Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(O)CCCN1C(=O)[C@H](C(C)C)NC(OC(C)(C)C)=O.C(OC(=O)C)(=O)C.[C:30]([O:33][C@H:34]1[C@H:39]([Br:40])[CH2:38][CH2:37][N:36]([C:41](=[O:54])[C@@H:42]([CH:51]([CH3:53])[CH3:52])[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:35]1)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:33][C@@H:34]1[C@@H:39]([Br:40])[CH2:38][CH2:37][N:36]([C:41](=[O:54])[C@@H:42]([CH:51]([CH3:52])[CH3:53])[NH:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:35]1)(=[O:32])[CH3:31]
Reactant: CC(=O)O[C@@H]1CN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)CC[C@H]1Br
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC(O)C1Br
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)CC[C@@H]1Br

Procedure:
0.57 g of bromo-N—(N-BOC-valyl)-piperidin-3-ol, dissolved in pyridine, is treated with 0.4 ml of acetic acid anhydride, the mixture obtained is stirred and a mixture of 3(R*)-acetoxy-4(R*)-bromo-N—(N-BOC-(R)-valyl)-piperidine (COMPOUND A) and 3(S*)-acetoxy-4(S*)-bromo-N—(N-BOC-(R)-valyl)-piperidine (COMPOUND B) is obtained and is separated by chromatography.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17]=[C:18]2[C:21]2([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[CH:13][CH:12]=1)(C)(C)C.Cl>COC>[ClH:30].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2([C:18]3[C:19]4[C:14](=[CH:13][CH:12]=[C:11]([O:10][CH2:9][CH2:8][NH2:7])[CH:20]=4)[CH2:15][CH2:16][N:17]=3)[CH2:22][CH2:23]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Agent: COC
Agent: Cl
Product: NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Temperature: 25 °C

Procedure:
A solution of tert-butyl[2-({1-[1-(4-chlorophenyl)cyclopropyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]carbamate (440 mg, 1 mmol) methylenehloride (10 ml) was treated with 5N HCl in dimethylether (0.5 ml) and stirred over night at room temperature. The solvent was removed, the residue triturated with diisopropyl ether and the insoluble slid collected. Yield: 370 mg (0.98 mmol, 98%)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][NH2:25]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:25][N:24]([CH3:23])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Product: CCc1nn(C)c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1-methyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and methylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (ISP): 309.2 ((M+H)+.).
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][S-:13].[Na+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([S:13][CH3:12])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: C[S-]
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc2nc[nH]c12
Temperature: 120 °C

Procedure:
To a solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (2.01 g, 10.7 mmol) in DMF (21 mL) at room temperature was added sodium methanethiolate (1.88 g, 26.8 mmol). Mixture was heated at 120° C. for eight hours. An additional 801 mg of sodium methanethiolate was added and mixture stirred at 120° C. for fifteen hours. After adding an additional 340 mg of sodium methanethiolate and heating at 120° C. for five hours, reaction mixture was cooled to room temperature and poured into 100 mL of water. This was then extracted with ethyl acetate (5×150 mL) and combined organic layers were washed with 50% Brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 6-chloro-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.01, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:19])=[C:9]([N+:20]([O-])=O)[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.[Pd]>[NH2:20][C:9]1[C:8](=[O:23])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[CH3:19]
Reactant: CCCCCCn1cc(-c2ccccc2)c(C)c([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCn1cc(-c2ccccc2)c(C)c(N)c1=O
Reaction time: 4 h
Yield: 97.3 %

Procedure:
A mixture of 1-hexyl-4-methyl-3-nitro-5-phenyl-2-pyridone (0.093 g, 0.30 mmol) and 10% Pd/C in ethyl acetate (100 ml,) was hydrogenated at 45 psi in a Parr apparatus for 4 hours. The catalyst was removed by filtration, and the solvent was evaporated to give 3-amino-1-hexyl-4-methyl-5-phenyl-2-pyridone (0.083 g, 97%).
Reaction SMILES: [C:1]([NH:18][C:19]1[C:20](=[O:26])[CH:21]=[CH:22][C:23](=[O:25])[CH:24]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[ClH:27]>C(OCC)(=O)C>[C:1]([NH:18][C:19]1[C:20](=[O:26])[CH:21]=[C:22]([Cl:27])[C:23](=[O:25])[CH:24]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cl
Reactant: CCCCCCCCCCCCCCCC(=O)NC1=CC(=O)C=CC1=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)NC1=CC(=O)C(Cl)=CC1=O
Reaction time: 2 h
Yield: 64 %

