][CH:2]([CH2:25][N:36]1[C:35]([CH3:38])([CH3:37])[CH2:34][C:29]2([O:30][CH2:31][CH2:32][O:33]2)[CH2:28][C:27]1([CH3:39])[CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]([OH:24])[CH2:23][N:36]3[C:27]([CH3:39])([CH3:26])[CH2:28][C:29]4([O:30][CH2:31][CH2:32][O:33]4)[CH2:34][C:35]3([CH3:38])[CH3:37])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])=[CH:9][CH:10]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CC1(C)CC2(CC(C)(C)N1)OCCO2
Solvent: CC(C)(C)O
Product: CC(C)(c1ccc(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)cc1)c1ccc(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)cc1

Procedure:
To 50 ml of t-butanol were added 3.5 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane and 5.0 g of 7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane; the mixture was then reacted following the procedure described in Example 21 to give the desired Compound No. 126 in the form of a white powder having an Rf value of 0.38 on thin-layer chromatography on silica gel developed with a 20:2:1 by volume mixture of benzene, ethyl acetate and triethylamine.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[H-].[Na+].[CH3:9][C:10]([CH3:23])([O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19]Br)=[CH:15][CH:14]=1)[CH3:11]>CN(C=O)C>[CH3:23][C:10]([CH3:9])([O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][O:1][N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: On1cccn1
Reactant: CC(C)(C)Oc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(OCCOn2cccn2)cc1
Temperature: 70 °C
Yield: 92.6 %

Procedure:
A solution of 12.7 g (0.15 mol) of N-hydroxypyrazole in 20 ml of DMF was added dropwise to a suspension of 4.95 g (1.1 eq.) of NaH (80% dispersion in mineral oil) in 40 ml of DMF at RT, and the mixture was heated at 70° C. for 1 h. A solution of 40.95 g (0.15 mol) of 2-[4-(1,1-dimethylethoxy)phenoxy]ethyl bromide in 100 ml of DMF was added and the mixture was then heated at 125° C. for 15 h. The solvent was then stripped off in a rotary evaporator, the residue was taken up in ethyl acetate, and the solution was washed twice each with 5% strength NaOH solution and water. Drying and removal of the solvent under reduced pressured resulted in 38.4 g (93%) of the required compound as a pale oil which was employed without further purification in the next stage.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[CH:13]2[N:16](C)[CH:10]([CH2:11][CH2:12]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOC[CH2:20]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCOCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[NH:16][C:13]([CH3:20])([CH2:12][CH2:11]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Reactant: C1COCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC12CCC(CN(Cc3ccccc3)C1)N2
Reaction time: 18 h

Procedure:
To a solution of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione (28.3 g; 0.116 mol) in 200 ml of absolute dioxane LiAlH4 (7.6 g; 0.2 mol) was added and the mixture boiled under argon for 18 hours. Then a mixture of water (7.5 ml) and dioxane (40 ml) was added drop-wise to the reaction mixture. The suspension was mixed for 20 minutes and filtered trough a dense glass filter. The filtrate was evaporated and the residue was distilled on Büchi oven for distillation at 120° C. and 0.1 mbar. Yield 17.6 g (70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12](=[O:16])[O:13][CH2:14]Cl.[I-:17].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12](=[O:16])[O:13][CH2:14][I:17]
Reactant: [I-]
Reactant: N#Cc1cc(Br)c(OC(=O)OCCl)c(Br)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1cc(Br)c(OC(=O)OCI)c(Br)c1
Temperature: 30 °C
Yield: 160.1 %

Procedure:
A solution of carbonic acid chloromethyl ester 2,6-dibromo-4-cyanophenyl ester (10.0 g, 27.1 mmol) in 30 mL of acetone was added sodium iodide (8.12 g, 54.1 mmol) and heated to 30° C. for 3 h. The acetone was removed, and the resulting slurry was treated with ether. The resulting white precipitated solids were filtered off, and the filtrate was then concentrated to afford tannish solids which was recrystallized from ether/hexanes to afford white solids (20 g, 96%). 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.09 (s, 2H), 7.90 (s, 2H). Mp=103-105° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[C:18]#[N:19])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[N:34]([Si](C)(C)C)=[N+:35]=[N-:36].C([Sn](=O)CCCC)CCC>CN(C=O)C>[C:28]([N:12]1[C:11]2[CH:32]=[CH:33][C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:9][C:10]=2[N:14]=[C:13]1[C:15]1[CH:16]=[C:17]([C:18]2[N:34]=[N:35][NH:36][N:19]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)n1c(-c2cc(C#N)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Agent: CCCC[Sn](=O)CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2cc(-c3nn[nH]n3)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 100 °C
Yield: 9.1 %

