Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1I.[Li]CCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25].[NH4+].[Cl-]>C1COCC1>[C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1Oc1ccccc1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1ccccc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 1-(o-tolyloxy)-2-iodobenzene (40 g, 0.13 mol) in anhydrous THF (500 mL) cooled to −78° C. was added dropwise 1.6 M n-BuLi in hexanes (52 mL, 0.13 mol). After stirring for 1 h at −78° C., a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (35 g, 0.13 mol) in anhydrous THF (500 mL) was added dropwise. The mixture was allowed to warm to rt and stirred overnight. Sat'd aq NH4Cl (500 mL) was added and the mixture was extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na2SO4. Solvent removal and flash column chromatography afforded (2-(o-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone (23 g, 45%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].[C:16]([O:20][C:21](=O)[O:22]C(C)(C)C)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
L-tyrosine methyl ester hydrochloride 2 (104.3 g, 0.45 mol) and di-t-butylcarbonate (DBC, 98.2 g, 0.45 mol) were suspended in toluene (521.3 g), and triethylamine (50.1 g, 0.495 mol) was added dropwise thereto at 20° C. over 1.5 hrs. After further keeping at 20° C. for 4 hrs, the reaction mass was washed with 5% hydrochloric acid (328.1 g) and 5% aqueous sodium bicarbonate (378.1 g). The toluene solution thus obtained was dried over suitable amount of magnesium sulfate and then concentrated to about a half of the volume under reduced pressure. To the concentrate was added dropwise n-hexane (329.5 g) at room temperature over 1 hr. After keeping at 0° C. overnight, precipitates were filtered and dried under reduced pressure to give N-Boc-L-tyrosine methyl ester 3 (126.9 g, yield 95.5%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20](OC(C)(C)C)=O)[CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O.[CH3:34][S:35]([CH:38]=C)(=[O:37])=[O:36]>C(Cl)Cl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH2:15][CH2:14]1
Reactant: COc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
1,1-Dimethylethyl 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine-1-carboxylate (0.7 g, 2.0 mmol) was taken up in 20 mL of DCM and treated with 7 mL of TFA. The mixture stirred for 1 h and was then reduced in vacuo. The solids were transferred to a 50 mL sealed tube and taken up in 20 mL of dioxane. TEA (0.58 g, 5.75 mmol) was added followed by ethenyl methyl sulfone (0.51 g, 4.79 mmol). The mixture was heated to 30° C. for 24 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step B (0.7 g, 1.88 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.56 (s, 1H), 3.86 (s, 3H), 3.33-3.42 (m, 4H), 3.26 (t, J=6.68 Hz, 2H), 2.99 (s, 3H), 2.87 (t, J=6.59 Hz, 2H), 2.74-2.81 (m, 2H), 2.67-2.74 (m, 2H), 2.20 (s, 3H), 1.81-1.89 (m, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[F:17].[C:18]([CH:20]1[CH2:22][CH:21]1[C:23](N(OC)C)=[O:24])#[N:19]>CCCCCC.C1COCC1.ClCCl>[F:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C:23]([CH:21]1[CH2:22][CH:20]1[C:18]#[N:19])=[O:24]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CON(C)C(=O)C1CC1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: N#CC1CC1C(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.6 ml (4.12 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 1.00 g (4.12 mmol) of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene in 8 ml of THF at −78° C., and the mixture was stirred for 0.5 h. Then, at −78° C., a solution of 423 mg (2.74 mmol) of the compound from Example 73A in 2 ml of THF was added, and the mixture was allowed to warm to RT and was stirred at RT for 2 h. It was diluted with dichloromethane, and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 206 mg (29% of theory) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:10].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1>CN(C=O)C>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:8][C:9](=[O:10])[N:11]4[CH2:16][CH2:15][S:14][CH2:13][CH2:12]4)[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Reactant: O=C(CBr)N1CCSCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCC(=O)N4CCSCC4)cc3c21
Temperature: 70 °C

