Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:10](=[O:12])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:14])[CH3:13])[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methyl-propionic acid (10 g) in tetrahydrofuran (20 mL) were added 1-(benzyloxycarbonyl)piperazine (16.3 g), 1-hydroxybenzo-triazole (8.02 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (11.4 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in a mixed solvent of n-hexane and ethyl acetate (1/1) (40 mL) at 60° C. with heating, and the solution was stirred at room temperature overnight. To the mixture was added the same solvent (30 mL), and the mixture was further stirred overnight. The precipitated crystals were collected by filtration, and washed with the same solvent and dried under reduced pressure to give 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (13.5 g). To a solution of the obtained 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]-piperazine (5 g) in tetrahydrofuran (30 mL) was added hydrochloric acid (4 mol/L 1,4-dioxane solution, 40 mL), and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (3.65 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]([Cl:23])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:23].[CH3:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: Cc1cccc(/C=C/C(=O)Cl)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-methylcinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from 2-propanol/isopropyl ether yielded the titled compound. MW: 347.85; mp: 213.0-235.0° C.; 1H-NMR (DMSO) δ: 8.87-8.82 (1H, m), 8.33-8.20 (2H, m), 7.89 (2H, d, J=8.1 Hz), 7.81-7.74 (1H, m), 7.63-7.45 (5H, m), 7.40-7.24 (2H, m), 7.19 (1H, d, J=16.5 Hz), 2.35 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:11]=1[S:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: Nc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Nc1ccc(O)cc1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (98%) from 4-aminophenol (Aldrich) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manner as described in Example 421. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.39 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 6.89 (m, 2H), 6.61 (m, 2H). MS (EI): m/z 384 (M+H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1.[C:25]([O-])(=[O:27])C.[Na+]>CN(C=O)C>[CH:25]([C:13]1[CH:12]=[CH:11][C:10]([CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:9][C:8]=1[O:7][CH3:6])=[O:27]
Reactant: CC(=O)[O-]
Reactant: COc1cccc(CNCCOC(=O)C(C)(C)C)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=O
Reaction time: 0.67 h

Procedure:
POCl3 (5.8 g, 37.7 mmol) was added to 20 ml of DMF in an ice bath. After 40 minutes, 2,2-dimethylpropionic acid 2-[(3-methoxyphenyl)methylamino]ethyl ester (10 g, 37.7 mmol) dissolved in DMF (10 ml) was added dropwise. After the mixture was stirred for 16 hours, an aqueous sodium acetate solution (20%, 100 ml) was added dropwise thereto and the oily matter was subjected to extraction with ethyl acetate. Washing was performed with a saturated aqueous NaHCO3 solution (100 ml) and then with a saturated saline solution (100 ml). After drying over Na2SO4 and concentration, the residue was purified by silica gel chromatography to give a light yellow crystal (yield: 8.7 g (78.9%)).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.C(=N[CH:24]1[CH2:29][CH2:28]C[CH2:26][CH2:25]1)C.[C:30]([O:34][C:35]1[C:40]([F:41])=[CH:39][N:38]=[CH:37][C:36]=1[CH3:42])([CH3:33])([CH3:32])[CH3:31].C(Br)C=C.C1C[O:50]CC1>>[CH2:24]([CH:29]([C:37]1[C:36]([CH3:42])=[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])[C:40]([F:41])=[CH:39][N:38]=1)[CH:28]=[O:50])[CH:25]=[CH2:26]
Reactant: C1CCOC1
Reactant: Cc1cncc(F)c1OC(C)(C)C
Reactant: CC=NC1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CC(C)NC(C)C
