Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])N)[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:22])[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC1CN(c2cccc(C#N)c2)C(=O)N1C1CCN(C(=O)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
The free base of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.99 g, 6.72 mmol) in tetrahydrofuran (50 ml) and triethylamine (1.36 g, 13,44 mmol) was cooled to 0° C. and benzoyl chloride in tetrahydrofuran (10 ml) was added. After 4 h the reaction was complete; the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N HCl and brine, then dried (Na2SO4) and evaporated. The desired product was isolated by flash chromatography using silica get and 2:1 ethyl acetate as eluent. There was obtained 0.63 g of pure 1-(1-benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-imidazolidinone; LRMS (M+H)+ m/z 401.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: N#CC1=CCCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC=C(C#N)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Hydroxycyclohex-1-ene-1-carbonitrile (500 mg, 4.06 mmol) was dissolved in anhydrous DMF (5.1 mL) and then cooled to 0° C. Imidazole (276 mg, 4.06 mmol) and TBS-Cl (612 mg, 4.06 mmol) were added and the reaction mixture was allowed to stir at 0° C. for 2 hours. The reaction mixture was partitioned between water and DCM. The organic layer was collected and the aqueous layer was again extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]([CH3:44])[CH3:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([C:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=4[F:40])=[O:32])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([F:40])=[C:33]([C:31]([CH:28]2[CH2:29][CH2:30][N:25]([C:20]3[N:21]=[C:22]4[CH2:23][CH2:24][NH:15][CH2:16][C:17]4=[N:18][C:19]=3[NH:41][CH:42]([CH3:44])[CH3:43])[CH2:26][CH2:27]2)=[O:32])[CH:38]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanone TFA salt (41.7 mg, 0.066 mmol) and Pd(OH)2 on carbon (20 wt %, 5 mg, 0.036 mmol) in THF (328 μL) was stirred at rt under an atmosphere of hydrogen gas (balloon). After 3 h, the mixture was diluted with MeOH, filtered through a pad of Celite™, washing with MeOH, and concentrated to afford the title compound as its TFA salt (36 mg, 100%) as a yellow film, which was used without further purification. ESI-MS m/z [M+H]+ 432.3.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
To a stirring solution of 17 mL (180 mmol) of 4-fluoroaniline in 550 mL of THF at RT is added 26.7 mL (180 mmol, 1.0 equiv) of acetone, 10.3 mL (180 mmol, 1.0 equiv) acetic acid, and 57.22 g (270 mmol, 1.5 equiv) of sodium triacetoxyborohydride. The solution is stirred at RT for 15 h, cooled to 0° C., and then quenched by addition of H2O. The reaction mixture warmed to RT and is poured into EtOAc, the organic layer is separated, washed with brine (1×200 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane 1:1 as eluent afforded 14.9 g (54%) of (4-Fluoro-phenyl)-isopropyl amine. A solution of 6.68 g (43.6 mmol) of (this material in 50 mL of DCM is cooled to 0° C. and 6 mL (43.6 mmol, 1.0 equiv) triethyl amine is added, followed by dropwise addition of 2.27 mL (43.6 mmol, 1.0 equiv) of bromoacetyl bromide. The solution is stirred at RT for 15 h and then poured into DCM (200 mL). The organic layer is separated, washed with saturated aq NaHCO3 (4×50 mL), 1N HCl (6×50 mL), brine (1×50 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane (3:17) as eluent afforded 5.32 g of 2-Bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide: 1HNMR (CDCl3, 300 MHz) δ7.26-7.09 (m, 4H), 4.85 (m,1H), 3.51 (s, 2H), 1.05 (d, 6H, J=6.9); low resolution MS(FAB) m/e 274 (MH+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:32])=[CH:7][C:8]([NH:25][CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[C:9]([CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20](Cl)=[O:21])=[O:11])(=[O:4])=[O:3].C=[O:34].Cl[CH2:36][Cl:37]>>[NH2:1][S:2]([C:5]1[C:6]([Cl:32])=[CH:7][C:8]([NH:25][CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[C:9]([CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:34][CH2:36][Cl:37])=[O:21])=[O:11])(=[O:3])=[O:4]
Reactant: C=O
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)Cl)c(NCc2ccco2)cc1Cl
Reactant: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)OCCl)c(NCc2ccco2)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoyl chloride (813) (0.040 mole) and paraformaldehyde (0.040 mole) is heated in a sealed vessel at 90° C. for 3 hours. The reaction is cooled, and the solids are dissolved in dichloromethane. The solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give chloromethyl 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoate (815). See eg., Bodor, et al., J. Med. Chem., 23, 469 (1980), and Ulich, et al., J. Am. Chem. Soc., (1921) 43: 660.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:3]=1[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:27])C=1.S(=O)(O)[O-].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[O:27])[C:3]=1[C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(Sc2cccc(F)c2C#N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cccc(S(=O)c2cccc(F)c2C#N)c1