Procedure:
To a solution of 3-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-benzonitrile (example 7) (100 mg, 0.23 mmol) in DMF (5 mL) are added azidotrimethylsilane (0.06 mL, 0.46 mmol) and dibutyltin oxide (175 mg, 0.69 mmol) at room temperature. The solution is heated up to 100° C. for 5 hours in a microwave reactor. The solution is cooled down and is extracted with Sat. NH4Cl (10 mL) and EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by preparative HPLC to afford the title compound (10 mg, 9%) LCMS (ESMS): m/z: 479.40 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:13][C:6]1[CH:5]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (4 g, 0.01 mmol), 4-Trifluoromethyl phenylboronic acid (2.6 g, 0.012 mol), Palladium Tetrakis(triphenylphosphine) (1.3 g, 0.001 mol), Cesium carbonate (13.1 g, 0.04 mol) in DMF/water mixture (100 ml/5 ml) was stirred overnight at 100° C. Upon completion of reaction, the precipitate were removed by filtration. The filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash Column Chromatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate in 57% yield. (2.7 g). 1H NMR (CDCl3): 7.69 (bs, 4H); 7.36 (s, 1H); 7.17 (s, 1H); 4.18 (q, 2H); 3.59 (s, 2H); 3.39 (d, 2H); 1.28 (t, 3H); 0.96 (m, 1H); 0.41 (m, 2H); 0.01 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](Cl)=[O:20])=[N:14][CH:13]=[CH:12]3)[CH:3]=1.N1C=CC=CC=1.[C:28]([C:32]1[CH:33]=[C:34]([NH2:45])[N:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:36]=1)([CH3:31])([CH3:30])[CH3:29].O>C(Cl)Cl>[C:28]([C:32]1[CH:33]=[C:34]([NH:45][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][C:4]4[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][N:14]=2)=[O:20])[N:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:36]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(Cl)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2nccc3cc(Oc4cc(Cl)ncn4)ccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
454.6 mg (1.42 mMol) 6-(6-Chloropyrimidin-4-yloxy)-isoquinoline-1-carbonyl chloride is dissolved in 10 ml CH2Cl2 and cooled to 0° C. At this temperature 0.46 ml (5.9 mMol) pyridine are added followed by 418.0 mg (1.7 mMol) 5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine (Step 19.1). The reaction mixture is then allowed to warm to rt and stirred at ambient temperature for 1 h. It is worked up by addition of H2O and CH2Cl2. The organic layer is separated washed with brine and dried. After evaporation of the solvents the crude product is purified by chromatography (combi-flash: 40 g column, hexanes/EtOAc, gradient 0-50% EtOAc) to give the title compound as a yellow solid: m.p.: 156° C.; MS.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[OH:22])=S)=[CH:5][CH:4]=1)[CH3:2]>C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:22][C:14]3[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NC(=S)Nc2cc([N+](=O)[O-])ccc2O)cc1
Solvent: CC#N
Product: CCc1ccc(Nc2nc3cc([N+](=O)[O-])ccc3o2)cc1
Temperature: 0 °C

