Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](F)[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: Cc1cc(C#N)c(Cl)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(Cl)c(Cl)c1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 2,3-dichloro-4-fluoro-5-methylbenzonitrile (1.02 g), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (776 mg), the title compound was obtained as a colorless solid (yield: 68 mg) by an operation similar to that in Example 3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:54][O:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.Br[C:67]1[CH:72]=[CH:71][C:70]([C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:69][CH:68]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:54][O:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]1[CH2:64][CH2:63][N:62]([C:67]2[CH:72]=[CH:71][C:70]([C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:69][CH:68]=2)[CH2:61][CH2:60]1
Reactant: COC(=O)CCC1CCNCC1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)CCC1CCN(c2ccc(C(C)(C)C)cc2)CC1
Reaction time: 0.42 h
Yield: 48.5 %

Procedure:
A mixture of palladium (II) acetate (63 mg; 0.28 mmol), (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (258 mg; 0.41 mmol) and cesium carbonate (1.30 g; 4.00 mmol) in dioxane (3 mL) is placed in an ultrasonic bath for 25 minutes. 3-Piperidin-4-yl-propionic acid methyl ester hydrochloride (415 mg, 2.0 mmol, prepared in accordance with Example 138) and 1-bromo-4-tert-butyl-benzene (426 mg; 2.00 mmol) are then added and the reaction mixture is stirred for 7 hours under reflux. The mixture is then diluted with ethyl acetate, filtered and the filtrate is concentrated under high vacuum. The obtained residue is purified by column chromatography on silica gel (hexanes/dichloromethane 50:50 v/v to 100) to afford the desired compound (295 mg; 0.97 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([C:22]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)[CH2:24][CH2:23]1)[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([C:22]3([C:19]4[N:3]5[N:4]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=6)[CH:6]=[N:7][C:2]5=[N:1][CH:20]=4)[CH2:24][CH2:23]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (160 mg, 0.70 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (200 mg, 0.83 mmol) in isopropyl alcohol (6 mL) was heated at 110° C. for 24 h. The mixture was adjusted to pH 9 by adding triethylamine and then the volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-60%) to afford the desired product (130 mg, 44%). LCMS: (M+H)=421.1.
Reaction SMILES: [F:1][C:2]([F:32])([C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[N+:33]([C:36]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:37]=1F)([O-:35])=[O:34].CN1C(=O)CCC1>C(N(CC)CC)C>[F:1][C:2]([F:32])([C:25]1[CH:26]=[C:27]([NH:31][C:37]2[CH:38]=[CH:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][C:36]=2[N+:33]([O-:35])=[O:34])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:17])([F:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Nc2cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
A mixture of 3-(perfluoro-n-octyl)benzenamine (2.04 g), 2,4-dinitrofluorobenzene (0.78 g), NMP (8 mL) and triethylamine (0.85 mL) was heated to 70° C. for 16 hr. Extraction and recrystallization from hexane-ethyl acetate gave N-[3-(perfluorooctyl)phenyl]-2,4-dinitrobenzenamine (2.25 g, mp 124.5-125° C.).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])[CH:8]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([B:22]([OH:27])[OH:23])=[CH:8][C:9]=1[O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)C(F)(F)COc1cc(Br)ccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)c(OCC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A 1.5 M solution of n-butyllithium in tetrahydrofuran (0.99 mL) was added to a solution of 4-bromo-1-chloro-2-(2,2,3,3-tetrafluoro-propoxy)-benzene (434 mg, 1.35 mmol) and triisopropyl borate (382 mg, 2.03 mmol) in anhydrous tetrahydrofuran (2.0 mL) at −78° C., and the mixture was stirred for 10 minutes. The reaction mixture was warmed to room temperature and stirred for 30 minutes. 6 N aqueous hydrochloric acid was then added to the reaction mixture, and the reaction was terminated, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was treated with a mixed solution of dichloromethane and hexane to give 4-chloro-3-(2,2,3,3-tetrafluoro-propoxy)-phenylboronic acid as a white solid (246 mg, 64%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10](OCC)=[O:11])=[N:5]1.Cl.[OH-].[NH4+:19]>>[F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10](=[O:11])[NH2:19])=[N:5]1