Procedure:
To 100 g of 2-palmitoylamino-1,4-benzoquinone were added 500 ml of ethyl acetate was stirring. The system was then allowed to undergo reaction at room temperature with hydrogen chloride gas blown thereinto for 2 hours. After completion of the reaction, the reaction system was washed with 1,000 ml of iced water. 50 ml of concentrated nitric acid was then added to the system which was then allowed to undergo reaction at room temperature for 30 minutes. After completion of the reaction, the reaction system was washed with 500 ml of water and then with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. To the resulting ethyl acetate solution was added 1,500 ml of acetonitrile. The reaction system was then cooled for crystallization. The resulting crystal was filtered off, and then dried to obtain 70 g of 2-palmitoylamino-5-chloro-1,4-benzoquinone. (Yield: 64%)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O1[CH2:20][CH2:19][NH:18]C1=O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:20][CH2:19][NH2:18])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C1NCCO1
Agent: [K+]
Agent: [OH-]
Product: NCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
ExxonMobil™ Aromatic 100 solvent (300 mL) was added into a 3-neck round bottom flask containing 4-phenylphenol (50.00 g, 294 mmol) and stirred for 15 minutes at room temperature. Potassium hydroxide pellets (1.9 g, 293 mmol) were added and the mixture heated to reflux temperature for 10 minutes. 2-oxazolidinone (26.5 g, 294 mmol) was added, and the reaction mixture continued to stir at reflux temperature for 4 hours. Additional 2-oxazolidinone (8.05 g, 92.4 mmol) was added and the reaction mixture was allowed to continue stirring at reflux for an additional 4 hours. After indication of complete conversion of 4-phenylphenol by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was filtered and the filtrate was collected. The solvent was evaporated in vacuo to obtain 14.5 g (23%) of the amine as a white solid. 1H NMR (DMSO, 400 MHz) δ 7.63-7.55 (m, 4H), 7.45-7.40 (m, 2H), 7.34-7.28 (m, 1H), 7.05-7.00 (m, 2H), 3.95 (dd, 2H, J=5.8, 5.8 Hz), 2.89 (dd, 2H, J=5.8, 5.8 Hz). 13C NMR (DMSO, 400 MHz) δ 158.3, 139.8, 132.4, 128.8, 127.7, 126.6, 126.1, 1 f4.9, 70.3, 41.0. MS (ESI) for C14H15NO [M+H] calc. 213.28. found 213.96.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])C(=O)OC(C)(C)C)=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.Cl.O1CCOCC1>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:6]([NH:7][CH2:15][CH3:16])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: CCN(C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCNc1cn(-c2cccnc2)nc1Cl
Temperature: 1 °C
Reaction time: 0.33 h

