Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1>CC#N>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:15]1[CH2:16][CH2:17][CH2:18][C:13](=[O:19])[CH2:14]1)([O-:3])=[O:2]
Reactant: O=C1C=CCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: CC#N
Product: O=C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of 5-nitroindole (4.00 g, 25.61 mmol) in dry MeCN (5.00 mL) was added cyclohex-2-enone (7.40 mL, 76.83 mmol) and Bi(NO3)3 (0.12 g, 0.26 mmol) and the mixture stirred overnight at room temperature. The solvent then was evaporated and the crude was purified by column chromatography (50% Hexane:50% EtOAc) to obtain the title compound (2.70 g, 41%) as a yellow solid. 1H-NMR (CDCl3) δ 1.81-2.09 (m, 3H), 2.26-2.34 (m, 1H), 2.37-2.55 (m, 2H), 2.65 (dd, 1H, J=9.9, 12.9 Hz), 2.77-2.85 (m, 1H), 3.47-3.56 (m, 1H), 7.15 (d, 1H, J=2.1 Hz), 7.41 (d, 1H, J=9.0 Hz), 8.12 (dd, 1H, J=2.1, 9.0 Hz), 8.51 (s, 1H), 8.59 (d, 1H, J=2.1 Hz); EI-MS (m/z, %) 258 (M+, 100).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH:29][CH:30]1[CH2:39][CH2:38][CH2:37][C:36]2[N:35]=[C:34]([C:40]#[N:41])[CH:33]=[CH:32][C:31]1=2>C(#N)C.C(OCC)(=O)C>[C:40]([C:34]1[CH:33]=[CH:32][C:31]2[CH:30]([N:29]([CH2:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:39][CH2:38][CH2:37][C:36]=2[N:35]=1)#[N:41]
Reactant: CCOC(=O)CCCCBr
Reactant: COc1ccccc1CCNC1CCCc2nc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCN(CCc1ccccc1OC)C1CCCc2nc(C#N)ccc21

Procedure:
17.07 ml (0.11 mol) of ethyl 5-bromopentanoate, 8.43 g (0.05 mol) of potassium iodide and 22.61 g (0.21 mol) of anhydrous sodium carbonate were added to a solution of 31.22 g (0.10 mol) of 5-{[2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile in 300 ml of dry acetonitrile, and the mixture was heated under reflux for 4 days. The reaction was then concentrated to a volume of about 50 ml on a rotary evaporator. The solution obtained was taken up in 250 ml of ethyl acetate and 400 ml of saturated aqueous sodium chloride solution, and the organic phase was then removed. The aqueous phase was extracted twice with in each case 150 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated to dryness. The residue obtained was applied to 25 g of silica gel and purified by column chromatography on silica gel (80 g cartridge; flow rate: 60 ml/min; mobile phase: petroleum ether/ethyl acetate 95:5→80:20 over 30 min). This gave 28.89 g (0.05 mol, content 80%, 52% of theory) of the target compound as an orange oil.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[I:16])[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C.C([O-])(=O)C.[Na+]>C=O.O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:7][CH:6]1[I:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1cc(-c2ccccc2)nc1I
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCN1C(CO)=C(c2ccccc2)NC1I

Procedure:
1-Butyl-2-iodo-4-phenyl-1H-imidazole (3.26 g) is dissolved in formaldehyde (16.1 mL). Acetyl alcohol (5.5 mL) and sodium acetate (20 g) are added to the solution and the mixture is refluxed under N2 for 4 hours. The reaction mixture is diluted with H2O, adjusted to pH 9, extracted with ethyl acetate, and dried over Na2SO4. Concentration and purification of the extract via flash chromatography yields (1-butyl-2-iodo-4-phenyl-3H-imidazol-5-yl)-methanol.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][C:9](OC)=[C:8]([Cl:14])[CH:7]=1)[OH:5].[K+].[Br-:16]>>[ClH:14].[NH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:16])[CH:7]=1)[OH:5]
Reactant: [Br-]
Reactant: COc1ccc([C@H](O)CN)cc1Cl
Agent: Cl
Agent: [K+]
Product: NC[C@@H](O)c1cccc(Br)c1

