Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[I:12]I>C(O)C.O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: II
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59%). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33% ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97%). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75%). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:18][CH2:19][C@H:20]([S:22][CH2:23][C@@:24]([CH3:29])([C:26]([OH:28])=[O:27])[NH2:25])[CH3:21])=O)C1C=CC=CC=1.[ClH:30]>>[ClH:30].[NH2:18][CH2:19][C@H:20]([S:22][CH2:23][C@@:24]([CH3:29])([C:26]([OH:28])=[O:27])[NH2:25])[CH3:21]
Reactant: C[C@H](CNC(=O)OCc1ccccc1)SC[C@](C)(N)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CN)SC[C@](C)(N)C(=O)O
Temperature: 25 °C

Procedure:
The product of Example-3C, S-[(1R)-2-(Benzyloxycarbonylamino)-1-methylethyl]-2-methyl-L-cysteine trifluoroacetate, (0.5 g, 1.14 mmol) was dissolved in 6N HCl and refluxed for 1.5 hour. The mixture was then cooled to room temperature and extracted with EtOAc. The aqueous layer was concentrated in vacuo to give the title product, (2R, 5R)-S-(1-amino-2-propyl)-2-methyl-cysteine hydrochloride (0.29 g), which was used without further purification. 1H NMR (H2O, 400 MHz) δ 1.2 (m, 3H), 1.4 (m, 3H), 2.7 (m, 1H), 2.8-3.2 (m, 2H), 3.4 (m, 1H). (some doubling of peaks due to rotameric forms). MS m/z (electrospray): 193 [M+H+] (61%), 176 (53), 142 (34), 134 (100), and 102 (10).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[N:3]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: BrCC1CCOCC1
Reactant: Cc1nc(N)sc1C
Product: Cc1sc(=N)n(CC2CCOCC2)c1C
Temperature: 85 °C
Yield: 12.6 %

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (0.36 g, 2.8 mmol) and 4-bromomethyltetrahydropyran (0.75 g, 4.2 mmol) was heated at 85° C. for 16 hours. The residue purified by preparative HPLC to afford 80 mg (13%) of the title compound
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:14]2[O:15][C:16]3[C:21]([C:22]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:4]([N:25]2[CH2:26][CH2:27][C:22]3([C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[C:14]=4[O:15][C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1Oc1ccccc1C21CCN(C(=O)C2CC2)CC1
Reaction time: 8 h

Procedure:
A solution of cyclopropane carboxylic acid chloride (1.2 ml.) in methylene chloride (10 ml.) is added dropwise with stirring to a mixture of 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.) and triethylamine (1.6 ml.) in methylene chloride (40 ml.) at 5° C. The mixture is allowed to reach room temperature and stirred overnight. The mixture is washed with 3 N hydrochloric acid, 3 N sodium hydroxide solution and water, dried MgSO4 and the methylene chloride evaporated to dryness, to give 1'-cyclopropylcarbonyl-4-methoxyxanthene-9-spiro-4'-piperidine (I.R. amide band 1620 cm.-1 ; t.l.c.--single spot) which is used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17].[OH-].[Na+]>C(O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To 0.604 mmol 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester in 1.97 ml ethanol was added 1.21 mmol 2 N aq NaOH solution and the reaction mixture was stirred at 80° C. for 0.5 hour. After such time the solvent was removed in vacuo, the residue was taken in water and acidified by addition of 2N HCl to yield after filtration the title compound as a white solid (88%).MS (m/e): 311.0 ([M−H]−, 100%)
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[C:9](=[O:10])[N:8]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]1[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:5].[CH3:36][Mg+].[Br-]>CCOC(C)=O>[C:4]([C@H:6]1[C:9](=[O:10])[N:8]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:7]1[CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:5])[CH3:36]
Reactant: C[Mg+]
Reactant: COC(=O)C[C@H]1[C@H](C(=O)N(C)OC)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1[C@@H](C(C)=O)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 35.5 %

