Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][CH2:11]Br.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][C:18]=1[O:20][CH2:11][CH2:10][CH2:9][O:8][CH3:7]
Reactant: COCCCBr
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(Br)ccc1OC

Procedure:
66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Re (hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10](I)[CH2:11][CH3:12].C(N(CC)CC)C>O1CCCC1>[CH2:10]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][CH3:12]
Reactant: CCCI
Reactant: NCCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNCCc1ccccc1

Procedure:
1.2 ml (9.5 mmol) of phenylethylamine, 0.93 ml (9.5 mmol) of n-propyl-iodide, 5 ml of triethylamine and 5 ml of THF (tetrahydrofuran) were placed in a flask, and the reaction mixture was heated at reflux temperature of the reaction mixture for 3.5 hours and then cooled. A salt formed was filtered off, the solution was evaporated and a desired compound was purified by column chromatography on silica gel (silica gel 60, mobile phase: CHCl3:CH3OH=10:3). This yields 0.62 g (40%) of N-propyl-(β-phenylethyl)amine in the form of the oil (molecular weight: 163.264, formula: C11H17N).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11]2.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11]3)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)ccc2c1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4cc(C#N)ccc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 148 °C

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)naphthalene-2-carbonitrile (33 mg, 0.13 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (38 mg, 0.20 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 148° C. for 1.5 hours. LC showed formation of the title product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[N+:12]([C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17](=[O:20])[CH2:18]Br)([O-:14])=[O:13].Br>>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:18][C:17]([C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[N+:12]([O-:14])=[O:13])=[O:20])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: Br
Product: Cc1nc2n(CC(=O)c3ccccc3[N+](=O)[O-])cccc-2c1C

Procedure:
The title compound was prepared on a 5 mmol scale from 2,3-dimethylpyrrolo[2,3-b]pyridine and o-nitrophenacyl bromide in the same manner as described in example 27 yielding 1.3 g (66%) pure hydrobromide as a yellow solid. Reprocessing of the motherliquor gave additional material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][Mg]I)=[CH:5][CH:4]=1.Br[CH2:14][CH:15]=[CH2:16]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][CH2:16][CH:15]=[CH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC[Mg]I)cc1
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CCCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution containing 4-methoxyphenethyl magnesium iodide (prepared from 60 g, 0.23 mol of 4-methoxyphenethyl iodide and excess magnesium turnings) in anhydrous tetrahydrofuran (200 ml) at 0° C. under a nitrogen atmosphere was treated with 3-bromoprop-1-ene (46.7 g, 0.33 mol) and then stirred at room temperature for 14 hours. The resulting solution was washed with saturated aqueous ammonium chloride solution (3×100 ml) and the aqueous washings were back extracted with dichloromethane (3×100 ml). The tetrahydrofuran and dichloromethane solutions were combined, washed with aqueous sodium thiosulphate solution, dried (MgSO4) and the solvent was evaporated off under reduced pressure to yield an oil which was distilled to yield 5-(4-methoxyphenyl)pent-1-ene as a pale yellow oil (b.p. 65° C., 0.3 mm. Hg) having the following structural characteristics:
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:20])[C:13]=3[O:18]C)[C:8](=[O:21])[C:7]=2[CH:6]=[C:5]([C:22]([O:24]C)=[O:23])[CH:4]=1>Br>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:20])[C:13]=3[OH:18])[C:8](=[O:21])[C:7]=2[CH:6]=[C:5]([C:22]([OH:24])=[O:23])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2c(c1)C(=O)c1ccc(F)c(OC)c1C2=O
Agent: Br
Product: O=C(O)c1cc(O)c2c(c1)C(=O)c1ccc(F)c(O)c1C2=O

Procedure:
A suspension of methyl 4,5-dimethoxy-6-fluoro-9,10-dihydro-9,10-dioxoanthracene 2-carboxylate (306 mg) in 47% aqueous hydrobromic acid was stirred at reflux for 18 hours. The yellow suspension was cooled and concentrated to yield a yellow solid. This was triturated with water, filtered, washed well with water and dried to yield 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-6-fluoro-anthracene 2-carboxylic acid as a deep yellow solid, m.p. >275° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 4-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (3:1). 0.59 g (87%) of 1-benzyl-piperidin-4-yl 4-fluoro-benzoate was obtained as a greenish oil.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:11]1[C:15]([C:16]([F:19])([F:18])[F:17])=[C:14]([CH3:20])[C:13]([Br:21])=[C:12]1[C:22]([O:24]CC)=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C1COCC1.O>[CH2:4]([N:11]1[C:15]([C:16]([F:17])([F:18])[F:19])=[C:14]([CH3:20])[C:13]([Br:21])=[C:12]1[C:22]([OH:24])=[O:23])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1c(Br)c(C)c(C(F)(F)F)n1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Yield: 85.5 %