Procedure:
In an ice bath under nitrogen gas, 15 mL of acetonitrile was slowly added to KO2 (12.05 mmol, 5 eq) with stirring. Then, the compound (a) synthesized in Example 1 (2.41 mmol, 1 eq) in 20 mL of acetonitrile was slowly added to said solution containing KO2. The mixture was reacted at room temperature for 16 hours, and then the reaction solution was diluted with 30 mL of ice water. This solution was extracted with dichloromethane, and washed two times with saturated aqueous NaCl solution. After drying with anhydrous MgSO4, the precipitate obtained by removing the solvent under reduced pressure was filtered under reduced pressure with EtOAc:hexane=1:10 (V/V) to yield the title compound (b). Yellow powder (88%), mp 172-173° C.; 1H NMR (Acetone-d6, 400 MHz) δ 9.805 (s, 1H), 8.229 (s, 1H), 8.109 (d, J=8.8 Hz, 1H), 7.764 (d, J=8.4 Hz, 2H), 7.615 (d, J=9.2 Hz, 1H), 7.278 (d, J=8.8 Hz, 2H), 2.651 (q, J=7.6 Hz, 2H), 1.230 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:7]2.F[B-](F)(F)F.[H+].[CH3:31][Si](C=[N+]=[N-])(C)C.O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH3:31])=[N:7]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: O
Product: COCC(C)(C)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
7-Fluoro-2-(2-hydroxy-1,1-dimethylethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-99) (50 mg, 0.15 mmol) was dissolved in methylene chloride (0.5 ml), aqueous 42% tetrafluoroboric acid solution (32 μl, 0.15 mmol) was added, then with cooling with ice, trimethylsilyldiazomethane (2 M hexane solution, 77 μl, 0.15 mmol) was dropwise added, followed by stirring at 0° C. for 10 minutes, further trimethylsilyldiazomethane (2 M, hexane solution, 77 μl, 0.15 mmol) was dropwise added, followed by stirring at 0° C. for 1 hour. After the reaction, water was added followed by extraction with methylene and washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with n-hexane/ethyl acetate (5:1, v/v) to obtain the entitled compound (41.2 mg, 79%) as a colorless transparent oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[O-:18][CH2:19][CH3:20].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:18][CH2:19][CH3:20])=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(I)cc2c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(I)cc2c1OCC
Temperature: 100 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
To the suspension of 4-chloro-6-iodo-quinoline-3-carboxylic acid ethyl ester (example 1c, 1.5 g, 4.1 mmol) in anhydrous ethanol (25 mL) was added sodium ethoxide (0.7 g, 10.3 mol). The mixture was heated to 100° C. under a pressure tube and stirred for 4 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-4-ethoxy-quinoline-3-carboxylic acid ethyl ester (0.58 g, 38%) as a yellow solid. LC-MS m/e 372 (MH+)
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(N(CC)CC)C.[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)([CH3:14])([CH3:13])[CH3:12]>C(O)C>[OH:2][N:3]=[C:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16](=[O:26])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:23][CH:22]=1)[NH2:25]
Reactant: [NH3+]O
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 1.40 g (20.16 mmol, 2.2 eq.) of hydroxylammonium chloride and 2.81 ml (20.16 mmol, 2.2 eq.) of triethylamine were added to a solution of 2.0 g (9.16 mmol) of tert-butyl-(4-cyanophenyl)carbamate in 45 ml of ethanol. The reaction mixture was heated under reflux for 4 h and concentrated under reduced pressure. The residue was stirred with 100 ml of water at RT for 1 h. The reaction mixture was filtered and the filter cake was washed with water. The residue was dissolved in ethyl acetate. The aqueous phase that remained was separated off and the organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was used for the next step without purification. Yield: 2.10 g (purity 95%, 87% of theory)
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[NH4+:20]>>[CH2:15]([N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:20])[C:11]=2[N:12]=[CH:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: [NH4+]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [OH-]
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
A mixture of 4.0 g (0.0154 mole) of 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline (from Example 77) and 25 cc of concentrated ammonium hydroxide was placed in a metal bomb and heated at 150° C. for about 16 hours. After cooling the solid was separated by filtration, washed with water and recrystallized from ethanol to provide white crystals of 1-isobutyl-1H-imidazo [4,5-c]quinolin-4-amine, m.p. 288°-291° C. Recrystallization from N,N-dimethylformamide is preferred. Analysis: Calculated for C14H16N4 : % C, 70.0; H, 6.7; % H, 23.3; Found: % C, 69.3; % H, 6.6; % N, 23.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ncccc2Cl)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (25 mg, 0.14 mmol) and 4-(3-Chloro-2-pyridyl)-benzoic acid (D84) (50 mg, 0.17 mmol) as a brown solid. MS(ES): MH+ 362/360, M-H+ 360/358.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.O.[SH2:13].[Na].O.C(O)(=O)C>CN(C)C=O>[CH3:11][N:10]1[C:6]2[CH:5]=[CH:4][NH:3][C:2](=[S:13])[C:7]=2[N:8]=[CH:9]1
Reactant: S
Reactant: Cn1cnc2c(Cl)nccc21
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1cnc2c(=S)[nH]ccc21
Temperature: 5 °C
Yield: 94.5 %