Product: C=CCC(C=O)c1ncc(F)c(OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of LDA (1.75 mmol, prepared from diisopropylamine (0.23 mL) and n-BuLi (2.5 M in hexanes, 0.70 mL) in THF (2.0 mL) at 0° C. was added N-(ethylidene)-cyclohexylamine (1.70 mmol, prepared in situ from acetaldehyde and cyclohexylamine) dropwise, and the reaction mixture was warmed to room temperature and stirred for 15 minutes. To this solution was added 4-t-butoxy-5-fluoro-3-methylpyridine (0.10 mL, 0.50 mmol) in THF (0.5 mL) dropwise and the mixture was stirred for 1 hour. To this mixture was added allyl bromide (0.15 mL, 1.75 mmol) dropwise., The exothermic reaction was stirred for 20 minutes, then quenched with water (3 mL). The mixture was then diluted with acetic acid (1M, 20 mL) and hexanes (20 mL) and stirred vigorously for 1 hour. The mixture was extracted with ether, and the organic layer was separated, washed with water, saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel, eluting with 5% to 10% ethyl acetate in hexanes, to afford the title compound (0.095 g, 73% yield) as an oil. MS 266 (M+H)+ ; 1H NMR (CDCl3) δ1.41 (d, 9H, J=1.1 Hz), 2.25 (s, 3H), 2.55-2.67 (m, 1H), 2.81-2.93 (m, 1H), 3.85 (m, 1H), 4.93-5.04 (m, 2H), 5.65-5.80 (m, 1H), 8.27 (d, 1H, J=1.8 Hz), 9.74 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:12][CH:13]([F:16])[CH2:14][NH2:15]>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:14][CH:13]([F:16])[F:12])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: NCC(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)CNc1nc(Cl)nc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (2 g, 10.58 mmol, Arkpharm), DCM (20 mL) and TEA (2.95 mL, 21.16 mmol). A solution of 2,2-difluoroethanamine (0.858 g, 10.6 mmol, Matrix) in DCM (5 mL) was added drop-wise and the mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure. To the residue was added 1,4-dioxane (20 mL), TEA (2.95 mL, 21.2 mmol) and a solution of 2,2-difluoroethanamine (0.858 g, 10.58 mmol, Matrix) in 1,4-dioxane (5 mL). The mixture was stirred at rt for about 4 h, and then at about 55° C. overnight. The mixture was concentrated under reduced pressure, and the residue was taken up in EtOAc (120 mL) and water (25 mL). The organic layer was isolated and washed with water (2×25 mL). The combined aqueous layers were washed with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL), dried with MgSO4, filtered, concentrated under reduced pressure, and dried in a vacuum oven at about 70° C. over 2 days to give 2-chloro-N-(2,2-difluoroethyl)furo[3,2-d]pyrimidin-4-amine (2.20 g, 89%): LC/MS (Table 2, Method c) Rt=1.69 min.; MS m/z: 234 (M+H)+.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C(N(CC)CC)C.Br[C:15]1[C:16]([F:23])=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.CCOC(C)=O>[F:23][C:16]1[C:15]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:21][OH:22]
Reactant: OCc1cccc(Br)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(CO)c1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, ethynyl(trimethyl)silane (9.0 ml) was mixed with triethylamine (50 ml), and (3-bromo-2-fluorophenyl)methanol, bis(triphenylphosphine)palladium chloride (II) (1.54 g), and copper iodide (420 mg) were added thereto, followed by stirring at 90° C. overnight. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol (4.88 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH:24]([F:26])[F:25])=[CH:20][CH:21]=3)[C:16]([C:27]3[N:28]=[C:29]4[C:35]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][N:33]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:30]4=[N:31][CH:32]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([Cl:54])(=O)C>CO>[ClH:54].[C:38]([NH:37][C:36]([C:35]1[C:29]2[C:30](=[N:31][CH:32]=[C:27]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[C:19]([O:23][CH:24]([F:25])[F:26])[CH:18]=4)[N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:15]=3)[N:28]=2)[N:33]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:34]=1)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccc(OC(F)F)cc34)nc12
Solvent: CO
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCNCC4)c4ccc(OC(F)F)cc34)nc12
Product: Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