Reactant: [NH4+]
Reactant: CCOC(=O)C1=NN(CC(F)(F)F)C(=O)C1
Agent: Cl
Agent: [OH-]
Product: NC(=O)C1=NN(CC(F)(F)F)C(=O)C1
Reaction time: 120 h

Procedure:
0.71 Mole (169 g) of 1-(2',2',2'-trifluoroethyl)-3-carbethoxy-2-pyrazolin-5-one were stirred for 8 hours in concentrated ammonium hydroxide and left standing afterwards for 5 days in a sealed recipient at room temperature. After filtration the filtrate obtained was poured out on ice and acidified with hydrochloric acid. As soon as the product had crystallized out completely, it was filtered and washed with water.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].FC(S(O[Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])(=O)=O)(F)F>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 10 °C
Reaction time: 0.2 h
Yield: 949.6 %

Procedure:
To a stirred solution of 6-bromo-1H-indole (2.04 g, 1.04 mmol) in THF under nitrogen at 0° C. was added sodium hydride (60%, 1.25 g 31.2 mmol), portionwise over 0.2 h. The mixture was stirred at 0-20° C. for 1 h then was cooled in an ice-MeOH bath, whereupon triisopropylsilyl trifluoromethylsulfonate (3.83 g, 12.5 mmol) was added dropwise over 3 h. The resulting mixture was stirred at 0° C. for 1 h then at 20° C. for 72 h. The mixture was quenched (caution,) with a mixture of THF (30 mL) and water (1 mL) with external ice cooling and the resulting clear solution was partitioned between water (100 mL) and DCM (3×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (3.48 g) as a colourless oil. 1H NMR (CDCl3): 7.66-7.64 (1H, m), 7.50 (1H, d), 7.25-7.21 (2H, m), 6.61 (1H, d), 1.76-1.64 (3H, m), 1.17 (18H, d).
Reaction SMILES: I[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][CH:13]=[C:12]2[O:11][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[CH:8][S:9][C:10]=2[C:2]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4ncsc4c3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4ncsc4c3-c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
4-(7-Iodo-benzothiazol-6-yloxy)-6,7-dimethoxy-quinoline (compound 294) (40 mg), phenylboronic acid (40 mg), and tetrakistriphenylphosphine palladium (20 mg) were dissolved in N,N-dimethylformamide (5 ml) to prepare a solution. A 2 M aqueous potassium carbonate solution (0.3 ml) was added to the reaction system, and the mixture was stirred at 80° C. for 20 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium 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 (35 mg, yield 98%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[C:27]=[O:28].Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:27]([NH:26][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:30]=4)=[O:28])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc(Oc5ccccc5)c4)ccc3C2=O)C(=O)N1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
TEA (0.20 g, 2.00 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and 1-isocyanato-3-phenoxy-benzene (0.212 g, 1.00 mmol) in acetonitrile (10 mL) under nitrogen at RT. After 3 hrs, 1N HCl (10 mL) was added, and the mixture was stirred for 10 min. The solids were isolated by filtration, and washed with water (20 mL) and acetonitrile (10 mL). The crude product was dissolved in a minimal amount of DMF and the product was precipitated by slow addition of water (˜30 mL). The solids were collected by filtration, washed with Et2O, and dried in vacuo for 18 hrs to give the product as a white solid (422 mg, 87%): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 35/65, CH2CN/0.1% H3PO4, 3.76 min (99.3%); mp: 224-226 0C; 1H NMR (DMSO-d6) δ 1.99 (s, 4H, CH, CH3), 2.29-2.46 (m, 1H, CH), 2.55-2.66 (m, 1H, CH), 2.80-3.01 (m, 1H, CH), 4.18-4.56 (m, 4H, CH2, CH2), 5.10 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.71 (t, J=5.9 Hz, 1H, NH), 7.23-7.36 (m, 1H, Ar), 7.36-7.48 (m, 2H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.55 (s, 1H, NH), 9.75 (s, 1H, NH), 10.67-11.27 (m, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 23.82, 31.18, 42.77, 47.12, 51.56, 118.12, 119.57, 121.85, 122.91, 126.88, 130.26, 133.18, 135.70, 142.36, 144.94, 155.29, 167.67, 167.95, 170.98, 172.85; LCMS: MH+=485; Anal. Calcd. for C27H24N4O5: C, 66.93; H, 4.99; N, 11.56. Found: C, 67.03; H, 4.72; N, 11.41.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH3:8])SC)#[N:2].[CH2:9]([NH2:12])[CH2:10][NH2:11]>C(#N)C>[CH3:8][NH:7][C:4]([NH:11][CH2:10][CH2:9][NH2:12])=[N:3][C:1]#[N:2]