Procedure:
Oven-dried LiC1 (0.276 g, 6.511 mmol, 7.3 equiv) was vigorously stirred in THF (9.0 mL) until fully dissolved. Trans β-lactam 15 (0.420 g, 0.889 mmol, 1.0 equiv) was added and cooled to 0° C. A solution of MeMgBr (0.98 mL, 0.987 mmol, 1.1 equiv, 1M THF) was added dropwise and stirred at 0° C. for 2 h, at which time the ice-bath was removed and the reaction allowed to slowly warm to room temperature. After stirring for 48 h sat. NHCl(aq) was added to quench the reaction, which was further diluted with EtOAc. The organics were washed with water, followed by brine and dried over Na2SO4. The organics were concentrated in vacuo and purified by flash column chromatography (35% EtOAc/hexanes) to provide the pure ketone 16 (Rf=0.32, 0.135 g, 36% yield) and recovered starting material 15 (Rf=0.16, 0.249 g) representing an 87% yield (based on recovered starting material, brsm). m.p.=52-54° C.; [α]D23=+71.875° (c=0.8, MeOH); 1H NMR (500 MHz, CDCl3): δ 7.31-7.36 (m, 9H); 7.20-7.22 (m, 6H); 5.41 (ddd, J=2.2, 3.5, 10.3 Hz, 1H); 4.03 (d, J=2.1 Hz, 1H); 3.57 (s, 3H); 2.36 (s, 3H); 2.13 (dd, J=10.3, 16.2 Hz, 1H); 1.73 (dd, J=3.5, 16.2 Hz, H); 13C NMR (125 MHz, CDCl3): δ 200.04, 170.45, 163.17, 141.83, 129.82, 128.26, 128.00, 74.54, 66.68, 52.01, 52.01, 37.15, 30.70; IR (thin film): 3059, 2953, 1759, 1714, 1597, 1493, 1444, 1359, 1337, 1177, 1034, 752, 700, 639 cm−1; HRMS for [M+Na]C27H25NO4Na calc'd., 450.16758, found, 450.16980 (Error=4.9322 ppm).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[CH2:26]([NH:29][C:30]([NH2:32])=[O:31])[C:27]#[CH:28]>CN(C=O)C.I[Cu].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]#[C:27][CH2:26][NH:29][C:30]([NH2:32])=[O:31])=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: C#CCNC(N)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3nc(C#CCNC(N)=O)cnc3N)[nH]c2c1
Yield: 82 %

Procedure:
5-Bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (50 mg, 0.1644 mmol), Et3N (166.4 mg, 229.2 μL, 1.644 mmol), iodocopper (31.3 mg, 0.1644 mmol), Pd(PPh3)4 (9.5 mg, 0.0082 mmol) and the relevant prop-2-ynylurea (24.2 mg, 0.2466 mmol) in DMF (2 mL) were heated at 100° C. for 30 minutes under microwave conditions. The reaction mixture was purified directly by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (43.3 mg, 82% Yield). 1H NMR (400.0 MHz, DMSO) δ 2.45 (3H, s), 4.7 (2H, s), 6.1 (1H, s), 7.1-7.15 (1H, m), 7.4 (1H, vbr s), 7.6 (1H, vbr s), 7.85 (2H, s), 8.65 (1H, s), 9.5-9.7 (2H, m), 10.6 (1H, br s); MS (ES+) 332.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2c(F)cc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C2CCCCC2)oc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methanone (3.1 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (50 mL) and methanol (5 mL), and sodium borohydride (90%, 0.93 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (5 mL) and 1N hydrochloric acid (10 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.1 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[N:8][CH:7]=1>>[OH:16][C:9]1[C:10]2[C:15](=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][CH:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: Oc1ncnc2ccccc12
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2c(O)ncnc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 581.7 %