In a round-bottomed flask, 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (102 mg, 0.143 mmol) was suspended in methanol (1.4 ml). The suspension was cooled to 0° C. and acetyl chloride (0.20 ml, 2.81 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated at room temperature and the residue dried under high vacuum to afford 92 mg (99%) of 2-(5-difluoromethoxy-1-piperidin-4-yl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide hydrochloride as a yellow solid which was used without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(Oc1ccccc1-c1ccccc1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with 2-hydroxy biphenyl.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:25][O:26][C:27](=[O:56])[C@H:28]([CH2:52][CH2:53][S:54][CH3:55])[NH:29][C:30](=[O:51])[CH2:31][N:32]([CH2:44][C@@H:45]([NH2:50])[CH:46]([CH3:49])[CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.CCN(CC)CC>CN(C=O)C>[CH3:25][O:26][C:27](=[O:56])[C@H:28]([CH2:52][CH2:53][S:54][CH3:55])[NH:29][C:30](=[O:51])[CH2:31][N:32]([CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[CH2:44][C@@H:45]([NH:50][C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C@@H:46]([CH3:49])[CH2:47][CH3:48]
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CCC(C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
4-Imidazoleacetic acid (0.064 g, 0.395 mmol), dissolved in DMF (5 mL) was treated with HOBT (0.053 g, 0.40 mmol), EDC (0.076 g, 0.40 mmol), and N-[2(S)-amino-3-methylpentyl)-N-(1-naphtylmethyl)glycyl-methionine methyl ester hydrochloride (0.175 g, 0.329 mmol). The pH was adjusted to 7.5 with Et3N (0.15 mL, 1.1 mmol) and the mixture was stirred at ambient temperature for 24 h. After concentration, and the mixture was partitioned between EtOAc (20 mL) and saturated NaHCO3 solution (10 mL). The aqueous layer was washed with EtOAc (1×20 mL). The organic layers were combined, washed with brine (1×10 m), dried (Na2SO4), filtered and concentrated to give 0.170 g of crude product. Purification by chromatography (silica gel, eluting with 1 to 3% methanol in methylene chloride) gave 0.080 g of pure product. 1H NMR (CD3OD); δ8.30-8.25 (d, 1H, J=9 Hz), 7.91-7.86 (d, 1H, J=6 Hz), 7.85-7.79 (d, 1H, J=9 Hz), 7.56 (s, 1H), 7.55-7.38 (m, 4H), 6.9 (s, 1H), 4.37-4.27 (m, 1H), 4.23-4.04 (m, 3H), 3.67 (s, 3H), 3.49 (ABq, 2H), 3.25 (ABq, 2H), 2.90-2.70 (m, 2H), 2.21-1.97 (m, 2H), 1.95 (s, 3H), 1.88-1.74 (m, 1H), 1.64-1.46 (m, 2H), 1.44-1.25 (m, 1H), 1.14-0.98 (m, 1H), 0.93-0.77 (m, 6H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>O>[OH2:29].[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][N:26]([CH2:27][CH2:28][OH:29])[CH3:25])[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1.[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][N:26]([CH3:25])[CH2:27][CH2:28][OH:29])[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CNCCO
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Agent: Cl
Solvent: O
Product: CN(CCO)Cc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Temperature: 130 °C

Procedure:
2-Chloromethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (Example 28, prepared from 1.4 g of the alcohol) was added to N-methylethanolamine (20 mL). The mixture was heated in an oil bath for 3 hr at about 130° C. The solution was diluted with water and the mixture extracted with diethyl ether (7×200 mL). The combined extracts were washed with saturated sodium chloride solution and evaporated to dryness to yield an orange solid. The crude product was recrystallized from methanol/dichloromethane. m.p. 188°-195° C. Analysis: Calculated: C, 68.1; H, 6.5; N, 18.9. Found: C, 68.4; H, 6.5: N, 18.7.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:27][CH3:28])([CH3:16])([CH3:17])[CH3:18]
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.8 mL, 13.0 mmol) was added to a mixture of N2-phenylpyridine-2,3-diamine (800 mg, 4.32 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (960 mg, 4.75 mmol), HOAt (650 mg, 4.75 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (910 mg, 4.75 mmol) in anhydrous DCM (25 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 16 h. After re-cooling to 0° C., additional amounts of (S)-2-tertbutoxycarbonylaminobutyric acid (610 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (580 mg), HOAt (410 mg) and triethylamine (1.0 mL) were added and stirring at RT continued for 1 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a dark oil. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method J): RT 2.67 min [M+H]+ 371.2.