Reactant: CN=C(NC#N)SC
Reactant: NCCN
Solvent: CC#N
Product: CNC(=NC#N)NCCN

Procedure:
Combine the product of Step 1 and ethylenediamine (4 ml) in acetonitrile (CH3CN) (15 ml) and stir for 60 hours. Filter the resultant solution and recrystallize from EtOH to obtain N-methyl-N'-aminoethyl-N"-cyanoguanidine (15 g).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(OC([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH:23]1[O:25][CH2:24]1)=O)(C)(C)C.S([O-])(O)(=O)=O.[K+]>CN1C(=O)N(C)CC1>[OH:25][CH:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][NH:18]1)[CH2:24][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: OC(COCc1ccccc1)[C@@H]1CCCN1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (347 ml) was added to a suspension of sodium hydride (60% dispersion in oil, 89.6 g) in DMI (2.0 l), and the mixture was stirred at 60° C. for 1 hour. A solution of (S)-1-(tert-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (478.4 g) obtained in Example 4-a), in DMI (150 ml) was dropwise added, and the mixture was stirred at said temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of potassium hydrogensulfate and the mixture was extracted with toluene. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue (547.9 g) was dissolved in ethanol (3.0 l) and a 30% aqueous solution (1 l) of potassium hydroxide was added. The mixture was stirred at 76° C. for 3 hours. The reaction mixture was concentrated, acidified with 1.2N hydrochloric acid and washed with ethyl acetate. The aqueous layer was made basic with 10% sodium hydroxide and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and concentrated to give the title compound (178.2 g).
Reaction SMILES: [CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:3][CH2:2]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:27])[CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:2][CH2:3]1
Reactant: CC(=O)N(C1CC1)C1CC(C)Nc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C1CC1)C1CC(C)N(C(=O)c2cccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To the solution of N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-acetamide (82 mg, 0.34 mmol) in DCM (5 mL) was added nicotinoyl chloride hydrochloride (71 mg, 0.40 mmol), followed by DIPEA (104 mg, 0.80 mmol). The reaction mixture was stirred at r.t. for overnight. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 mL). The reaction mixture was washed with sat. sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford slightly yellow solid product (81 mg, 68%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:14]=[C:13]([F:15])[C:11]([NH2:12])=[C:10]([F:16])[CH:9]=1.C(N(CC)CC)C>C1COCC1>[Br:7][C:8]1[CH:14]=[C:13]([F:15])[C:11]([NH:12][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[C:10]([F:16])[CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1c(F)cc(Br)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (1.05 ml) was added to a solution of 4-bromo-2,6-difluoroaniline (1.00 g) and triethylamine (1.61 ml) in THF (10 ml) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, passed through NH silica gel pad and concentrated in vacuo. The solid was washed with IPE/hexane to give the title compound (1.08 g) as a white solid.
Reaction SMILES: COC1C=CC(C[CH:8]([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][C:20]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:19][C:18]=4[N:17]=[C:16]([NH2:31])[C:15]=3[N:14]=[C:13]2[CH2:32][O:33][CH2:34][CH3:35])=CC=1>FC(F)(F)C(O)=O>[NH2:31][C:16]1[C:15]2[N:14]=[C:13]([CH2:32][O:33][CH2:34][CH3:35])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:36]([NH2:39])(=[O:38])=[O:37])[C:24]=2[C:23]2[CH:22]=[CH:21][C:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][C:18]=2[N:17]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCC(Cc1ccc(OC)cc1)S(N)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCS(N)(=O)=O
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
A solution of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide (0.50 g, 0.88 mmol) in trifluoroacetic acid (5 mL) was stirred at ambient temperature for four hours and then concentrated under reduced pressure. The residue was dissolved in methanol and concentrated under reduced pressure; this process was repeated three times. The residue was then suspended in water, and 2 M aqueous sodium hydroxide was added to adjust to pH 7. The mixture was stirred for 30 minutes, and the resulting solid was isolated by filtration, washed with water, and purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 30:70). The purified product was dried overnight under high vacuum at 80° C. to provide 0.31 g of 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as tan needles, mp 250–251.5° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:35]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