Procedure:
To a solution of 2 g (7.7 mmol) of 2-fluoro-6-[(3-methoxyphenyl)thio]benzonitrile (Example 13) was added portionwise 1.6 g (9.3 mmol) of m-chloroperbenzoic acid. The resultant mixture was stirred for 24 h. Additional 0.16 g of m-chloroperbenzoic acid was added and the resultant mixture was stirred for 15 min. Excess sodium bisulfite was added, followed by water. The H2O solution was extracted with EtOAc. After drying over MgSO4 and solvent removal, the resultant crude product was purified by flash column chromatography on silica gel with methylene chloride as the eluent. This resulted in 1.7 g of 2-fluoro-6-[(3-methoxyphenyl)sulfinyl]benzonitrile as a solid: mp 103°-111° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:21][NH:20][C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)Cc1ccc(CCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
4-(Chloromethyl)phenylacetic acid (5.0 g, 27.1 mmol) was suspended in dichloromethane (50 ml), and oxalyl chloride (9.2 ml, 0.11 mol) and N,N-dimethylformamide (2 drops) were added. After stirring at room temperature for 1 hr, and the mixture was concentrated under reduced pressure. Dichloromethane (50 ml) and tert-butyl carbazate (4.29 g, 32.5 mmol) were added to the residue, and the mixture was cooled to 0° C. N,N-diisopropylethylamine (14 ml, 81.3 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue and the resulting precipitate was collected by filtration. The filtrate was concentrated and added with diethyl ether to recover the secondary crystals. They were dried to give tert-butyl 2-{[4-(chloromethyl)phenyl]acetyl}hydrazinecarboxylate (5.9 g, primary and secondary crystals, total yield 73%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([OH:21])=O)=[CH:17][CH:18]=[C:7]2[CH2:6]1)=[O:4].[NH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:21])=[CH:17][CH:18]=[C:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: NCc1cccnc1
Product: COC(=O)N1Cc2ccc(C(=O)NCc3cccnc3)n2Cc2ccccc21

Procedure:
The title compound was prepared by coupling the 10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step A with 3-(aminomethyl)pyridine (1.2 equiv.), in the manner of Example 1, Step G.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.O=[C:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15]([C:14]1[C:13]([CH3:20])=[N:1][C:2]2[C:3]([C:10]=1[NH2:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[O:16])[CH3:19]
Reactant: COc1ccc(N)c(C#N)n1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2ccc(OC)nc2c1N

Procedure:
Prepared as in Example 2a from 3-amino-6-methoxypicolinonitrile (Example 11b) and ethyl 3-oxobutanoate as an off white solid (45%). MS 262 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[CH:4]=[CH:3]1.F[C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([F:22])[N:16]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[F:22][C:17]1[N:16]=[C:15]2[O:13][C:11]([C:9]3[CH:10]=[C:5]4[CH:4]=[CH:3][N:2]([CH3:1])[C:6]4=[N:7][CH:8]=3)=[N:21][C:20]2=[CH:19][CH:18]=1
Reactant: Cn1ccc2cc(C(=O)O)cnc21
Reactant: Nc1ccc(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc2cc(-c3nc4ccc(F)nc4o3)cnc21
Temperature: 150 °C
Yield: 12.9 %

Procedure:
To a suspension of 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (68 mg, 0.38 mmol) in CH2Cl2 (2 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (50 μL, 0.38 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (2 mL) before 2,6-difluoro-pyridin-3-ylamine (50 mg, 0.38 mmol) was added in one portion. After an additional 30 minutes the reaction mixture was concentrated to dryness affording a residue, to which was added DMF (2 mL) and K2CO3 (53 mg, 0.38 mmol). The resulting mixture was heated by microwave to 150° C. for 10 min, after which the resulting mixture was filtered and concentrated. The resulting residue was purified by reverse phase chromatography affording 5-fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-oxazolo[5,4-b]pyridine (13.1 mg, 0.049 mmol, 13% yield). ES MS (M+H+)=269; 1H NMR δ (ppm)(DMSO-d6): 9.07 (1H, d, J=2.12 Hz), 8.75 (1H, d, J=2.13 Hz), 8.42 (1H, t, J=7.74 Hz), 7.70 (1H, d, J=3.52 Hz), 7.29 (1H, d, J=8.41 Hz), 6.69 (1H, d, J=3.52 Hz), 3.89 (3H, s); HRMS m/z 269.0831 (C14H9FN4O+H+ requires 269.0833).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:12]=[N:11][C:10]1=2.CCOCC>CO>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7])=[O:21])[CH:12]=[N:11][C:10]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCNCCO
Solvent: CCOCC
Solvent: CO
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCNCCO
Reaction time: 1 h
Yield: 38 %