Procedure:
The title material was prepared according to the general procedure outlined for the synthesis of (S)-2-amino-1-[3-chloro-4-methoxyphenyl]ethanol hydrochloride. LRMS [M+H]+ 217.9; IR (KBr, cm−1) 3025, 3443, 2891; 1H NMR (500 MHz, DMSO-d6) δ 7.93 (b s, 2H), 7.60 (s, 1H), 7.52 (d, 1H), 7.41 (s, 1H), 7.35 (d, J=7.7 Hz, 1H) 6.17 (s, 1H), 4.82 (m, 1H), 3.08 (ddd, J=2.6, 12.7, 9.6 Hz, 2H); 13C NMR (DMSO-d6, 75.5 MHz) δ 144.4, 130.5, 128.7, 125.0, 121.6, 68.3, 45.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[NH2:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([F:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:9]2)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1F
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)CC[C@H]1F

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate and 3-amino-6-bromopicolinic acid were reacted yielding after purification (+/−)-tert-butyl 1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (20%). LCMS (m/z): 510.9 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8]4[CH2:18][CH2:17][C:16](=[O:19])[C:9]=4[CH:10]=[CH:11][C:12]=3[NH:13][C:14]=2[CH:15]=1.[H-].[Na+].Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl.C1C2NC3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl.O.C(Cl)(Cl)Cl.CO.C(Cl)Cl.C(OCC)(=O)C>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:13]1[C:12]2[CH:11]=[CH:10][C:9]3[C:16](=[O:19])[CH2:17][CH2:18][C:8]=3[C:7]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][C:14]1=2
Reactant: CN(C)CCCCl
Reactant: COc1ccc2c(c1)[nH]c1ccc3c(c12)CCC3=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc2c3c4c(ccc3n(CCCN(C)C)c2c1)C(=O)CC4
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
Compound 36 (1.0 g, 3.98 mmol) was suspended in CH2Cl2 (10 mL); NaH (0.75 g, 12.0 mmol, 3 eq.) was added. The mixture was stirred at room temperature for 5-10 min; then 3-dimethylamino-1-propyl chloride hydrochloride (0.75 g, 4.74 mmol, 1.2 eq.) was added. The reaction mixture was heated to 70° C., kept at this temperature for 2 h (TLC monitoring, eluent: CH2Cl2-ethyl acetate, 1:1—the presence of initial carbazole, CHCl3-MeOH, 9:1—purity of the product). The resulting mixture was diluted with water, extracted with ethyl acetate, evaporated, and purified on a short thick column with silica gel, eluent: CHCl3-MeOH 99:1→90:10. Yield of 37: 0.84 g (63%).
Reaction SMILES: [CH:1]([N:4]([CH:15]([CH3:17])[CH3:16])[CH2:5][CH2:6][NH:7][C:8](N1C=CN=C1)=[O:9])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[C@@H:29]2[O:33][C@H:32]([C:34]([NH:36][CH2:37][CH3:38])=[O:35])[C@@H:31]([OH:39])[C@H:30]2[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:21]=1.C(O)(C)C.C1(C)C=CC=CC=1>ClCCl.C(OCC)C>[CH:15]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][NH:7][C:8]([NH:18][CH2:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[C@@H:29]2[O:33][C@H:32]([C:34]([NH:36][CH2:37][CH3:38])=[O:35])[C@@H:31]([OH:39])[C@H:30]2[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:21]=1)=[O:9])([CH3:17])[CH3:16]
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 44.2 %

Procedure:
N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (84 mg, 0.35 mmol) (Preparation 27) was added to a stirred suspension of (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (100 mg, 0.23 mmol) (Preparation 11) in dichloromethane (5 ml) at room temperature. The reaction was then heated to reflux and a drop of isopropanol was added to help dissolve the reagents. The reaction mixture was heated under reflux for 20 minutes and then toluene (5 ml) was added. The dichloromethane was boiled off and the reaction was then heated under reflux for 30 minutes. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume increasing to 80:20:2 by volume). The solvent was removed under reduced pressure to give a yellow oil. The oil was dissolved in dichloromethane (2 ml) and diethylether was added to induce crystallisation. Filtration gave the title compound as a white solid (70 mg).
Reaction SMILES: BrC1C=CC(N)=CC=1F.C(OCC)(=O)/C=C/C.[NH2:18][C:19]1[C:24](F)=[CH:23][C:22](/[C:26](/[CH3:33])=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:21]([F:34])[CH:20]=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22](/[C:26](/[CH3:33])=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:21]([F:34])[CH:20]=1
Reactant: CCOC(=O)/C=C(\C)c1cc(F)c(N)cc1F
Agent: C/C=C/C(=O)OCC
Agent: Nc1ccc(Br)c(F)c1
Product: CCOC(=O)/C=C(\C)c1ccc(N)cc1F
Yield: 17 %