Procedure:
Lithium hydroxide monohydrate (8.89 g, 371.6 mmol) was added to the ice cold solution of ethyl 1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (29 g, 74.32 mmol) in THF (300 mL) and H2O (100 mL) warmed to RT and then heated at 100° C. for 14 h, cooled to RT and then diluted with H2O and acidify with 6N HCl (pH-2). The aqueous layer was extracted with EtOAc (2×350 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was triturated with diethyl ether to afford title compound (23 g, 85.48% yield, white color solid).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>>[CH2:6]([C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:1][CH:3]2[O:5][CH2:4]2)=[CH:19][CH:20]=1)=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cc1ccccc1)c1ccc(OCC2CO2)cc1

Procedure:
A 100 ml 3-neck round-bottom flask equipped with a magnetic stir bar, thermometer and reflux condenser was charged with 11.0 g epichlorohydrin, 5.0 g 4-hydroxyphenyl benzyl ketone, and 0.1 ml H20. The reactants were stirred on a hotplate. NaOH was then added, ~0.2 g per addition, up to a total of 0.95 g NaOH. The rate of NaOH addition was controlled to keep the reaction temperature below 100° C. At the end of the exothermic reaction, excess epichlorohydrin was removed by vacuum distillation with the flask temperature kept below 150° C. The residue was air-dried, then recrystallized twice from ethanol and redried. The yield was 2.8 g (44%), m.p. 81.0°-82.4° C. A 1H-NMR spectrum of this compound, with peak assignments, is provided in FIG. 1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(N=C=NC(C)C)(C)C.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>ClCCl>[F:29][C:30]1[C:35]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]
Reactant: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: O=C(CCCCCN1C(=O)c2ccccc2C1=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Yield: 101.3 %

Procedure:
Referring to scheme 12, compound 41a (13.3 g, 51 mmol) was dissolved in anhydrous dichloromethane (40 mL) and cooled to 0° C. under argon. To the solution were added diisopropyl carbodiimide (6.31 g, 7.7 mL, 50 mmol) and pentafluoro phenol (42, 9.2 g, 50 mmol). After overnight the reaction mixture was evaporated to dryness. To the residue ethyl acetate (100 mL) was added and the filtered to remove diisopropyl urea. The precipitate was washed with ethyl acetate (50 mL). The combined organic layer was washed with saturated sodium bicarbonate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Compound 43a (Rf=0.8 in 10% EtOAc/Hexane, 21.65 g, 92%) was obtained, which was directly used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]([O:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:32]=4)[N:27]([C:41](OC(C)(C)C)=O)[N:26]=3)[CH:22]=[N:21][CH:20]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:49]>C1COCC1.CCOC(C)=O>[CH:38]([O:37][C:35](=[O:36])[CH:34]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:41])[N:26]=[C:25]2[C:23]1[N:24]=[C:19]([O:18][C@H:12]2[CH2:11][N:10]([C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[CH2:17][CH2:16][C:13]32[CH2:14][CH2:15]3)[CH:20]=[N:21][CH:22]=1)[CH3:49])([CH3:39])[CH3:40]
Reactant: CC(C)OC(=O)Cc1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
NaH in mineral oil (7.72 mg, 0.193 mmol) was added to a solution of (R)-tert-butyl 3-(6-((6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-4-yl)oxy)pyrazin-2-yl)-5-(2-isopropoxy-2-oxoethyl)-1H-indazole-1-carboxylate (40 mg, 0.064 mmol) in THF (643 μl) at 0° C.; this was stirred for 15 min before iodomethane (12.04 μl, 0.193 mmol) was added. After 1 h at 0° C.; the mixture was warmed to RT and stirred for 1.5 h. The mixture was diluted with EtOAc (100 ml), added to a separatory funnel, and washed with saturated aqueous NH4Cl (2×75 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% MeOH/DCM to give (4R)-tert-butyl 4-((6-(5-(1-isopropoxy-1-oxopropan-2-yl)-1-methyl-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (30 mg, 0.055 mmol, 85% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 550.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=O)[CH:4]=[CH:3]1.[CH3:9][N:10]1[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[N:11]1>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:13]2[C:12]([CH3:16])=[N:11][N:10]([CH3:9])[C:14]=2[NH2:15])=[CH:4][CH2:3]1
Reactant: Cn1ccc(=O)cc1
Reactant: Cc1cc(N)n(C)n1
Product: Cc1nn(C)c(N)c1C1=CCN(C)CC1
Reaction time: 8 h