Procedure:
Into a 500 mL three-necked round bottom flask equipped with a magnetic stir bar was added a solution of tert-butyl (3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamate (21 g, 65.1 mmol) in 1.4-dioxane (35 mL). This pale yellow solution was placed into an ice bath and cooled to 1° C. A solution of 4M HCl/dioxane (65 mL, 260 mmol) was added in one portion. After stirring for 20 minutes, the ice bath was removed and the suspension was stirred further at ambient temperature for 16 hours. The reaction was diluted with 200 mL of ethyl ether and the solid was filtered and washed with ether and placed in a vacuum oven at 40° C. for 18 hours. The title compound was isolated as a pale yellow solid (18.2 g, 95%): 1H NMR (400 MHz, MeOD) δ 9.52 (d, J=2.5 Hz, 1H), 9.17 (s, 1H), 9.14 (ddd, J=8.7, 2.5, 1.1 Hz, 1H), 8.93 (ddd, J=5.7, 1.1, 0.6 Hz, 1H), 8.31 (ddd, J=8.7, 5.7, 0.5 Hz, 1H), 3.58 (q, J=7.3 Hz, 2H), 1.48 (t, J=7.3 Hz, 3H); ESIMS m/z 223 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)#[N:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1ccc(NCCCCO)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 4-(4-hydroxy-butylamino)-3-nitro-benzonitrile (10.0 g, 42.5 mmol) in pyridine (100 mL) was cooled to 0° C. under nitrogen. Pivaloyl chloride (5.8 mL, 47 mmol) was dropwise added and the resulting solution allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue stripped with toluene. The residue was suspended in ethyl acetate, filtered, and the filtrated concentrated to give 2,2-dimethyl-propionic acid 4-(4-cyano-2-nitro-phenylamino)-butyl ester (13.3 g, 98%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[C:11](O)=[O:12])=[CH:4][C:3]=1[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[C:11]([Cl:22])=[O:12])=[CH:4][C:3]=1[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)C1CCc2cc(CC3CCCC3)c(Cl)cc21
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CCc2cc(CC3CCCC3)c(Cl)cc21

Procedure:
3.22 g of 6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid is heated under reflux for one hour with 10.5 ml of thionyl chloride and concentrated, thus yielding 3.45 g of 6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid chloride as an oil. The acid chloride is reacted with triethyl phosphite as described in Example 2, yielding 3 g of (6-chloro-5-cyclopentylmethyl-1-indanylidene)hydroxymethanephosphonic acid diethyl ester, mp 126° C. The resultant compound is reacted with diethyl phosphite under the conditions mentioned in Example 2, thus obtaining the (6-chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethane-bis(phosphonic acid diethyl ester).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:21][CH2:20]2)=[O:32])=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(CN3CCC(N)CC3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1cc2nccc(CN3CCC(NC(=O)Nc4ccc(Cl)cc4)CC3)c2cc1OC
Yield: 22 %

Procedure:
1-((6,7-Dimethoxyquinolin-4-yl)methyl)piperidin-4-amine (150 mg, 0.50 mmol) was dissolved in DCM (5 mL). While stirring, 4-chlorophenyl isocyanate (84 uL, 0.65 mmol) was added dropwise at rt, and the reaction was allowed to stir for 15 hours. The solvent was removed and the crude compound was columned using 100% DCM to 5% MeOH to give the desired product 1-(4-chlorophenyl)-3-(1-((6,7-dimethoxyquinolin-4-yl)methyl)piperidin-4-yl)urea (50 mg, 0.11 mmol, 22% yield). MS (ESI pos. ion) m/z: 455.2 (MH+). Calc'd exact mass for C24H27ClN4O3: 454.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18]>CN(C)C1C=CN=CC=1.Cl>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:22]([CH2:21][O:20][C:17](=[O:19])[CH3:18])=[O:23])=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C=O)cc1
Reactant: CC(=O)OCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.5 %

Procedure:
To a solution of 4-aminobenzaldehyde (1 g, 8.52 mmol) at 0° C. under nitrogen atmosphere were added triethylamine (2.3 mL, 16.5 mmol), 4-dimethylaminopyridine (0.1 g, 0.82 mmol) and acetoxyacetyl chloride (1.77 mL, 16.5 mmol). The reaction mixture was allowed to warm up to room temperature and was stirred for 2.5 h. Triethylamine (1.15 mL, 8.25 mmol) and acetoxyacetyl chloride (0.88 mL, 8.25 mmol) were added and the reaction mixture was stirred for 1 h more. The reaction mixture was poured into a 1 M hydrochloric acid solution (60 mL), then extracted with methylene chloride (20 mL×3) and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The crude solid (3.17 g) was purified by flash column chromatography to provide pure acetic acid (4-formyl-phenylcarbamoyl)-methyl ester (1.14 g, 62% yield) as an orange solid. A mixture of 2-amino-4,6-dimethoxy-benzamide (0.15 g, 0.76 mmol), Acetic acid (4-formyl-phenylcarbamoyl)-methyl ester (0.169 g, 0.76 mmol), sodium hydrogensulfite (0.087 g, 0.84 mmol) and p-toluenesulfonic acid (15 mg, 0.076 mmol) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 4.5 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with cold water (60 mL) to obtain a yellow solid. The yellow solid was filtered off, washed with cold water (20 mL×2), methanol and dried under vacuum to provide crude compound (230 mg, 75%).
Reaction SMILES: OC1CC(=O)C(CC[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=C1.OCCCCOC1CC(=O)C(CCCCCCC(O)=O)=C1.O1C[CH2:42][CH2:41][CH2:40][CH:39]1[O:44][CH:45]1[CH2:49][C:48](=[O:50])[C:47]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]([C:63]([OH:65])=[O:64])[CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)=[CH:46]1.O1C=CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:15]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[O:16][CH2:42][CH2:41][CH2:40][CH2:39][O:44][CH:45]1[CH2:49][C:48](=[O:50])[C:47]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]([C:63]([OH:65])=[O:64])[CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)=[CH:46]1
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Reactant: O=C1CC(OC2CCCCO2)C=C1CCCCCC(C(=O)O)C1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CCCCCCC1=CC(OCCCCO)CC1=O
Solvent: ClCCl
Solvent: O
Product: O=C1CC(OCCCCOC2CCCCO2)C=C1CCCCCC(C(=O)O)C1CCCCO1

