Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([N:10]([C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:11](=[O:26])[NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]=2[OH:25])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:36]C[CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([O-:42])=[O:41].[CH3:45]N(C)C=O>>[ClH:36].[C:40]([O:42][CH2:45][O:25][C:14]1[C:15]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[NH:12][C:11]([N:10]([CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[O:26])(=[O:41])[C:39]([CH3:44])([CH3:43])[CH3:38]
Reactant: CN(C)C=O
Reactant: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(OCOC(=O)C(C)(C)C)c(C(C)(C)C)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, 0.407 g of 62.4% sodium hydride was added to a mixture of 4.00 g of 2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol, 1.9 ml of chloromethylpivalate and 40 ml of dimethylformamide (DMF), and the temperature of the mixture was gradually raised to room temperature. The mixture was further stirred at room temperature for 2 hours. A saturated saline solution was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) and precipitated crystals were recrystallized from an isopropyl ether solution. The obtained crystals were dissolved in 10 ml of dichloromethane, and 5 ml of 4N hydrogen chloridedioxane solution was added to the solution. The mixture was evaporated to dryness under reduced pressure. The residue was crystallized from a diethyl ether solution to give 1.65 g of O-pivaloyloxymethyl-2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol hydrochloride (melting point: 114°-118° C. (decomposed)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].ClCCl>CS(C)=O>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCN(C(=O)OC(C)(C)C)CC5)nccc34)no2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCNCC5)nccc34)no2)cc1Cl
Yield: 64.5 %

Procedure:
1,1-Dimethylethyl 4-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]-1-piperazinecarboxylate (D15; 24 mg, 0.044 mmol), trifluoroacetic acid (1 ml, 13.0 mmol) and dichloromethane (1 ml) were stirred at room temperature for 1 h. The samples were dissolved in DMSO (1 ml) and purified by Mass Directed Preparative HPLC (supelcosil ABZ+Plus alkylamide phase column), eluting with solvents A/B (A: water+0.1% formic acid, B: MeCN:Water 95:5+0.05% formic acid). The solvent was evaporated in vacuo to give the title compound as a white solid (16 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:48][NH:49][C:50]([NH2:52])=[S:51]>C1COCC1.CN(C=O)C>[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:48][NH:49][C:50](=[S:51])[NH2:52])=[O:33])=[CH:35][CH:36]=2)=[CH:13][CH:12]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: NNC(N)=S
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)O)cc2)Cc2ccc(C#N)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)NNC(N)=S)cc2)Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.9 mg (0.05 mmol) of oxalyl chloride are slowly added dropwise to a solution of 12.7 mg (0.02 mmol) of 4-[(4E)-5-{2-[(4-tert-butylbenzyl)oxy]phenyl}-3-(4-cyanobenzyl)pent-4-en-1-yl]-benzoic acid from Example 100A in 0.2 ml of dry THF with 1 drop of DMF while cooling in ice. The reaction mixture is stirred at RT for 30 minutes and then concentrated in vacuo, and the residue is coevaporated twice with dichloromethane and then taken up in 0.2 ml of THF. This solution is added dropwise to a solution of 4.2 mg (0.05 mmol) of thiosemicarbazide in 0.25 ml of THF at 0° C. The mixture is stirred at RT for 1 hour and then concentrated, and the residue is reacted without further purification in the next stage.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[SH:72][CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76].C(N(C(C)C)C(C)C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:12]2[N:13]=[C:9]([NH:8][C:5]3[N:6]=[CH:7][C:2]([S:72][CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76])=[CH:3][C:4]=3[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:10][CH:11]=2)[CH2:15][CH2:16]1)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 95 °C

Procedure:
A mixture of 1-(4-(2-(5-Bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone (40.0 g, 84.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (2.44 g, 4.22 mmol), Pd2dba3 (1.93 g, 2.11 mmol), methyl 3-mercaptopropanoate (18.7 mL, 169 mmol), N-ethyl-N-isopropylpropan-2-amine (15.4 mL, 88.7 mmol), and dioxane (250 mL) was heated to 95° C. under nitrogen for 2 hours. The reaction was cooled to ambient temperature and the resultant solids were filtered through celite washing with CH2Cl2. The filtrate was concentrated to a yellow oil and purified on silica eluting with 3%-5% MeOH/EtOAc to afford methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate as a yellow oil.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[CH2:30]1[C@H:33]([C:34]([OH:36])=[O:35])[NH:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:32]1[CH2:31][CH2:30][C@@H:33]1[C:34]([OH:36])=[O:35]
Reactant: O=C(O)[C@H]1CCN1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC[C@@H]4C(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and D-Azetidine-2-carboxylic acid (20.03 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 16 mg of (2R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) azetidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (2H, dd, J=8.57, 2.86 Hz), 7.82 (2H, dd, J=8.02, 1.65 Hz), 7.58-7.70 (5H, m), 5.16-5.29 (1H, m), 4.89-5.10 (1H, m), 3.84-4.05 (2H, m), 3.18-3.41 (2H, m), 2.96-3.03 (2H, m), 2.51-2.61 (1H, m), 1.63-1.76 (2H, m), 0.97 (3H, t, K=7.25 Hz). MS (m+1)=475. HPLC Peak RT=3.5 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].CCN(CC)CC.[CH3:20][C:21](OC(C)=O)=[O:22]>CCOCC.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:21](=[O:22])[CH3:20])=[CH:6][C:5]=1[OH:11]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1ccc(OC(C)=O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.4 %

Procedure:
2,4-Dihydroxy-benzoic acid methyl ester (11.76 g, 70 mmol) was dissolved in Et2O (175 mL). Then Et3N (10.78 mL, 77 mmol), Ac2O (7.28 mL, 77 mmol), and DMAP (catalytic amount) were added. The reaction solution was then stirred for one hour at room temperature. Then the reaction solution was concentrated by rotary evaporation and the resulting residue was purified with a silica gel column and dichloromethane as eluent. Obtained 3.44 g 4-Acetoxy-2-hydroxy-benzoic acid methyl ester in 23% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:28]2[CH2:29][CH2:30][N:26]([CH3:25])[C:27]2=[O:31])[CH:7]=1)[CH3:2]
Reactant: CN1CCNC1=O
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCN(C)C2=O)c1

Procedure:
Prepared according to the procedure described in Example 116, Step 1, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 1-methyl-2-imidazolidinone.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([C:8]#[C:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:1]([C:7]#[C:8][C:11]4[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=4)[CH:2]=3)[CH:14]=[CH:13][C:12]=2[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC
Reactant: C#Cc1ccccc1
Solvent: ClCCl
Product: C(#Cc1ccc(-c2ccc(C#Cc3ccccc3)c(C#Cc3ccccc3)c2)cc1C#Cc1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
Analysis of the crude reaction mixture by LC at this point indicated a significant amount of unreacted starting material and products of intermediate conversion. An additional 10 g of phenylacetylene and 1 g of catalyst were added and the reaction mixture was heated at 85° C. for one hour. At this time, the LC indicated conversion was complete. The cooled reaction mixture was diluted with 500 mL of CH2Cl2 and washed with three 1-L portions of 10 percent HCl. The CH2Cl2 solution was isolated and evaporated to provide a crude solid product which was suspended in hexane. The solid was collected by filtration and purified by washing excessively with hot CCL4. This wash removeddiscoloration and many of the by-products, but it was not sufficiently effective at removing the residual Pd (II) catalyst from the monomer. The monomer was further purified by chromatography over neutral alumina using tetrahydrofuran as an eluent. The resulting monomer was isolated (32.0 g, 58 percent yield) as a light yellow solid with an m.p. of 172° C. to 174° C. with properties:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C([O-])(=O)C.[Na+].Cl(O)(=O)(=O)=O.CN(C)[CH:19]=[C:20]([CH3:33])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=O>C(O)(=O)C>[CH3:33][C:20]1[CH:19]=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[C:21]=1[C:23]1[CH:24]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cc[nH]n1
Reactant: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: Cc1cnc2ccnn2c1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 1.84 g, of 3-aminopyrazole, 50 ml. of glacial acetic acid, 1.80 g. of sodium acetate and 7.90 g. of 3-dimethylamino-2-methyl-3'-(trifluoromethyl)acrylophenone perchlorate is refluxed for 6 hours and then evaporated. The residue is reacted as described in Example 1, giving the desired product, m.p. 168°-169° C.