Procedure:
Cesium carbonate (1.7 g, 5.22 mmol, 3 eq) was added to a mixture of 4-(bromoacetyl)thiomorpholine (468 mg, 2.09 mmol, 1.2 eq, prepared according to the method described in Part C of Example 30) and 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.74 mmol, 1.0 eq) in 20 mL of DMF. The reaction mixture was heated to 70° C. and maintained for 14 hours. The reaction mixture was then cooled to ambient temperature, filtered, diluted with 50 mL of dichloromethane, concentrated under reduced pressure, and filtered to afford crude material. The crude material was purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60), concentrated under reduced pressure, and crystallized from acetonitrile to afford 231 mg of 2-(methoxymethyl)-8-(2-oxo-2-thiomorpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off white solid, mp 214-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCOc1cccc(CN)c1
Product: CCOc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-ethoxybenzylamine (58.3 mg, 0.39 mmol). The title compound was obtained as a solid (71 mg, 45% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.36 (1H, m), 8.99 (2H, s), 8.48 (1H, s), 7.22 (1H, m), 6.81 (3H, m), 4.36 (2H, m), 3.99 (2H, q), 1.30 (3H, t). MS m/z: 482.13, 484.10 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][N:10]=1.[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br-:25].[CH2:11]([N:7]1[CH:8]=[CH:9][N+:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]1[CH:2]1[O:1][CH2:5][CH2:4][O:3]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(Cn2ccnc2C2OCCO2)cc1
Product: [Br-]
Product: c1ccc(Cn2cc[n+](Cc3ccccc3)c2C2OCCO2)cc1
Yield: 79.8 %

Procedure:
A reaction mixture of 12.5 g (54 mmol) of 2-(1,3-dioxolan-2-yl)-1-benzylimidazole and 9.3 g (54 mmol) of benzyl bromide was heated on a steam-bath with stirring for 1/4 h and the resulting mixture was stirred at room temperature overnight. The mixture was triturated with ether/ethyl acetate and filtered to afford 17.3 g (79.8%) of 3-benzyl-2-(1,3-dioxolan-2-yl)-1-benzyl imidazolium bromide (Formula VI: A=1-benzylimidazole;Y=2-(1,3,-dioxolan-2-yl);R1 =R6 =H;Z- =Br-).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:26])[CH:21]=3)[NH:16][C:15]=2[CH:14]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:26])[CH:21]=3)[NH:16][C:15]=2[CH:14]1[C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCc2c([nH]c3ccc(Cl)cc23)C1c1cccc(O)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC(=O)N1CCc2c([nH]c3ccc(Cl)cc23)C1c1cccc(O)c1

Procedure:
(tert-Butoxy)-N-{3-[1-(3-hydroxyphenyl)-6-chloro-(1,2,3,4-tetrahydro-beta-carbolin-2-yl)]-3-oxopropyl}carboxamide was treated with HCl in dioxane (4 N, 10 equiv) for 30 min, and the solvent was removed to give a residue which was purified to yield 3-(2-beta-alanyl-6-chloro-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)phenol 23.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:25]1OC(O)C[O:27][CH:26]1O.CC(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH2:25][CH2:26][OH:27]
Reactant: OC1COC(O)CO1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCO)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 56.2 %

Procedure:
A solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (350 mg, 1.05 mmol), glycolaldehyde dimer (130 mg, 1.05 mmol) and AcOH (0.15 ml, 2.1 mmol) in DCM (5 ml) was stirred at room temperature for 18 hours. Saturated aqueous sodium carbonate (10 ml) and DCM (10 ml) were added and the mixture was shaken and partitioned. The aqueous phase was extracted with DCM (2×10 ml) and the combined organics dried (K2CO3), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:1) to provide the title compound as a clear colourless oil (223 mg, 0.59 mmol, 56%). 1H NMR (400 MHz, CDCl3) δ 1.70-1.90 (m, 6H), 1.96 (s, 3H), 2.00 (quintet, 2H), 2.14 (m, 2H), 2.37 (t, 2H), 2.40-2.60 (m, 6H), 2.65 (t, 2H), 3.35 (t, 2H), 3.50 (m, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.89 (d, 2H), 7.19 (d, 2H). HRMS ESI+ m/z 377.2796 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16](OCC)=[O:17]>C1COCC1>[CH3:13][O:14][CH2:15][C:16]([CH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:17]
Reactant: Cc1csc(C)n1
Reactant: CCOC(=O)COC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC(=O)Cc1nc(C)cs1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
3.00 g (26.5 mmol) of 2,4-dimethylthiazole are dissolved in 30 ml of abs. THF and, at −78° C., 11.7 ml (29.2 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 5.32 g (45.1 mmol) of ethyl methoxyacetate are added as solution in 15 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. 4.2 g (68% of theory) of the title compound are obtained in 80% purity (GC-MS) and are employed without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: COC(=O)C(=O)Cl
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@@H]1CN(C(=O)C(=O)OC)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (200 mg, 0.593 mmol) was suspended in dichloromethane (5 mL). Methyl chloroglyoxylate (0.070 mL, 0.76 mmol), triethylamine (0.250 mL, 1.80 mmol) and DMAP (catalytic amount) were added under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=7/3→1/0) to obtain 208.1 mg of the title compound as a colorless oily substance (91%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]#[N:5].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[H-].[Na+]>>[C:4]([CH2:3][CH2:2][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)#[N:5]
Reactant: c1c[nH]cn1
Reactant: N#CCCCl
Agent: [H-]
Agent: [Na+]
Product: N#CCCn1ccnc1

