Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17].C([O-])([O-])=[O:19].[Ca+2]>COCCOC.O>[Br:1][C:2]1[C:11]([CH2:12][OH:19])=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17]
Reactant: COc1c(Br)c(CBr)c(OC)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: COCCOC
Product: COc1c(Br)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Yield: 104.4 %

Procedure:
Following a modified procedure of Smith et al.,25 dibromide 36 (1.73 g, 4.80 mmol) was dissolved in 1,2-dimethoxyethane (50.0 mL), and then added to CaCO3 (2.50 g, 25.0 mmol) in H2O (50.0 mL) at room temperature. The reaction was heated under reflux for TIME and then cooled to room temperature. The reaction was extracted with EtOAc (75.0 mL), and the organic layers are washed with brine. The organic layer was dried over MgSO4 and filtered. The resulting pink solid was then purified by flash column chromatography (1:3 EtOAc:hexanes) to provide 37 (1.49 g, 5.01 mmol, 105%) as a pink solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:16]=3[C:17]=1[CH3:18])=[O:12])[CH2:3]2>C(O)(=O)C.[Zn]>[ClH:1].[ClH:1].[NH2:23][C:20]1[CH:21]=[CH:22][C:15]2[S:14][C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])=[C:17]([CH3:18])[C:16]=2[CH:19]=1
Reactant: Cc1c(C(=O)N[C@H]2CN3CCC2CC3)sc2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c(C(=O)N[C@H]2CN3CCC2CC3)sc2ccc(N)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
317 mg (0.83 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-5-nitro-1-benzothiophene-2-carboxamide hydrochloride are suspended in 2 ml of acetic acid. 300.0 mg (4.59 mmol) of zinc are added, and the mixture is then stirred at RT for 1 h. The reaction mixture is filtered through kieselguhr, and the filter cake is washed with methanol. The filtrate is concentrated under reduced pressure and the residue is purified by preparative HPLC. The product fraction is dissolved in 4M HCl in dioxane, concentrated under reduced pressure and recrystallized from acetonitrile. 154 mg (47.8% of theory) of the title compound are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:11]([O:15][C:16](=[O:24])[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[C:11]([O:15][C:16]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:19]1)=[O:24])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)(C)C(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (R)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 2 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (2.884 g, 88%). 1H NMR (CDCl3, 300 MHz): 5.09 (1H, bs), 4.25-4.07 (2H, m), 3.73 (1H, bs), 2.63-2.52 (3H, m), 2.49 (1H, bs), 2.31-2.24 (1H, m), 1.74-1.61 (1H, m), 1.59-1.49 (3H, m), 1.44 (9H, s), 1.21 (9H, s).
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[C@@H:4]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH2:3]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:6]1[C@H:2]([CH3:1])[CH2:3][C@H:4]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[C:5]1=[O:7])[CH3:37]
Reactant: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)[C@@H](CCC2(C)OCCO2)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-7 (355 mg, 1.67 mmol) and THF (10 mL) at −78° C. was added NaN(TMS)2 (1.83 mL, 1.83 mmol, 1.0 M in THF). After 20 min, ethyl bromoacetate (0.203 mL, 1.84 mmol) was added and the reaction was warmed to 0° C. After 30 minutes, the reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4), and concentrated to give 11-8 as a yellow oil.
Reaction SMILES: [C:1]1([S:7]/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>C(O)(=O)C.O>[C:1]1([S:7](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C[C@@H](NC(=O)/C=C/Sc1ccccc1)C(=O)OCC
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C[C@@H](NC(=O)/C=C/S(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 36 h
Yield: 63 %

Procedure:
Diethyl N-[3-phenylthio-2(E)-propenoyl]-(R)-aspartate (3.51 g, 10 mmol) was dissolved in glacial acetic acid (30 ml) and a 30% solution of hydrogen peroxide (1.4 ml) was added and the mixture was stirred at room temperature for 36 hours, then diluted with water (100 ml) and extracted twice with dichloromethane (50 ml each). The organic phase was dried over anhydrous sodium sulfate, the solvents were evaporated and the residue was suspended in carbon tetrachloride and filtered to give a crude product which was recrystallised from toluene, yielding the desired product (2.3 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13]C(=O)C(F)(F)F)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>C1COCC1>[NH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C(F)(F)F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Temperature: 25 °C

Procedure:
tert-Butyl-(3R)-3-[(trifluoroacetyl)amino]pyrrolidine-1-carboxylate 6-1 (6.30 g, 22.32 mmol) was dissolved in 80 mL of 4:1 THF: H2O. Lithium hydroxide hydrate (1.873 g, 44.64 mmol) was added and the reaction was stirred at room temperature. After 24 hours more lithium hydroxide hydrate (2.810 g, 66.96 mmol) was added. After 30 hours the solution was concentrated in vacuo (to remove THE) then extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate 6-2 as a yellow oil. Free base: 1H NMR (DMSO-d6) δ 3.45-3.14 (m, 4H), 2.88-2.83 (m, 1H), 1.92-1.77 (m, 1H), 1.61 (s, 2H), 1.56-1.46 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N[SiH2:14][NH:15][C:16]([CH3:19])(C)C)(C)(C)C>>[F:1][C:2]1([F:8])[CH2:7][CH2:6][CH2:5][N:4]([SiH2:14][N:15]2[CH2:16][CH2:19][CH2:7][C:2]([F:8])([F:1])[CH2:3]2)[CH2:3]1
Reactant: CC(C)(C)N[SiH2]NC(C)(C)C
Reactant: FC1(F)CCCNC1
Product: FC1(F)CCCN([SiH2]N2CCCC(F)(F)C2)C1
Reaction time: 0.5 h