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:26](C4CCCCO4)[N:25]=[CH:24][C:13]=3[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16]=2[CH:17]=1.[O-][N+]1C=CC=CC=1C1C=CC2C3NN(C4CCCCO4)CC=3C(=O)N(CC(F)(F)F)C=2C=1.[ClH:65].O>O1CCOCC1>[ClH:65].[O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[NH:26][N:25]=[CH:24][C:13]=3[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:20])[F:21])[C:16]=2[CH:17]=1
Reactant: O=c1c2cnn(C3CCCCO3)c2c2ccc(-c3cccc[n+]3[O-])cc2n1CC(F)(F)F
Agent: Cl
Agent: O=c1c2c(c3ccc(-c4cccc[n+]4[O-])cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Solvent: O
Solvent: C1COCCO1
Product: O=c1c2cn[nH]c2c2ccc(-c3cccc[n+]3[O-])cc2n1CC(F)(F)F
Yield: 99 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. by treating 7-(1-oxidopyrid-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(1-oxidopyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with 4M HCl in dioxane, in the form of a white powder (hydrochloride, 1 H2O; yield 99%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31].[OH-].[Na+]>CO>[CH2:29]([O:28][CH2:27][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:31])[C:11]=2[N:12]=1)[CH3:30]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccccc2)no1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccccc2)no1

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[(3-phenylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.48 g, 3.53 mmol) was treated with a solution of 7 M ammonia in methanol (25 mL) at 150° C. for 17 hours. The volatiles were removed under reduced pressure and the resulting oil was diluted with dichloromethane and 1 M hydrochloric acid. A white solid formed and 50% aqueous sodium hydroxide was added to dissolve the solid. The aqueous layer was separated and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil. Upon treatment of the oil with diethyl ether, a solid formed. The solid was purified by flash chromatography (silica gel, eluting with a mixture of 95% dichloromethane and 5% of a solution of 80% chloroform, 18% methanol, and 2% NH4OH (CMA)) followed by several recrystallizations from acetonitrile to provide 2-(ethoxymethyl)-1-[(3-phenylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.505 g) as a white powder, mp 215.0-216.0° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH2:5][C:4]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:3]1.[OH-:14].[Na+].Cl>>[C:4]1([CH2:3][C:2]([OH:1])=[O:14])([CH2:5][C:6]([NH2:7])=[O:8])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CC2(CCCCC2)CC(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(=O)CC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
9 g of 2,4-dioxo-3-azaspiro[5,5]undecane and 30 g of 10% NaOH are placed in a 250 ml flask equipped with mechanical agitator, thermometer and condenser. The mixture is heated under reflux for 1 hour, cooled to 25° C. and acidified with 36% HCl to pH 5. The precipitate formed is filtered off, washed with water and dried under vacuum. 6.4 g of cyclohexanediacetic acid monoamide are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][N:10]1[CH2:27][C:28]([N:30]([CH:41]1[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]1)[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl>[O:8]=[C:9]1[C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][N:10]1[CH2:27][C:28]([N:30]([CH:41]1[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]1)[C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3.0 mL, 39 mmol) was added to a solution of the product of Example 166C (279 mg, 0.439 mmol) in CH2Cl2 (3 mL), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then cooled to 0° C., diluted with CH2Cl2 (25 mL) and quenched by slow addition of 2 N aqueous NaOH solution (25 mL). The mixture was separated and the aqueous phase was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Ether was added to the residue which caused a solid to form, which was collected by vacuum filtration and washed with minimal ether and air-dried. The material was then chromatographed on silica gel (Analogix® Intelliflash™ 280; SF10-8 g column; 10% methanol/CH2Cl2) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.68 (d, J=8.3, 2H), 7.36 (d, J=8.2, 2H), 7.32-7.15 (m, 10H), 4.85-4.69 (m, 1H), 3.68 (s, 2H), 3.45 (t, J=6.4, 2H), 3.17-3.06 (m, 2H), 2.76 (td, J=12.4, 1.9, 2H), 2.66-2.56 (m, 2H), 2.00-1.65 (m, 5H), 1.40-1.21 (m, 2H); MS (DCI+) m/z 536 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.