Procedure:
In the manner of Example 147 the mixture of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one and 4-(4-hydroxybutoxy)-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 268) is converted to a mixture of the subject compound and 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cyclopent-2-en-1-one with dihydropyran and p-toluenesulfonic acid monohydrate in methylene chloride.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][N:12]([CH3:36])[CH:13]([CH2:34][CH3:35])[CH2:14][CH2:15][NH:16][C:17]1[CH:33]=[CH:32][C:20]2[N:21]=[CH:22][N:23](COCC[Si](C)(C)C)[C:19]=2[CH:18]=1.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:47]2[CH:48]=[C:49]([CH:52]=[CH:53][C:54]=2[O:55][CH3:56])[CH:50]=[O:51])=[CH:39][N:38]=1>C1COCC1>[CH3:36][N:12]([CH3:11])[CH:13]1[CH2:14][CH2:15][N:16]([C:17]2[CH:33]=[CH:32][C:20]3[N:21]=[C:22]([C:50]([C:49]4[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:47]([C:40]5[C:41]6[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=6)[CH:37]=[N:38][CH:39]=5)[CH:48]=4)=[O:51])[NH:23][C:19]=3[CH:18]=2)[CH2:35][CH2:34]1
Reactant: CCC(CCNc1ccc2ncn(COCC[Si](C)(C)C)c2c1)N(C)C
Reactant: COc1ccc(C=O)cc1-c1cncc2ccccc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)cc3[nH]2)cc1-c1cncc2ccccc12
Reaction time: 0.08 h
Yield: 17.1 %

Procedure:
To a cooled (−78° C.) 1M solution of lithium hexamethyldisilazane (0.88 mL, 0.88 mmol) in THF was added N3,N3-Dimethyl-N1-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazol-5-yl]-pentane-1,3-diamine (82 mg, 0.22 mmol) in 1 mL THF. Solution turned bright orange. After 5 min, the reaction mixture was treated with 3-isoquinolin-4-yl-4-methoxy-benzaldehyde (58 mg, 0.22 mmol) in 1 mL THF. After 20 minutes, the reaction mixture was removed from cold bath, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was then dissolved in DCM: TFA. After 1 hour, the reaction mixture was concentrated and purified by HPLC (Deltapak C18, acetonitrile: 0.1% trifluoroacetic acid), then neutralized using PL-HCO3 SPE to obtain 19 mg [6-(4-dimethylamino-piperidin-1-yl)-1H-benzoimidazol-2-yl]-(3-isoquinolin-4-yl-4-methoxy-phenyl)-methanone in 17% yield. MS m/z 506.5 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[C:11]([C:14]1[C:15]([CH3:29])=[C:16](Br)[C:17](=[O:27])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:19]=1)(=[O:13])[CH3:12]>O.CN(C)C=O>[C:11]([C:14]1[C:15]([CH3:29])=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[C:17](=[O:27])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:19]=1)(=[O:13])[CH3:12]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Br)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Sc2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 97% sodium hydroxide (51 mg) in a mixture of water (3 ml) and N,N-dimethylformamide (10 ml) was added 4-chlorothiophenol (0.19 g), followed by stirring at room temperature for 30 minutes. Then, 6-acetyl-4-bromo-2-(4-chlorophenyl)-5-methyl-3(2H)-pyridazinone (0.30 g) was added, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting crude crystals were recrystallized from ethyl acetate/hexane to obtain 6-acetyl-2-(4-chlorophenyl)-4-(4-chlorophenylthio)-5-methyl-3(2H)-pyridazinone (260 mg) (Compound No. 1-29).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][CH:7]([CH3:9])[CH3:8])([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:9][CH:7]([NH:6][C:5]1[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)Nc1ccccc1N
Reaction time: 8 h