Procedure:
Using 2.35 ml of 3-chloropropionitrile, 2.0 g of imidazole and 1.3 g of sodium hydride (60%), 3.2 g of 1-(2-cyanoethyl)imidazole was obtained by the same manner as the procedure of Reference Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[CH2:15][CH:16]=[CH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][CH:14]([C:18]3[CH:19]=[CH:20][C:21]([I:24])=[CH:22][CH:23]=3)[CH2:15][CH:16]=[CH2:17])[C:30]2=[O:31])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=CCC(CNCCNc1cc(Cl)cc(Cl)c1)c1ccc(I)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCC(CN1CCN(c2cc(Cl)cc(Cl)c2)C1=O)c1ccc(I)cc1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To a stirred solution of N-(3,5-dichloro-phenyl)-N′-[2-(4-iodo-phenyl)-pent-4-enyl]-ethane-1,2-diamine (0.386 g, 0.81 mmol) in toluene (10 mL) was added CDI (0.18 g, 1.1 mmol, 1.4 eq). The mixture was heated to 100° C. for 16 h, then cooled to room temperature, diluted with EtOAc (25 mL) and washed twice with saturated aqueous NaCl (25 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give a dark brown oil. The crude product was purified by flash column chromatography eluting with 10% EtOAc/hexanes to give 1-(3,5-dichloro-phenyl)-3-[2-(4-iodo-phenyl)-pent-4-enyl]-imidazolidin-2-one (0.128 g, 0.255 mmol, 30%) as a pale foam. 1H NMR (300 MHz, CDCl3): δ 7.74 (d, 2H), 7.54 (d, 2H), 7.20 (m, 3H), 5.75 (m, 1H), 5.10 (m, 2H), 3.74 (m, 3H), 3.38 (m, 2H), 3.22 (m, 1H), 3.08 (m, 1H), 2.50 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: COc1ncc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ncc(-c2cncc(Cl)c2N2CCC(C(N)=O)CC2)cn1

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27 mmol), 2-methoxypyrimidine-5-boronic acid (53 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 96:4-82:18, biotage 25+S) to furnish the title compound as an off white solid (20 mg, 21%), along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide as a white solid (32 mg, 43% RSM), LC-MS (ESI, 4 min) Rt 1.76 min, m/z 348 (100%, [M+H]+); m/z (ESI) C16H18N5O2Cl requires 347.1149, found [M+H]+ 347.1147.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[Cu:13]>O.[Cl-].C([N+](CC)(CC)CC)C.C(O)C>[C:1]([O-:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-:6])=[O:5].[Cu+2:13]
Reactant: [Cu]
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1ccccc1C(=O)[O-]
Product: [Cu+2]
Yield: 25.25 %

Procedure:
To a reaction flask was charged 19.93 g (0.120 mole) of phthalic acid, 100 g of ethanol and 0.50 g of tetraethylammonium chloride hydrate. Copper foil was used as the anode and a graphite rod as the cathode. After passing 9,964 coulombs of electricity, 3.0 g (0.047 mole) of copper was consumed. The solvent was stripped off at reduced pressure to give a blue solid of copper phthalate containing 25.25% copper.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16](OC)=[O:17]>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([NH:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:17]
Reactant: Cc1cccc(CCN)c1
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCc2cccc(C)c2)cc1OC
Yield: 51 %