Procedure:
0.500 (4,80 mmol) 2-(2-aminoethylamino)ethanol and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated at 120° C. with stirring in a 10 ml round bottom flask for one hour. The reaction mixture was chromatographed on a 15 g silica-gel column using an eluant of 60% methanol/40% ethyl acetate. After 200 ml of solvent had passed through column, the eluant was changed to 80% methanol/20% ethyl acetate and finally to 100% methanol. The fractions containing the product were combined and evaporated to yield a colorless oil. The oil was treated with 50 ml ether and 5 ml methanol and was agitated with a spatula. The oil was allowed to stand overnight and the resulting white solid was obtained by filtration (120 mg). The solid was washed with ether and was found to be somewhat hygroscopic. Yield: 38%.
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:41].[NH4+].ClCCl.C(O)C>C(O)C>[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:41])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.1 g (2.27 mmol) of 2-[N-(4-cyanophenyl)aminomethyl]benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide was stirred in 100 mL of ethanol saturated with hydrogen chloride for 5 hours, first at 0° C. and then at room temperature, until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off at a maximum bath temperature of 30° C. and the oily residue was taken up in 100 mL of absolute ethanol and mixed with 1.6 g (22 mmol) of ammonium carbonate. After 18 hours stirring at room temperature, the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water/methanol=19:1 to 4:1). When the eluates are evaporated down the desired compound is obtained as a white foam. Yield: 0.77 g (63% of theory), C27H27N5O3S (501.60); Rf value: 0.19 (silica gel; dichloromethane/ethanol=3:7); mass spectrum: (M+H)+=502.
Reaction SMILES: [C:1]([O:5][CH:6]([C:20]([OH:22])=[O:21])[N:7]([CH2:17][CH2:18]Br)[CH:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:32]([SH:34])[CH3:33]>ClCCl>[C:1]([O:5][CH:6]([C:20]([OH:22])=[O:21])[N:7]([CH2:17][CH2:18][S:34][CH2:32][CH3:33])[CH:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(C(=O)O)N(CCBr)C(OC(C)(C)C)C(=O)O
Reactant: CCS
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCSCCN(C(OC(C)(C)C)C(=O)O)C(OC(C)(C)C)C(=O)O

Procedure:
3.52 g (10 mmol) of N,N-bis-(tert-butoxycarboxy-methyl)-2-bromoethylamine is dissolved in 50 ml of absolute dichloromethane and mixed with 1.29 g (10 mmol) of diisopropylethylamine and 0.621 g (10 mmol) of ethylmercaptan. The reaction mixture is refluxed overnight. Then, the solution is extracted twice with semi-saturated, aqueous sodium bicarbonate solution. The organic phase is dried on sodium sulfate, and the solvent is evaporated in a vacuum. The residue is chromatographed on silica gel (eluant: dichloromethane/methanol 99:1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:29]([N:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[CH:14]=[CH:15][C:16]3[C:7]4[N:6]([CH2:26][CH2:27][CH3:28])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:25][C:8]=4[C:9]([NH2:24])=[N:10][C:11]=3[CH:12]=2)[CH2:23][CH2:22]1)(=[O:31])[CH3:30]
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(C)=O)CC4)ccc3c21
Reaction time: 36 h
Yield: 48.8 %

Procedure:
2-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.3 mmol) was slurried in dichloromethane (13 mL). Acetic anhydride (0.122 mL, 1.3 mmol) was added dropwise to the slurry and the mixture was stirred for 36 hours. Saturated aqueous sodium carbonate (5 mL) was added and the reaction was stirred for 1 hour. The layers were separated and the organic fraction was purified by chromatography on a HORIZON BPFC system (silica gel, gradient elution with 1-22% CMA in chloroform). The resulting amorphous solid was triturated with boiling acetonitrile. Filtration afforded 0.270 g of 7-[(1-acetylpiperidin-4-yl)oxy]-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 178-179.5° C.
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:14])[NH:7][CH:6]=1.[C-:17]#[N:18].[Na+]>C(O)C>[CH3:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:5]([CH2:4][C:17]#[N:18])=[CH:6][NH:7]2
Reactant: Cc1cccc2[nH]cc(C[N+](C)(C)C)c12
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2[nH]cc(CC#N)c12
Temperature: 25 °C