Procedure:
Chlorosulfonic acid (4.10 mL, 62.6 mmol) was slowly added to quinazolin-4-ol (1.09 g, 0.26 mmol). The resulting mixture was heated to 140° C. and stirred for 3 hours at the same temperature. After cooling to room temperature, the reaction mixture was poured into crushed ice. The mixture was extracted with DCM (100 mL×3), the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified via flash chromatography (5% PE: Ethyl Acetate) to give 370 mg of 4-hydroxyquinazoline-8-sulfonyl chloride. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (t, J=7.79 Hz, 1H) 8.26 (ddd, J=9.67, 7.92, 1.48 Hz, 2H) 9.02 (s, 1H). LC-MS: m/z 245.7 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[F:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:16][C:15]=2[F:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(NC(=O)OCc3ccccc3)cc2F)C1

Procedure:
To a solution of 4 g of (3R)-3-(2-fluoro-4-nitro-phenyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.29 mmol) in 100 ml ethyl acetate and 50 ml methanol were added 1 g of Pd/C 10%. The suspension was stirred under hydrogen. The reaction was monitored by TLC. The catalyst was filtered, the filtrate evaporated to dryness, and the residue was dissolved in 100 ml of acetone. 25 ml of a saturated solution of sodium bicarbonate was added, than a 0° C. 3.63 ml of benzyl chloroformate (25.8 mmol). The reaction was stirred over night at rt and monitored by TLC. The acetone was evaporated, the water layer extracted twice with ethyl acetate, the org layer washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography, using a 1/1 ethyl acetate/hexane mixture as eluent.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].O1CCOC[CH2:12]1.CO>Cl>[CH3:12][O:9][C:8](=[O:10])[C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[NH:2][CH3:1]
Reactant: C1COCCO1
Reactant: CN[C@@H](CC(C)C)C(=O)O
Agent: Cl
Solvent: CO
Product: CN[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
N-methyl-L-leucine (1.3 g, 8.95 mmol) was dissolved in 4M HCl, 1,4-dioxane (10 mL) and methanol (10 mL). The solution was stirred overnight at room temperature, then concentrated to afford the title compound as a white solid (100%). MS (ESI): 160.0 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([Cl:17])=[C:11]([F:18])[C:7]=1[C:8](O)=[O:9]>CN(C)C=O>[Cl:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([Cl:17])=[C:11]([F:18])[C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)c(Cl)c(F)c(F)c1Cl

Procedure:
160 ml of thionyl chloride are initially introduced into the reaction vessel at room temperature. 36.8 g (0.15 mol) of 2,5-dichloro-3,4,6-trifluorobenzoic acid are added in portions, while stirring. After addition of 0.5 ml of dimethylformamide, the mixture is slowly heated to 80°-90° C. and is stirred at this temperature for 5 hours. It is then concentrated and the residue is distilled under a high vacuum.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8](OC3C=CC=CC=3)[C:7]=2[N:21]=1)[CH3:2].[NH3:26]>CO>[CH2:1]([NH:3][C:4]1[N:5]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([NH2:26])[C:7]=2[N:21]=1)[CH3:2]
Reactant: N
Reactant: CCNc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)C
Solvent: CO
Product: CCNc1nc2c(N)nc(C)c(C)c2n1CC(C)C
Temperature: 170 °C

Procedure:
N-Ethyl-6,7-dimethyl-1-(2-methylpropyl)-4-phenoxy-1H-imidazo[4,5-c]pyridin-2-amine (1.3 g, 3.8 mmol) and ammonia (25 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 170° C. for four days. The resulting solution was allowed to cool to ambient temperature and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 2-4% methanol in dichloromethane with 1% aqueous ammonium hydroxide added) to provide 294 mg of N2-ethyl-6,7-dimethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]pyridine-2,4-diamine as a yellow powder, mp 168-170° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[N-:23]=[C:24]=[O:25].[K+].Cl>>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[NH:23][C:24](=[O:25])[NH:2][C:3]=2[CH2:21][CH3:22])[CH:7]=[C:8]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]=1[OH:16])([CH3:14])([CH3:13])[CH3:15]
Reactant: [N-]=C=O
Reactant: CCC(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Product: CCc1[nH]c(=O)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 50.2 %