[H-].[Na+].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[O:9][C:17](=[O:18])[NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc(O)c(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc2oc(=O)[nH]c2n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,4-Diamino-pyrimidin-5-ol (500 mg, 3.97 mmol) [prepared according to the method of Hull. J. Chem. Soc. 1956, 2033-2035] was suspended in DMF (10 mL). To this was added consecutively NaH (86.7 mg, 3.77 mmol) and CDI (707 mg, 4.36 mmol), and the reaction mixture was heated with vigorous stirring at 60° C. for 3 h. The mixture was cooled to ambient temperature, and then quenched with water (25 mL). The solvent and water were removed via rotary evaporation, and the residue was then triturated in water (5 mL). The solid was then collected by filtration and dried, affording 230 mg (38%): 1H NMR (400 MHz, d6-DMSO) δ 11.90 (br s, 1H), 7.72 (br s, 1H), 6.72 (s, 2H); Analysis calc'd for C5H4N4O2.0.2; H2O: C, 38.56; H, 2.85; N, 35.98. Found: C, 39.01; H, 2.71; N, 35.58; [M+H]+ m/z 153.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)C#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].CN(C=[O:31])C>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)=[O:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(Br)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Br)c2)n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred solution of (3-bromo-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-acetonitrile (40 g, 0.1 M) in anhydrous DMF (300 mL) in a water bath under an atmosphere of nitrogen, was added 60% sodium hydride (4.92 g, 0.12 M) in portions. After 30 min, oxygen gas was bubbled into the reaction mixture for 2 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 34.6 g (89%) of a white solid. m.p. 122-123° C.; 1H NMR (200 MHz, CDCl3) δ 1.17 (6H, d, J=7.1 Hz), 2.36 (3H, s), 2.77 (1H, m), 3.92 (3H, s), 4.05 (3H, s), 7.54-7.56 (2H, m), 7.75 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]([OH:14])=[O:13].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.Br>C(#N)C>[Br-:10].[C:12]([CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[CH:4]1)([OH:14])=[O:13]
Reactant: O=C(O)CBr
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1ccc2ccccc2c1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)Cn1c[n+](CCc2ccc3ccccc3c2)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 2-bromoacetic acid (2.15 g, 15.46 mmol) was added to the solution and refluxed for 2.5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 2-(2-bromoethyl)naphthalene (1.73 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=[C:14]2[C:22]2[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:9][CH:8]=1.C([Si]([O:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][CH:64]2[CH2:66][O:65]2)=[CH:58][CH:57]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:32]([NH:31][C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:14]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][CH2:66][CH:64]([OH:65])[CH2:63][O:62][C:59]4[CH:60]=[CH:61][C:56]([OH:55])=[CH:57][CH:58]=4)=[CH:8][CH:9]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:23]=1)=[O:30])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)Nc1cccc(-c2nc3cccnc3n2-c2ccc(CCN)cc2)c1
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: CO
Product: CCCCCCNC(=O)Nc1cccc(-c2nc3cccnc3n2-c2ccc(CCNCC(O)COc3ccc(O)cc3)cc2)c1
Yield: 40.8 %

Procedure:
N-(3-{3-[4-(2-aminoethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}phenyl)-N′-hexylurea formate (0.27 g, 0.539 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.217 g, 0.54 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.19 g, 0.22 mmol).