Procedure:
4.00 g (23.9 mmol) of 4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine in 27 ml of dimethylformamide were stirred at 115° C. for 18 hours with 8.10 g (95.6 mmol) of sodium hydrogen sulphide hydrate. After cooling the mixture was treated with 110 ml of water, adjusted to pH 4 with acetic acid and stirred at 5° C. while cooling with ice for 15 min. The precipitate was filtered off and washed with water. After drying there were obtained 3.73 g (95%) of 1-methyl-1,5-dihydro-imidazo[4,5-c]pyridine-4-thione as white crystals with m.p. >300° C.
Reaction SMILES: NCCCC(NC1C=C2C(=CC=1)N=CN=C2NC1C=CC(OCC2C=CC=C(F)C=2)=C(Cl)C=1)=O.C(OC(=O)[NH:41][CH2:42][CH2:43][CH2:44][C:45](=[O:66])[NH:46][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[N:53]=[CH:52][N:51]=[C:50]2[NH:57][C:58]1[CH:63]=[CH:62][C:61]([F:64])=[C:60]([Cl:65])[CH:59]=1)(C)(C)C>>[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([NH:46][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[N:53]=[CH:52][N:51]=[C:50]2[NH:57][C:58]1[CH:63]=[CH:62][C:61]([F:64])=[C:60]([Cl:65])[CH:59]=1)=[O:66]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Yield: 95.1 %

Procedure:
The procedure of (87-1) of Example 87 was repeated except for using 0.08 g of the compound obtained in Example 96 instead of the compound obtained in Example 86 to obtain the title compound (0.06 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[CH:3]=1.[I:31]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[C:3]=1[I:31]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)cc3c2ncn3C)c(OC)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)c(I)c3c2ncn3C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
In a round bottom flask, tert-butyl 6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1D, 7.887 g, 19.08 mmol) was dissolved in MeCN (200 mL) and cooled to 0° C. N-Iodosuccinimide (4.51 g, 20.03 mmol) was dissolved in the remaining MeCN (50 mL) and added dropwise to the reaction mixture over 40 min. The reaction mixture was stirred at 0° C. for an additional 10 min and was quenched with 2 M sodium hydrogensulfite (125 mL). Stirring and temperature were maintained for 50 min. The mixture was transferred to a separatory funnel The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography using an Isco 120 g column eluting with 20-100% ethyl acetate/CH2Cl2 to provide tert-butyl 6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (8.436 g, 82% yield) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.O>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH:17]=[CH:16][C:14]=1[O:15][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:8]=[O:7]
Reactant: C[Si](C)(C)CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
Chloromethyltrimethylsilane (36.7 g, 0.3 mol) is added dropwise over 10 minutes to a mixture of vanillin (45.6 g, 0.3 mol) and potassium carbonate (41.4 g, 0.3 mol) in 300 ml of dry DMF maintained at 100° C., and while sparging with nitrogen. The mixture is left at 100° C. for 2 hours. The reaction mixture is filtered and the solvent is removed from the filtrate by distillation under vacuum. The final traces of DMF are removed via a stage at 60° C. under a vacuum of 2 mmHg. 70 g of a pink syrup, which crystallizes, are obtained. After recrystallization from an 80/20 ethanol/water mixture, 35.5 g (yield: 50%) of 3-methoxy-4-trimethylsilanylmethoxybenzaldehyde are obtained in the form of white crystals (m.p. 45° C.), which are used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]2=[O:22].[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][N:29]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:22])[C:6]([C:19]([OH:21])=[O:20])=[CH:7][N:8]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:3][C:2]=2[F:1])[CH2:28]1)[CH3:24]
Reactant: O=C(O)c1cn(CC(F)(F)F)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC(F)(F)F)c3c2F)C1
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To 0.76 g (2.33 mmol) of 6,7,8-trifluoro-1-(2,2,2-trifluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 7.0 ml of acetonitrile was added 0.355 g (2.33 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene in 5 ml of acetonitrile followed by 0.29 g (2.33 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for one hour and kept at room temperature overnight. The solids were collected and washed with ether to give 0.77 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, mp 222°-224° C.