A solution of 95 mg of 1,1-diethyl-3-[3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea in 3 mL of dichloromethane, to which 750 μL of trifluoroacetic acid are added, is stirred at ambient temperature for 48 hours. The reaction medium is concentrated to dryness and then purified by preparative LC/MS: injection of the product in 2.5 mL of DMSO, elution with a gradient of 5% to 95% of acetonitrile in water, containing respectively 0.07% of TFA, in 12 minutes. 49 mg of 1,1-diethyl-3-[3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]urea are isolated in the form of a trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.23 (t, J=7.0 Hz, 6H); 3.00 (m, 4H); 3.41 (m partially masked, 4H); 3.78 (m, 4H); 7.11 (broad d, J=8.0 Hz, 1H); 7.33 (broad d, J=12.0 Hz, 1H); 7.99 (s, 1H); 9.78 (s, 1H); 13.0 (broad m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[NH:24])=[CH:21][C:13]1=2)C(=O)OC(C)(C)C.[ClH:30]>CO>[ClH:30].[ClH:30].[CH3:1][NH:2][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[NH:24])=[CH:21][C:13]1=2
Reactant: CN(CCN1CCOc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCCN1CCOc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of tert-butyl methyl(2-(6-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)carbamate (0.07 g, 0.168 mmol) in HPLC grade MeOH (10 mL) was added 3M hydrochloric acid (0.56 mL, 1.681 mmol). The resulting yellow solution was heated to reflux under an atmosphere of argon. After 60 minutes, the reaction was cooled to room temperature and concentrated. The residue was diluted with H2O (20 mL) and rinsed sequentially with CH2Cl2 (20 mL) and EtOAc (20 mL). The aqueous layer was concentrated and dried to yield the title compound 10 as a yellow solid (37 mg, 56.5%). 1H NMR (DMSO-d6) δ 11.37 (brs, 1H), 9.72 (brs, 1H), 9.23 (brs, 2H), 8.66 (brs, 1H), 8.21-8.08 (m, 2H), 7.37 (app t, 1H, J=4.4 Hz), 7.03 (s, 1H), 6.84 (d, 1H, J=8.3 Hz), 6.60 (d, 1H, J=7.3 Hz), 4.31-4.20 (m, 2H), 3.70-3.45 (m, 2H, merged with H2O peak), 3.40-3.34 (m, 2H), 3.18-3.02 (m, 2H), 2.60-2.50 (m, 3H); ESI-MS (m/z, %): 317 (MH+, free base, 100); ESI-HRMS calculated for C16H21N4OS (MH+, free base): 317.1430; observed: 317.1422.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].CC(C)([O-])C.[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19].Cl>CS(C)=O>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH3:19]
Reactant: CCOC(CBr)OCC
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(CN1C(=O)C(=O)c2ccccc21)OCC
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 31.8 g of isatin in 300 ml of dry dimethyl sulfoxide was added dropwise to a suspension of 25.4 g of potassium t-butoxide in 200 ml of dry dimethyl sulfoxide at 10° C. in a nitrogen stream. After stirring the mixture at that temperature for 30 minutes, 39 ml of bromoacetaldehyde diethyl acetal was added thereto, followed by stirring at 70° C. for 6 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=20/1) to give 31.4 g (55%) of the title compound as a red powder.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:11]([CH3:14])([O-])=O.CN(C)C(=N)N(C)C>C(O)C>[CH:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][CH:1]([OH:10])[CH2:14][NH2:11])=[CH:5][CH:6]=1
Reactant: O=CCCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: CCO
Product: NCC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.70 g of dihydrocinnamaldehyde are dissolved in 20 ml of anhydrous ethanol, and 10 ml of nitromethane and 1 ml of tetramethylguanidine are added, and the mixture is stirred at RT for 1 h. It is concentrated in vacuo, the residue is taken up in 200 ml of ethanol and 5 ml of glacial acetic acid, 10 g of activated Raney nickel are added and the mixture is then hydrogenated at 50° C. and under 25 bar H2 pressure for 5 h. The catalyst is then filtered off, the filtrate is concentrated in vacuo, the residue is taken up in saturated aqueous sodium bicarbonate solution, and non-polar impurities are removed by extraction with diethyl ether. Extraction 3 times with tetrahydrofuran, drying over sodium sulfate, and concentration in vacuo provides 5.75 g of (D,L)-4-phenyl-2-hydroxy-1-butylamine as a colorless oil.