Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=2)[O:3]1>Cl.CO>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:22])[O:3][B:4]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl
Solvent: CO
Product: CC1(C)OB(C2=CCNCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
The mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.0 g, 12.9 mmol) in HCl/MeOH (20 mL) was stirred at room temperature for 1 hour. Then it was concentrated to give 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine hydyochloride (2.9 g, 11.8 mmol, yield: 91.4%) which was used in the next step without further purification. ESI-MS (M+1): 210 calc. for C11H20BNO2 209.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2.[H-].[Li+]>C1COCC1>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH:18]([OH:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydro-9-(2-methylbenzylamino)acridin-1(2H)-one (4.15 g) was suspended in 100 ml of THF and chilled with ice-water. 1M lithium hydride in THF (8.0 ml) was added dropwise through a syringe and then the reactionh mixture was stirred 30 minutes in the cold. It was quenched by the sequential addition of 0.5 ml of water, 0.5 ml of 15% sodium hydroxide and 1.5 ml of water. The inorganic salts were filtered and the organic phase was evaporated to obtain an amorphous solid product. Recrystallization from ethyl acetate gave 3.38 g, mp 167°-169° C.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(F)c1
Product: CC(=O)Nc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3,4-difluoroaniline (28.2 g) was added acetic anhydride (30 ml) slowly. After allowed to stand for 30 minutes, the reaction mixture was poured into ice water (100 ml). The resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (34.7 g) as colorless needles, mp 127°-127.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([CH3:13])[N:12]=1.[CH3:20][N:21]=[C:22]=[S:23]>O1CCCC1>[CH3:13][C:11]1[N:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22]([NH:21][CH3:20])=[S:23])[NH:9][C:10]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN=C=S
Reactant: Cc1nc(-c2ccccc2N)[nH]c1-c1cccnc1
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccccc1-c1nc(C)c(-c2cccnc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.8 g) in tetrahydrofuran (10 ml) was added methyl isothiocyanate (0.33 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for one hour, and refluxed for 20 hours. The resulting precipitate was collected by filtration, and washed with tetrahydrofuran and diethyl ether to give 4-methyl-2-[2-(3-methylthioureido)phenyl]-5-(3-pyridyl)imidazole (0.71 g).
Reaction SMILES: CN(C)[CH:3]([CH2:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]#[CH:5]>CO.CCOCC>[CH:5]#[C:4][CH:3]=[CH:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CC(CC(=O)CCCCC)N(C)C
Solvent: CO
Solvent: CCOCC
Product: C#CC=CC(=O)CCCCC
Reaction time: 5 h

Procedure:
To a solution of 3-(dimethylamino)-1-decyn-5-one (2.2 g), described in Example 39, in methanol (20 ml) p-toluenesulfonic acid (1 g) is added. The solution is allowed to stay at room temperature for 5 hr. then diluted with ether. The organic layer is washed with water, dried (MgSO4) and evaporated to dryness. Chromatographic purification of the residue on 25 g silica gel with ether-hexane (1:4) affords 3-decen-1-yn-5-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:38].[H][H]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:19][CH:18]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:38]
Reactant: [H][H]
Reactant: COCC#Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: [Pd]
Solvent: CO
Product: COCCCc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 96 %

Procedure:
In a similar manner to Step 1 of Example 328, 4-(3-methoxy-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (157 mg, 0.306 mmol) was dissolved in methanol (6.3 mL), and the solution was added with 10% Pd—C (46 mg) to react hydrogen. The reaction mixture was filtered using Celite. The solvent of the filtrate was evaporated under reduced pressure to obtain 4-(3-methoxypropyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (152 mg, yield 96%).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:17]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:15])[CH2:5][CH2:6][N:7]([CH2:9][CH2:10][O:11][CH3:12])[CH3:8].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:3][C@@H:4]([NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:17]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:15])[CH2:5][CH2:6][N:7]([CH2:9][CH2:10][O:11][CH3:12])[CH3:8]
Reactant: COCCN(C)CC[C@H](NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(C)CC[C@@H](CO)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 70 °C
Yield: 32.3 %

Procedure:
(S)-2-{[5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-[(2-methoxyethyl)-methylamino]-butyric acid methyl ester (0.023 g, 0.043 mmol) and NaBH4 (0.016 g, 0.43 mmol) were dissolved in THF/MeOH (7 mL, 5:2) and heated to 70° C. in a sealed vial for 5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and chromatographed eluting with TEA/ethyl acetate (1:4) to provide 0.007 g of the product as viscous oil (31% yield). MS (APCI+) m/z 505 (M+1) detected.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)[CH3:9].Cl[C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=1.O>C(#N)C>[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=2)[CH2:15]1)[CH3:9]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Temperature: 90 °C
Yield: 60.9 %