Procedure:
1-Methyl-4-pyridinone (1.1 mole) is added to 1,3-dimethyl-5-pyrazolamine (1 mole). The reaction mixture is kept at a temperature between 70° C. and 80° C. for a period of about 8 hours. After distillation under vacuum the residue is poured into water and neutralized with NaOH 10%. The compound of the title is recovered by filtration. M.p. 262°-265° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[S:5][C:6]([N:32]2[C:36]3[CH:37]=[CH:38][C:39]([C:41]4[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=4)=[CH:40][C:35]=3[N:34]=[CH:33]2)=[CH:7][C:8]=1[O:9][CH:10]([C:12]1[CH:13]=[C:14]([O:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH:15]=[CH:16][CH:17]=1)[CH3:11])=[O:3].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:46][N:44]1[CH:45]=[C:41]([C:39]2[CH:38]=[CH:37][C:36]3[N:32]([C:6]4[S:5][C:4]([C:2]([NH2:1])=[O:3])=[C:8]([O:9][CH:10]([C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]6[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]6)[CH:13]=5)[CH3:11])[CH:7]=4)[CH:33]=[N:34][C:35]=3[CH:40]=2)[CH:42]=[N:43]1
Reactant: CC(Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCNCC2)c1
Temperature: 0 °C
Yield: 68.3 %

Procedure:
(+/−)-1,1-Dimethylethyl 4-({3-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate (0.378 g, 0.588 mmol) was dissolved in 12 mL of DCM with stirring and cooled to 0° C. TFA (3.0 mL, 39 mmol) was added, and the reaction was stirred for 1.5 h. The reaction was pipeted onto 80 mL of aqueous 2N NaOH solution, rinsing with DCM. The mixture was extracted three times with 4:1 DCM/i-PrOH. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 0.218 g (68%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.17 (s, 1H), 7.93 (m, 1H), 7.90 (s, 1H), 7.75 (br s, 1H), 7.55 (dd, J=8.4, 1.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.26 (dd, J=8.1, 7.9 Hz, 1H), 7.11-7.06 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 6.84 (dd, J=8.1, 2.2 Hz, 1H), 5.69 (q, J=6.4 Hz, 1H), 4.34 (m, 1H), 3.84 (s, 3H), 2.90-2.81 (m, 2H), 2.53-2.43 (m, 2H), 1.88-1.76 (m, 2H), 1.67 (d, J=6.4 Hz, 3H), 1.42-1.26 (m, 2H). MS (APCI): 543 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH2:13]
Reactant: Cc1cccc(-c2ncc[nH]2)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2ncc[nH]2)c1N
Reaction time: 0.45 h

Procedure:
To a solution of the title compound of Step A (0.1 g, 0.49 mmol) in ethanol (20 mL) was added palladium hydroxide (20 wt % on carbon) (measured as the amount covering the tip of a small laboratory spatula). The flask was twice evacuated and flushed with nitrogen and then twice evacuated and flushed with hydrogen. The mixture was vigorously stirred under a balloon of hydrogen for 0.45 hour before being evacuated, exposed to air and filtered through a pad of Celite®. Concentration gave the title compound of Step B as an off white solid (82 mg).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:10]#[N:11])/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[S:19]([O:1]/[N:2]=[C:3](\[C:10]#[N:11])/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#C/C(=N\O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)O/N=C(\C#N)c2ccccc2)cc1
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of (Z)—N-hydroxybenzimidoyl cyanide (8 g, 55.1 mmol) and 4-methylbenzene-1-sulfonyl chloride (10.51 g, 55.1 mmol) in toluene (70 mL) was heated at reflux. After 2 h, the reaction was allowed to cool, diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield (Z)—N-(tosyloxy)benzimidoyl cyanide (10 g, 33.3 mmol, 60.4% yield) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([CH2:27][O:28][C:29]2[N:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][O:28][C:29]2[N:34]=[CH:33][C:32]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(OCC5CC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 6-(cyclopropylmethoxy)pyridine-3-boronic acid pinacol ester (ABCR, Karlsruhe, Germany, 36 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: tR 2.88 min (Method A); M+H=441 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.29-8.23 (m, 1H), 8.16-8.04 (m, 2H), 7.92-7.85 (m, 1H), 7.80-7.72 (m, 1H), 7.49-7.43 (m, 1H), 6.98-6.90 (m, 1H), 4.15-4.09 (m, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H), 1.31-1.17 (m, 1H), 0.62-0.48 (m, 2H), 0.40-0.30 (m, 2H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][NH2:12])[N:4]=1.[ClH:13].[N:14]#[C:15][NH2:16]>C(O)C>[ClH:13].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][NH:12][C:15]([NH2:16])=[NH:14])[N:4]=1
Reactant: N#CN
Reactant: COc1cc(OC)nc(NN)n1
Agent: Cl
Solvent: CCO
Product: COc1cc(OC)nc(NNC(=N)N)n1
Yield: 92 %