Procedure:
Using 4-bromo-3-fluoroaniline (10.0 g) and ethyl crotonate (10.9 ml), Compound 11a (2.01 g, 17%) was obtained as a brown solid in the same manner as Compound 10a was synthesized.
Reaction SMILES: CO.C(OC(=O)[N:9]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:30])[CH2:12][CH2:11]1)(C)(C)C.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][NH:9][CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[C:27]5[C:22](=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][C:19]4=[O:30])[CH2:12][CH2:11]3)=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Reaction time: 1.5 h

Procedure:
To 1.5 mL of methanol solution containing 0.182 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 1.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.13 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-methoxyquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([S:10]([CH3:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:20]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:14][C:15]1[CH:16]=[C:17]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=[CH:33][N:32]=2)[CH:18]=[C:19]([C:2]2[S:6][C:5]([C:7]([S:10]([CH3:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=2)[CH:20]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(c1ncc(Br)s1)S(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)S(C)(=O)=O)s2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
The product of Step 1 (112 mg, 0.40 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 3, 150 mg, 0.40 mmol), and PdCl2(dppf)-CH2Cl2 (29 mg, 0.040 mmol) were combined in a flask, sealed, and purged with nitrogen (2×). Dioxane (2.4 mL) and 2 M Na2CO3 (0.59 mL, 1.19 mmol) were added, and the reaction was purged again with nitrogen (2×). The mixture was stirred in an oil bath at 100° C. overnight. The dark brown reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded N-(3-methyl-5-{2-[2-(methylsulfonyl)propan-2-yl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (140 mg, 78%) as a colorless solid. MS ESI: [M+H]+ m/z 457.0. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.84 (d, J=4.9, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.49 (s, 1H), 7.29 (d, J=4.9, 1H), 7.22 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 1.83 (s, 6H). rhSYK activity=+++
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1.Br[CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.CCOC(C)=O>C1COCC1.CCCCCC>[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:22][CH2:23][CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[C:10]=2[CH:9]=1
Reactant: BrCCC1OCCO1
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(CCC1OCCO1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A solution of n-BuLi (2.5 M in hexane, 6.4 mL, 16.0 mmol) was slowly added into a cooled (-78° C.) solution of 2-methoxyfluorene (prepared according to example 10; 3.1 g, 15.8 mmol) in 100 ml THF. The reaction mixture became dark red and a solid started to precipitate out. After 30 minutes 2-(2-bromoethyl)-1,3-dioxolane (5.8 g, 32.0 mmol) was added to the cold solution and the solution was warmed up to room temperature. The reaction mixture was stirred overnight at room temperature. TLC (silica, 25% EtOAc in hexane) was used to monitor the reaction. The reaction was quenched with water and the product was extracted into EtOAc. The organic layer was washed with water (×3), dried over magnesium sulfate and evaporated. Short path chromatography (5% ethyl acetate/hexane) afforded 3.2 g (62.5%) of the product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:14]([N:21]([CH2:23][CH2:24]Cl)[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:14]([N:21]([CH2:23][CH2:24][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CN(CCCl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(OCCN(C)Cc2ccccc2)c(C=O)c1
Temperature: 70 °C

Procedure:
In a similar manner to the previous example, a solution of 2-hydroxy-5-methoxybenzal dehyde (25.0 g) in DMF (50 ml) was added to a stirred suspension of sodium hydride (6.84 g of a 60% dispersion in mineral oil) in dry DMF (125 ml) at ambient temperature under nitrogen with stirring. The mixture was heated at 70° C. for 2 hours and then cooled to ambient temperature and a solution of N-benzyl-2-chloro-N-methylethylamine in toluene (75 ml) was added [prepared from 48.5 g of the hydrochloride salt]. The oil obtained after work up was distilled under vacuum to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-methoxybenzaldehyde as an oil. A sample of this oil which boiled at 202°-206° C. at 0.65 mbar was dissolved in ether and acidified with ethereal hydrogen chloride. The precipitate was collected by filtration, washed with ether to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-methoxybenzaldehyde hydrochloride, m.p. 167°-169° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(OCC)(=O)C.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cc(I)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Into a 50 mL round bottom flask was placed the 1-iodo-3-nitro-5-(trifluoromethyl)benzene (1 g, 3.15 mmol), N-methylpiperazine (0.379 g, 3.78 mmol), bis(dibenzylideneacetone)palladium (0.029 g, 0.0315 mmol), sodium tert-butoxide (0.424 g, 4.416 mmol), 2-dicyclohexyl-2′-(N,N-dimethylamino)biphenyl (0.037 g, 0.094 mmol), and toluene (25 mL). Reaction was heated to 80° C. with stirring for 20 hours. Reaction was cooled to room temperature and water (1 mL) and ethyl acetate (10 mL) were added. The organic layer is separated, concentrated under reduced pressure and purified via silica column eluting with 0 to 20% methanol in dichloromethane. The title compound was obtained as an orange oil.
Reaction SMILES: [F:1][C:2]([F:15])([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3](OCC)=[O:4].[CH3:16][NH:17][CH3:18]>>[CH3:16][N:17]([CH3:18])[C:3](=[O:4])[C:2]([F:15])([F:1])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: CNC
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Product: CN(C)C(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C