Procedure:
By following the same procedure as in Example 6 using 3.3 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydrochloride, 1.62 g of potassium isocyanate, and 1.6 ml of concentrated hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-oxo-4-imidazoline was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:3]=1.O.[NH2:27][NH2:28]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH:5]=3)=[CH:15][CH:14]=2)[NH:28][N:27]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NCc3ccccc3Cl)nc(N)n2)cc1F
Solvent: CCO
Solvent: O
Product: Nc1nc(NCc2ccccc2Cl)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Yield: 18.2 %

Procedure:
To 4-(2-amino-6-{[(2-chlorophenyl)methyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (800 mg, 2.27 mmol) in ethanol (2 mL) was added hydrazine monohydrate (3 mL, 74 mmol), and the reaction mixture was heated to 100° C. for 1 hour in a BiotageInitiator® microwave synthesizer. Upon cooling, the reaction mixture was concentrated in vacuum and purified by RPHPLC (BiotageSP1) (gradient: 30% CH3CN/H2O to 60% CH3CN/H2O) to afford the title compound (151 mg) as an off-white solid. LC-MS (ES) m/z=366 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 4.61 (d, J=5.6 Hz, 2H), 5.37 (s, 2H), 6.07 (s, 2H), 6.40 (s, 1H), 7.34-7.27 (m, 2H), 7.46-7.41 (m, 4H), 7.70 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11]Cl)=[C:6]([CH:9]=1)[CH2:7]Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5]([CH2:10][CH2:11][N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7]2)=[CH:4][CH:3]=1
Reactant: ClCCc1ccc(Cl)cc1CCl
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)CN(c1ccccc1)CC2
Yield: 18.5 %

Procedure:
5-Chloro-2-(2-chloroethyl)benzyl chloride (8 g), was dissolved in chloroform (50 ml), then aniline (2.79 g,) and triethylamine (8.01 g,) were added to the solution. The mixture was refluxed for 18 hr. then cooled and washed with 2M sodium hydroxide solution (2×100 ml). The chloroform layer was dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled in vacuo to afford 7-chloro-2-phenyl-1,2,3,4-tetrahydroisoquinoline (1.35 g), b.pt. 170°-180°/0.6-0.8 mmHg) characterised by its nmr spectrum.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)=[CH:19][CH:18]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:26]2[CH2:25][CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Reactant: Clc1ccc(C2=CCNCC2)cc1
Product: CC(=O)N1CC(CCN2CC=C(c3ccc(Cl)cc3)CC2)c2ccccc21

Procedure:
In the manner described in Example 1, reaction of 1-acetyl-3-(2-bromoethyl)indoline with 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine gives white crystals, m.p. 116°-118°C., after recrystallization from dilute methanol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][NH:15][C:16]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[S:17]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1nccs1
Product: CN(C)CCNC(=S)NCCNCc1nccs1

Procedure:
Treating N-(2-thiazolylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40, then concentrating and separating by column chromatography gives the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:33]O)[C:22]1[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>>[Cl:32][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:33]=2)=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1cc(C(N)=NO)ccc1Cl
Product: COCc1cc(-c2nc(-c3ccc(Cl)c(C(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (461.34 mg; 1.80 mmol) and Intermediate 54 (342.95 mg; 1.50 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 8.68 (d, J=2.1 Hz, 1H), 8.43 (d, J=1.1 Hz, 1H), 8.25 (dd, J=8.3, 2.1 Hz, 1H), 8.17 (dd, J=7.9, 1.7 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.36-7.24 (m, 4H), 7.13 (d, J=7.2 Hz, 1H), 4.28-4.19 (m, 2H), 4 (s, 3H), 3.34 (s, 3H), 2.08 (s, 3H). LC/MS (Method B): 449.1 (M+H)+. HPLC (Method A) Rt 6.10 min (Purity: 96.0%).