Procedure:
Triethylamine (8.1 mL, 80 mmol) was added to a stirred solution of (R)-3-(2-ethoxy-phenoxy)-piperidine (10 g, 39 mmol) and ethyl 6-chloronicotinate (7.2 ml, 39 mmol) in acetonitrile (100 mL) at 0° C. The reaction mixture was heated at 90° C. for 16 h. The mixture was cooled to ambient temperature, water (150 mL) was added, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed sequentially with water (100 mL) and brine (100 mL), then were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (13% ethyl acetate-hexanes) to afford ethyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinate (8.8 g). MS (ES+) 371.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:29][CH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][CH:17]2[CH2:22][C:21]([CH3:23])([CH3:24])[N:20]([CH2:29][CH2:30][OH:31])[C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1CCO
Temperature: 25 °C
Yield: 37.1 %

Procedure:
A solution of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide (330 mg, 1 mmol, 1 eq), 2-bromoethanol (1.2 mmol), and anhydrous potassium carbonate (1.2 mmol) in 5 ml of acetonitrile was stirred for 18 hrs under reflux. The reaction mixture was cooled to a room temperature and filtered. The filtrate was concentrated in a reduced pressure. Silica gel column chromatography (mobile phase: 10 (v/v) % methanol in chloroform) afforded the title compound. Yield: 37.1% 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.65 (s, 1H), 7.37 (d, 1H), 7.27 (t, 1H), 7.10 (d, 1H), 6.51-6.45 (m, 1H), 4.64-4.45 (m, 1H), 3.88 (t, 2H), 3.49 (t, 2H), 2.08-1.96 (m, 3H), 1.28 (s, 6H), 1.13 (s, 6H), 1.0 (t, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[O:7]=[CH:8][C:9]([Cl:12])([Cl:11])[Cl:10].O>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([OH:7])[C:9]([Cl:12])([Cl:11])[Cl:10]
Reactant: Cn1cccc1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of N-methylpyrrole (810 mg, 10 mmol) dissolved in benzene (10ml) was added dropwise a solution of chloral (1.47 g, 10 mmol) dissolved in benzene (5 ml) under ice-cooling for 40 minutes. After the mixture was stirred for 1 hour at room temperature, water was added thereto and the mixture was extracted with ether. The extract was dried over sodium sulfate and concentrated to afford 1-methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (2.04 g) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=S)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C(C)=O)cc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 75 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([N:13]2[CH2:19][CH:18]3[O:20][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1.B(O)(O)[C:22]1[NH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1.Cl>C1(C)C=CC=CC=1.C(O)C.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>[CH2:11]([N:8]1[C:6]2=[N:7][C:2]([C:26]3[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=3)[NH:30][CH:22]=[CH:23]4)=[N:3][C:4]([N:13]3[CH2:19][CH:18]4[O:20][CH:15]([CH2:16][CH2:17]4)[CH2:14]3)=[C:5]2[CH:10]=[N:9]1)[CH3:12]
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Reactant: OB(O)c1cc2ccccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc4[nH]ccc4c3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (80 mg, 0.27 mmol), 5-indoylboronic acid (66 mg, 0.41 mmol), and tetrakis(triphenylphosphine)palladium(0) (35 mg, 10 mol %) in toluene/ethanol (1:1, 3 mL) and 2 M aqueous sodium carbonate solution (1 mL) was heated in a Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was acidified with concentrated hydrochloric acid and then concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column to provide 1-ethyl-6-(1H-indol-5-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. MS (ES+): 375.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][NH:18]C(OC(C)(C)C)=O)=[S:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[S:16])[NH:17][NH2:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NNC(=S)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=S)c1ccc(OCc2ccccc2)cc1