Procedure:
A 3-necked flask, equipped with magnetic stirrer, reflux condenser and gas inlet tube, was charged with 121 g (0.5 mole) of ethyl perfluorobutyrate. The contents of the flask were heated to 60° C. and a slow stream of dimethylamine was passed in. The reaction is exothermic and the gas flow rate was adjusted to keep the temperature in the range of 60°-70° C. without external heat. Gas flow was continued until the weight increase of the flask showed absorption of 22.5 g (0.5 mole) of the amine.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[C:19]=2[N:27]=1)[CH3:13]>>[NH2:26][C:20]1[C:19]2[N:27]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:3]([N:2]([CH3:1])[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:4])[CH2:32][CH2:31]3)[C:18]=2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N(C)c2ccccc2)CC1

Procedure:
Using the method of Examples 54-65, N-methyl-N-phenylcarbamoyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 465.3006.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O:11][C:12]1[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1.C1C=CC=CC=1>O>[CH3:2][C:1](=[N:18][C:13]1[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:11][CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1ccccc1N
Solvent: c1ccccc1
Solvent: O
Product: COc1ccccc1N=C(C)c1ccccc1

Procedure:
A solution of acetophenone (120 ml), o-anisidine (123 ml), benzene (100 ml) was refluxed with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(αmethyl benzylidene)-o-anisidine (IX) (90 C). It was then hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent to give N-(α-methyl benzyl)-o-anisidine (X). X had a boiling point of 117° C. at 0.3 millimeter.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.CN>C1COCC1>[NH2:3][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1)NC(=O)OCc1ccccc1
Agent: CN
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCCCON)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of 78 mg (0.15 mmol) of methyl (2S)-3-{4-[3-(1,3-dioxoisoindolin-2-yloxy)propoxy]phenyl}-2-[(phenylmethoxy)carbonylamino]propanoate, as prepared in the preceding step, in 5 mL THF was added 0.4 mL of 2M methylamine solution in THF. The solution was stirred at room temperature for 3 h. The solvent was then removed under reduced pressure. The mixture was chromatographed on a silica gel column using EtOAc/hexanes (3:7 to 7:3 v/v) as eluent to yield 47 mg (80%) of viscous liquid as product: 1H NMR (300 MHz, CDCl3) δ7.38-7.28 (m, 5H), 6.98 (d, J=8.70 Hz, 2H), 6.79 (d, J=8.70 Hz, 2H), 5.20 (d, J=8.20 Hz, 1H), 5.10 (d, J=12.34 Hz, 1H), 5.05 (d, J=12.34 Hz, 1H), 4.60 (m, 1H), 3.99 (t, J=6.30 Hz, 2H), 3.84 (t, J=6.20 Hz, 2H), 3.71 (s, 3H), 3.10-2.97 (m, 2H), 2.05 (quintet, J=6.24 Hz, 2H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(=O)C.O>C(O)C.O1CCOCC1.Cl>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)OCCOc1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C=Cc2ccc(OCCO)cc2)cc1
Yield: 77.3 %

Procedure:
4'-(2-Acetoxyethoxy)-4-methylsulfonylstilbene (17 g, 0.05 mol, Example 2) was dissolved in a mixture of 125 mL of ethanol, 25 mL of 1,4-dioxane and 4.2 mL of concentrated HCl, and heated at reflux overnight. While heating, water was added to the reaction mixture to near precipitation and the solution was cooled. The precipitate was filtered, washed with water and dried in vacuum to give 12.3 g (77%) of the white product. m.p.=224°-226° C.