Procedure:
A stirred solution of 2-(3-methylphenyl) ethylamine (28.3 g, 0.21 mol) and 36.9 g of methyl 3,4-dimethoxybenzoate (36.9 g, 0.19 mol) was heated at 180° for 4 h. The crude amide was taken up in CH2Cl2 and washed with dilute HCl, dilute Na2CO3 and water. Chromatography over neutral alumina afforded 29 g (51%) of the title compound (one spot by tlc) eluted with CH2Cl2. The analytical sample showed mp 108-109° after crystallization from i-PrOH.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12]C)[C:7]#[N:8])([CH3:3])=[CH2:2].Cl.N1C=CC=CC=1.Cl>>[OH:12][C:11]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:1]([CH3:3])=[CH2:2]
Reactant: C=C(C)c1cc(C#N)cc([N+](=O)[O-])c1OC
Agent: Cl
Solvent: c1ccncc1
Product: C=C(C)c1cc(C#N)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
A mixture of 3-isopropenyl-4-methoxy-5-nitrobenzonitrile (5.06 g, 23.19 mmol) and pyridine hydrochloride (10 g, 87 mmol) was placed in an oil bath at 200° C. for 4 min. The reaction mixture was then cooled to room temperature, added 1M HCl, and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a Horizon Biotage, 65i Si column, eluting with 1 column volume of 1% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 1% to 100% over 10 column volumes to afford the title compound. Mass spectrum (ESI) 203.1 (M−1).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:22])[CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1.CI>C1COCC1>[CH3:13][O:14][C:15](=[O:22])[CH:16]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[CH3:1]
Reactant: COC(=O)Cc1ccsc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccsc1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Anhydrous diisopropylamine (24.3 g) was added to Anhydrous THF (100 ml) which was then cooled by a dry ice-acetone bath. To this solution was first added dropwise n-butyllithium (15% w/o % in Hexane, 147 ml), then in a second step a THF solution (50 ml) of 3-thiophene acetic acid methyl ester (31.2 g). Thereafter, this solution was kept at the same temperature under cooling, while stirring was continued for 30 minutes. Then, methyl iodide (36.9 g) was added in one portion to the reaction mixture which after 30 minutes, was removed from the cooling bath to be allowed to reach to room temperature. After the reaction, THF was distilled off under reduced pressure and the formed residue was dissolved in water which was extracted by two portions of 200 ml ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by distillation to obtain 26.6 g 2-(3-thienyl)propionic acid methyl ester with bp 90°-92° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.NC(N)=[S:15].[CH3:17][C:18]1[CH:19]=[N:20][C:21]2[CH:22](Br)[CH2:23][CH2:24][CH2:25][C:26]=2[CH:27]=1.[OH-].[Na+]>O.C(O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:15][CH:22]3[C:21]4[N:20]=[CH:19][C:18]([CH3:17])=[CH:27][C:26]=4[CH2:25][CH2:24][CH2:23]3)[NH:3][C:4]=2[CH:10]=1
Reactant: NC(N)=S
Reactant: Cc1cnc2c(c1)CCCC2Br
Reactant: COc1ccc2nc(Cl)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(SC3CCCc4cc(C)cnc43)[nH]c2c1

Procedure:
0.55 Gram of 2-chloro-5-methoxybenzimidazole, 0.2 g of thiourea and 10 ml of ethanol were mixed together and refluxed for 2 hours. Then, 5 ml of an aqueous solution containing 0.5 g of 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline and 0.3 g of sodium hydroxide was added thereto, and the resulting mixture was refluxed for 5 hours. After the reaction was completed, ethanol was removed by evaporation, to the residue thus obtained was added water, then extracted with chloroform, the chloroform extract was dried with anhydrous magnesium sulfate, and chloroform was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to yield 0.5 g of 8-(5-methoxy-2-benzimidazolyl)thio-3-methyl-5,6,7,8-tetrahydroquinoline in the form of colorless caramel-like substance.