Procedure:
To a solution of 2-nitro-N-(propan-2-yl)aniline (828 mg, 4.6 mmol) in ethanol (10 mL) under a nitrogen atmosphere is carefully 20% palladium on carbon (50 mg, Degussa type) followed by ammonium formate (1.4 g, 23 mmol) and the reaction is stirred overnight. The suspension is carefully filtered through a bed of Celite and the filtrate is rinsed with additional ethanol (10 mL). The filtrate is concentrated and the residue is partitioned between water and ethyl acetate. The organic layer is dried (Na2SO4) and concentrated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([C:11]([CH:16](C)C)(NCC)[CH3:12])(C)[CH3:9].CC(C)C#C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][CH:11]([CH3:16])[C:8]#[C:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCNC(C)(C(C)C)C(C)C
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C#Cc1ccccn1
Temperature: 85 °C
Yield: 73.5 %

Procedure:
To a degassed solution of 2-bromopyridine (0.604 mL, 6.33 mmol), bis(triphenylphosphine)palladium(II) chloride (0.267 g, 0.380 mmol), copper (I) iodide (0.060 g, 0.316 mmol), and diisopropyldiethylamine (3.61 mL, 25.3 mmol) in N,N-dimethylformamide (20 mL) was added 3-methylbut-1-yne (0.647 g, 9.49 mmol). The reaction mixture was heated to 85° C. for 16 h, cooled to room temperature, and diluted with ethyl acetate (150 mL). The mixture was washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide (100 mL), washed with brine, and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (3/2) afforded (3-methylbut-1-ynyl)pyridine (696 mg, 4.65 mmol, 73% yield). The compound had an HPLC retention time=1.02 min.—Column: YMC COMBISCREEN® ODS-A 4.6×50 mm S-5; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90% MeOH—10% water—0.1% TFA. LC-MS: M+1=146.32. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 3H), 1.30 (s, 3H), 2.82 (dt, J=13.80, 6.90 Hz, 1H), 7.18 (dd, J=7.65, 4.89 Hz, 1H), 7.37 (d, J=7.78 Hz, 1H), 7.61 (td, J=7.72, 1.13 Hz, 1H), and 8.55 (d, J=4.77 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(I)cc1
Product: COc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 1-iodo-4-methoxybenzene (468 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 340 mg (98% isolated yield) of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C2CCOCC2)cc1
Agent: Cl
Product: Nc1ccc(C2CCOCC2)cc1
Temperature: 60 °C
Yield: 72.7 %

Procedure:
140 g of stannous chloride were added over 30 minutes at room temperature to a suspension of 43.4 g of 4-(p-nitrophenyl)-tetrahydropyran in 435 ml of concentrated hydrochloric acid and the mixture was heated at 60° C for 2 hours and was cooled to 4° C. The mixture was filtered and the recovered crystals were washed with water and dissolved in a mixture of 300 g of iced water and 300 ml of 2N sodium hydroxide. The solution was stirred at room temperature and was then filtered. The recovered crystals were dissolved in methylene chloride and the aqueous alkaline phase was extracted with methylene chloride. The combined methylene chloride phases were washed with water and dried and evaporated to dryness. The residue was crystallized from isopropyl alcohol to obtain 27 g of 4-(p-aminophenyl)-tetrahydropyran melting at 122° C.