Procedure:
Trimethyl-(4-methyl-1H-indol-3-ylmethyl)-ammonium iodide (2.6 g, 7.5 mmol) is suspended in ethanol (53 mL) and sodium cyanide (736 mg, 15 mmol), is added to the reaction. The reaction is stirred and heated to reflux overnight. After 16 hours the reaction is cooled to room temperature and evaporated in vacuo. The resulting oil is taken up in dichloromethane and washed with water 3×, dried (Na2SO4), filtered and evaporated in vacuo. The resulting material is purified on silica with hexanes/dichloromethane as the eluent (1.0 g, 5 mmol, 71%) LC/MS (M++1): 171.3.
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:30][CH3:31])=[N:21][N:22]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15])=[O:11])C1C=CC=CC=1.O.C(OCC)(=O)C>CO.[Pd]>[OH:8][NH:9][C:10]([CH2:12][NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:30][CH3:31])=[N:21][N:22]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15])=[O:11]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)NCC(=O)NOCc3ccccc3)ccc12
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCC(=O)NO)ccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 110.5 %

Procedure:
A mixture of 120 mg (0.285 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (benzyloxycarbamoyl-methyl)-amide and 0.08 g 10% Pd/C, 50% water wet, in 10 mL methanol and 10 mL ethyl acetate was placed on a Parr® hydrogenation apparatus and shaken under 30 psi H2 at room temperature for 40 minutes. The reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give 104 mg of a tan solid. Trituration with hexanes gave 69 mg (73%) of a tan crystalline powder: mp 105° C. (dec); HRMS calcd for C17H22N4O3+H: 331.1772. Found: 331.1769.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([F:9])([F:8])[F:7])[CH3:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][S:23][C:24]3[C:29]([C:30]#[N:31])=[C:28]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][OH:41])=[CH:34][CH:33]=4)[C:27]([C:42]#[N:43])=[CH:26][N:25]=3)[N:21]=2)=[CH:13][CH:12]=1.Cl.FC(F)(F)CNC>CN(C=O)C.O.C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][S:23][C:24]3[C:29]([C:30]#[N:31])=[C:28]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][OH:41])=[CH:34][CH:33]=4)[C:27]([C:42]#[N:43])=[C:26]([N:4]([CH2:2][CH3:3])[CH2:5][C:6]([F:9])([F:8])[F:7])[N:25]=3)[N:21]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCNCC(F)(F)F
Agent: CNCC(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC(F)(F)F)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
133 mg (0.81 mmol) of N-ethyl-2,2,2-trifluoroethanamine hydrochloride were dissolved in 2 ml of DMF, 130 mg Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. The mixture was then warmed to 60° C. and stirred at this temperature overnight. In a separate flask, another 87 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 88 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at 100° C. for 4.5 h. The mixture was then diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 37 mg (41% of theory) of the target compound.
Reaction SMILES: I.[CH3:2][N:3]1[C:7]([NH:8][C:9](=N)SC)=[CH:6][C:5]([CH3:13])=[N:4]1.[CH3:14][NH:15][CH2:16][CH2:17][NH2:18]>C(Cl)Cl>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]=[C:9]1[NH:8][C:7]1[N:3]([CH3:2])[N:4]=[C:5]([CH3:13])[CH:6]=1
Reactant: CNCCN
Reactant: CSC(=N)Nc1cc(C)nn1C
Agent: I
Solvent: ClCCl
Product: Cc1cc(NC2=NCCN2C)n(C)n1

Procedure:
N(1,3-Dimethyl-5-pyrazolyl)-5-methyl isothiourea hydroiodide (Example XXV) (20.0 g) and 11.5 g. N-methyl ethylenediamine were heated to 120° for 30 minutes and to 160° for 1 hour. After cooling, methylene chloride was added and the solid which formed was filtered and discarded. The methylene chloride solution was shaken with 15% KOH solution, dried over potassium carbonate, concentrated and the residue crystallized from acetonitrile to get 10.16 g. product, mp 128°-130°.