Procedure:
Di-t-butyl dicarbonate (10.8 g, 49.5 mmol) was added to a solution of 4-(benzyloxy)benzohydrazide (10 g, 41.3 mmol) in dichloromethane (206 mL) at 0° C. The resulting mixture was stirred for 2 d at room temperature, then concentrated and the residue was triturated with diethyl ether to yield tert-butyl 2-(4-(benzyloxy)benzoyl)hydrazinecarboxylate. A mixture of tert-butyl 2-(4-(benzyloxy)benzoyl)hydrazinecarboxylate (13.7 g, 40 mmol) and Lawesson's reagent (8.1 g, 20.0 mmol) in THF (200 mL) THF was stirred for 2 d. Solvent was removed under vacuum and the residue was chromatographed (silica gel, heptane-ethyl acetate) to yield tert-butyl 2-(4-(benzyloxy)phenylcarbonothioyl)hydrazinecarboxylate. A solution of tert-butyl 2-(4-(benzyloxy)phenylcarbonothioyl)hydrazinecarboxylate(12 g) in 1,4-dioxane (34 mL) and 4.0 N HCl (34 mL) in 1,4-dioxane was stirred for 5 h. The resulting solid was collected and washed with diethyl ether to yield 4-(benzyloxy)benzothiohydrazide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[C:28]#[C:29][CH3:30])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[C:28]#[C:29][CH3:30])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: CC#CC(=O)NCCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(=O)NCCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
A mixture of 106a (330 mg, 0.47 mmol) and LiOH.H2O (196 mg, 4.67 mmol) in THF/i-PrOH/water (5.0 mL/3.0 mL/2.0 mL) was stirred at rt for 1 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 106 (30 mg, 8% for two steps) as white solid. 1H NMR (500 MHz, CDCl3): δ 8.52 (s, 1H), 8.26 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.13-7.10 (m, 1H), 6.69 (s, 1H), 6.52 (d, J=8.0 Hz, 1H), 6.22 (d, J=8.5 Hz, 1H), 4.34 (s, 2H), 4.27 (t, J=5.0 Hz, 2H), 2.98-2.97 (m, 2H), 2.87-2.85 (m, 2H), 1.99-1.96 (m, 4H), 1.86 (s, 3H). ESI-LCMS: m/z=655 [C34H31FN6O5S+H]+
Reaction SMILES: [ClH:1].CO.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]3[C:13]=2[C:12]2[C:7](=[CH:8][C:9]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:10][CH:11]=2)[N:6]=1>O1CCOCC1>[ClH:1].[CH2:30]([O:29][C:9]1[CH:8]=[C:7]2[C:12]([C:13]3[N:17]4[CH2:18][CH2:19][NH:20][CH2:21][C:16]4=[N:15][C:14]=3[C:5]([NH2:4])=[N:6]2)=[CH:11][CH:10]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (20 mL of a 4 N solution in 1,4-dioxane) and methanol (20 mL) were added to tert-butyl 6-amino-3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (4.45 g, 9.98 mmol, prepared by the methods described in Example 368 Parts A through I), and the reaction was stirred at ambient temperature overnight. A precipitate was present and was isolated by filtration and washed with cold methanol. The solid was then recrystallized from methanol, isolated by filtration, washed with diethyl ether, and dried overnight under vacuum at 65° C. to provide 3.89 g of 3-benzyloxy-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:23][C:24]1[C:25]([NH2:38])=[CH:26][CH:27]=[C:28]([O:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:29]=1)[CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:19]([N:23]1[C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:27]=[CH:26][C:25]=2[N:38]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNc1cc(OCCN2CCCC2)ccc1N
Reactant: O=Cc1ccc(OCCc2ccc(Cl)cc2)cc1
Solvent: CCO
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2)nc2ccc(OCCN3CCCC3)cc21
Yield: 39.6 %

Procedure:
This compound was prepared according to the General Procedure K by refluxing a mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (synthesized via General Procedure A) (100 mg) and N2-Butyl-4-(2-pyrrolidin-1-ylethoxy)-benzene-1,2-diamine (synthesized via General Procedures G1 and G2 and H) (50 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 5% MeOH in DCM to give pure 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole (37.0 mg, 40%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([Cl:17])=[O:13])[CH:2]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-quinolinecarboxylic acid (580 mg, 3.35 mmol) in dichloromethane (25 mL) was added oxalyl chloride (2M in CH2Cl2, 3.4 mL, 6.7 mmol) dropwise at room temperature. DMF (1 drop) was added, resulting in immediate gas formation. The reaction mixture was stirred at room temperature for 2 h. Dichloromethane was evaporated. Additional dichloromethane (20 mL) was added to the residue. Concentration of the organic solvent gave the crude product. (640 mg, 99%).
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=C=O)=CC=1.[C:14]([O:18][CH2:19][CH2:20]O)(=[O:17])C=C.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH2:8][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: C=CC(=O)OCCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C=Cc1ccccc1
Product: CCOC(N)=O
Reaction time: 2 h

Procedure:
A hydroxyl polyester having an acid number of 0.3 and a hydroxy number of 48.1 was prepared from 714 g (11.5 moles) of ethylene glycol and 1460 g (10 moles) of adipic acid in the conventional manner. 400 ppm of hydroquinone were added to this polyester to obtain a 50% styrene solution of the polyester. 4676 g (2 equivalents) of this solution were allowed to react with 248 g (2.85 equivalents) of tolylene diisocyanate and 116 g (1 mole) of hydroxylethyl acrylate at 65° C. or less for two hours. To the resulting reaction product were added dropwise over 1.5 hours 364 g of styrene and 2.7 g of dibutyltin dilaurate. The reaction was allowed to continue at 70° C. for further two hours until no NCO remained in the reaction system, thereby to obtain a 50% styrene solution of an unsaturated acrylic urethane (hereinafter called Acrylic Urethane I). The urethane was found to have a weight-average extension of molecular chain of 600 A.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:43])([C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[CH2:44](O)[CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH3:51].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:43][C:14]([F:13])([C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:51][CH2:50][CH2:49][CH2:48]/[CH:47]=[CH:46]\[CH2:45][CH3:44])=[CH:30][CH:31]=2)=[N:22][CH:21]=1
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Reactant: CC/C=C\CCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC/C=C\CCCCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of DEAD (0.261 g, 1.50 mmol) in THF (20 ml) was added dropwise to a stirred solution of 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (0.858 g, 1.50 mmol), cis-5-octene-1-ol (0.192 g, 1.50 mmol) and triphenylphosphine (0.939 g, 1.50 mmol) in THF (30 ml) and the reaction mixture stirred at room temperature for 24 h. The solvent was removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to yield a colorless solid, which was recrystallized from ethanol.