Procedure:
A mixture of 17.0 g (0.1 mol) of 4,6-dimethoxy-2-hydrazino-pyrimidine, 8.3 ml of concentrated hydrochloric acid, 4.2 g (0.1 mol) of cyanamide and 100 ml of ethanol is boiled to reflux for 18 hours. The mixture is then evaporated, the residue is crystallized using diethyl ether, and the crystalline product is isolated by filtering off with suction. 22.9 g (92% of theory) of (4,6-dimethoxy-pyrimidin-2-yl-amino)-guanidine hydrochloride of melting point 214° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.CN.[C:19]([BH3-])#[N:20].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:20][CH3:19])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCOCC1)c1cccc(Br)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCOCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of 1-(3-bromophenyl)-2-(4-morpholinyl)ethanone (7.8 g, 27.0 mmol) in THF (50 mL) was added methylamine (100 mL, 200 mmol, 2M solution in THF). After stirring for 15 min at room temperature, sodium cyanoborohydride (3.40 g, 54 mmol) was added followed by acetic acid (2 mL). The resultant mixture was stirred at RT for 5 days. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with 5% NaHCO3 (200 mL) and brine (200 mL). The organic layer was dried (MgSO4) and concentrated to give [1-(3-bromophenyl)-2-(4-morpholinyl)ethyl]methylamine as yellow oil (8.10 g, 100%) which solidified after standing at room temperature. MS (ESI): 299.6 [M+H]+.
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH2:13]([C:15]1[NH:16][C:17]([CH2:22][OH:23])=[C:18](CO)[N:19]=1)[CH3:14].C(O)C>O1CCOCC1>[CH2:13]([C:15]1[NH:16][C:17]([CH2:22][OH:23])=[C:18]([Cl:1])[N:19]=1)[CH3:14]
Reactant: CCc1nc(CO)c(CO)[nH]1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1nc(Cl)c(CO)[nH]1
Reaction time: 0.17 h

Procedure:
1.53 Grams (6.6 mmol) of trichloroisocyanuric acid was added little by little to a solution consisting of 2.03 g (13 mmol) of the 2-ethyl-4,5-bis(hydroxymethyl) imidazole, 100 ml of ethanol and 40 ml of 1,4-dioxane at room temperature with stirring over a period of about 10 minutes. The mixture was stirred at the same temperature for one hour, the solvent was distilled off under reduced pressure, the reaction product was extracted with ethanol, and the extract was evaporated to dryness under reduced pressure. The resulting solid product was then extracted with acetone, the extract was concentrated and was then subjected to the column chromatography (silica gel-acetone), and the effluent was further concentrated and was recrystallized from acetonitrile to obtain a 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.78 g (yield, 37.4%). The TLC and spectra were measured to be the same as those of Example 3.
Reaction SMILES: [F:1][C:2]1([O:19][CH3:20])[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)[CH2:3]1.CS(O[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:13]=[C:8]([C:4]2[CH2:3][C:2]([F:1])([O:19][CH3:20])[CH:7]=[CH:6][CH:5]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(C2=CC=CC(F)(OC)C2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Product: COC1(F)C=CC=C(c2cc(C(=O)O)c(=O)n(CCCc3ccccc3Cl)n2)C1
Yield: 56 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a pale yellow solid (yield: 56.0%).