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1.[C:12]([O-:15])(=O)[CH3:13].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.ClCC(Cl)=O>[CH3:2][O:3][CH2:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][Cl:1])[CH2:7]1
Reactant: COCC[C@@H]1CCCNC1
Reactant: CC(=O)[O-]
Reactant: Cl
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCC[C@@H]1CCCN(C(=O)CCl)C1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a suspension of (S)-3-(2-methoxyethyl)piperidine hydrochloride (46.70 g, 260 mmol), sodium acetate (46.90 g, 572 mmol) and acetic acid (33.1 ml, 572 mmol) in tetrahydrofuran (470 ml) was added dropwise chloroacetyl chloride (28.3 ml, 7.53 mmol) under ice-cooling, and the mixture was stirred overnight at temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give (S)-3-(2-methoxyethyl)-N-(chloroacetyl)piperidine (45.0 g, yield 78.8%).
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].C(Cl)(=O)C1C=CC=C(C(Cl)=O)C=1.[F:25][C:26]([F:38])([C:29]([F:37])([F:36])[C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH2:27][OH:28]>>[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:10][C:11](=[O:12])[O:28][CH2:27][C:26]([F:38])([F:25])[C:29]([F:36])([F:37])[C:30]([F:34])([F:35])[CH:31]([F:32])[F:33])=[C:8]=[O:9]
Reactant: O=C=NCCCCCCN=C=O
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: O=C(Cl)c1cccc(C(=O)Cl)c1
Product: O=C=NCCCCCCNC(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F

Procedure:
399 g of hexamethylene diisocyanate (HDI) were initially introduced at 80° C. in a 1 l round-bottomed flask and 0.002 g of isophthaloyl dichloride was added. 73.4 g of 2,2,3,3,4,4,5,5-octafluoropentanol were slowly added dropwise and stirring was effected until the NCO value was 39.4% by weight. The mixture was separated by distillation on a thin-film evaporator and 40 g (=40% of theory) of the title compound having an NCO content of 12.4% by weight were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37])=O)(C)(C)C>CN(C=O)C>[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18 %

Procedure:
To a solution of 4-(4-t-butoxycarbonylpiperazin-1-yl)benzoic acid (1.0 g, 3.3 mmol) and 1-(t-butoxycarbonylamino)-2-aminobenzene (Method 17, 0.68 g, 3.3 mmol) in DMF (10 ml) was added 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (1.1 g, 4.0 mmol) (Method 18). The mixture was stirred at ambient temperature for 20 hours. The mixture was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was separated and the aqueous reextracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (eluting with 4:1-1:1 isohexane/ethyl acetate). The product was dissolved in 1,4-dioxane (2.5 ml) and treated with a 4M solution of hydrogen chloride in 1,4-dioxane (2.5 ml). The mixture was stirred at ambient temperature for 4 hours. The resulting solid was collected by filtration, trated with a 2M aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate to afford the title compound as a colourless solid (176 mg, 92%); NMR Spectrum: (DMSO-d6) 2.89 (t, 4H), 3.25 (t, 4H), 4.90 (s, 2H), 6.66 (t, 1H), 6.84 (d, 1H), 7.01 (m, 3H), 7.21 (d, 1H), 7.92 (d, 2H), 9.48 (s, 1H); Mass Spectrum: M+H+ 297.