Procedure:
A quantity of 0.1 mol 3,3-difluoropiperidine and 0.1 mol bis(t-butylamino)silane were mixed and stirred in a flask under the protection of nitrogen. Every 4 hours, the mixture was pumped with vacuum of 100 torr for 30 minutes. After 48 hours, the end-product bis(3,3-difluoropiperidino)silane was obtained by vacuum distillation at 118° C. / 10 torr.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[C:4](=[O:9])[C:5]#[C:6][CH2:7][CH3:8]>CCCCCC.N1C2C(=CC=CC=2)C=CC=1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[C:4](=[O:9])/[CH:5]=[CH:6]\[CH2:7][CH3:8]
Reactant: CCC#CC(=O)C(OC)OC
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CC/C=C\C(=O)C(OC)OC

Procedure:
Six grams of the 1,1-dimethoxy-3-hexyne-2-one (of Example I) is stirred under hydrogen gas at one atmosphere in 40 ml hexane containing 0.6 g Lindlar catalyst (palladium on calcium carbonate poisoned with lead acetate) and 4.0 g quinoline. The reaction is terminated when one percent of the starting material (1,1-dimethoxy-3-hexyne-2-one) remains after about 11/2 hours.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[O:5])[CH2:3][CH2:2]1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.[OH-].[K+]>CC(C)=O>[CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:13]([O:16][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:18]([F:17])([F:27])[F:28])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(O)ccc1NC(=O)C1CC1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(OCc2ccccc2C(F)(F)F)ccc1NC(=O)C1CC1
Reaction time: 4 h
Yield: 49.4 %

Procedure:
A mixture of 2-(cyclopropanecarbonyl-amino)-5-hydroxy-benzoic acid (7.0 g, 32 mmol) and 2-(trifluoromethyl)-benzyl bromide (9.09 g, 38 mmol) in 0.5 M KOH (158 mL, 79 mmol) and acetone (200 mL) was heated to reflux. After 4 hours, acetone was evaporated and the resulting mixture was diluted with more water and washed with CH2Cl2. The water phase was acidified with 1 M HCl and the resulting solid was collected by filtration. Recrystallisation in methanol gave the product as an off-white powder (6.0 g, yield 50%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:21]2[C:12](=[C:13]3[C:18](=[CH:19][C:20]=2[O:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][CH2:15][O:14]3)[C:11](=[O:26])[C:10]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:9]1)C>C(O)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:10]2[C:11](=[O:26])[C:12]3[C:21](=[C:20]([O:22][CH2:23][CH2:24][CH3:25])[CH:19]=[C:18]4[C:13]=3[O:14][CH2:15][CH2:16][CH2:17]4)[N:8]([CH2:7][C:6]([OH:35])=[O:5])[CH:9]=2)=[CH:28][CH:29]=1
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)OCC)c13)OCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)O)c13)OCCC2
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A 5N aqueous sodium hydroxide solution (10 ml) was added to an ethanol solution (30 ml) of ethyl[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetate (700 mg, 1.55 mmol) and heated for 2 hours under reflux. The mixture was cooled to room temperature and concentrated under reduced pressure. While ice-cooling the concentrate, water and concentrated hydrochloric acid were added to the residue to make it acidic. Subsequently, the formed insoluble matter was separated and dried, giving a yellow powder of [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetic acid (580 mg, yield: 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([NH:15][C:16]2[O:17][C:18]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[N:19][N:20]=2)=[O:14])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[CH3:27]>>[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:13]([NH:15][C:16]4[O:17][C:18]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)=[N:19][N:20]=4)=[O:14])[CH:3]=3)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[CH3:27]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cc(OC(F)(F)F)c1
Product: CCc1ccc(-c2ccc(-c3cc(OC(F)(F)F)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-5-trifluoromethoxybenzenecarboxamide prepared in Reference Example 40 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH:17]=1.Cl>[Pt]=O.CO>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]1
Reactant: CCN1CC=C(c2cccc(S(C)(=O)=O)c2Cl)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2Cl)CC1

Procedure:
Preparation according to Example 3: 4-[2-chloro-3-(methylsulfonyl)phenyl]-1-ethyl-1,2,3,6-tetrahydropyridine (0.6 g, 2.0 mmol), methanol (25 ml), platinum oxide (0.15 g). Yield: 0.35 g (58%). The amine was converted to hydrochlorid acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 264-265° C. MS m/z (relative intensity, 70 eV) 301 (M+, 6), 301 (13), 300 (11), 288 (35) 286 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CO)ccc1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1-c1ccccc1
Temperature: 0 °C

Procedure:
(2-Methoxy-biphenyl-4-yl)-methanol (170 mg, 0.79 mmol) [PCT Int. Appl. 1999, WO 9955726 A1 19991104] is dissolved in CH2Cl2 (2 mL) and cooled to 0° C. SOCl2 (1 mL) is then added dropwise. The mixture is then allowed to stir till no starting material left. The volatiles were then removed and the crude product is employed in the next step directly.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH3:18][NH2:19]>C1COCC1>[CH3:18][NH:19][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Solvent: C1CCOC1
Product: CNCCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A solution of 4-(3-iodoprop-1-yl)-1-tert-butoxycarbonyl-piperidine (728 mg, 2.06 mmol,) in 5.0 mL of THF was treated with 5.0 mL of methylamine (70% in water) and the resulting mixture was stirred at rt for 18 h. The mixture was partitioned between diethyl ether (50 mL) and water (50 mL) and the layers were separated. The organic layer was washed with 50 mL of sat'd NaCl, dried and concentrated to afford 457 mg (83%) of the title compound: 1H NMR (500 MHz, CDCl3): δ 1.05-1.68 (19H), 1.47 (s, 9H), 2.45 (s, 3H), 2.56-2.68 (4H), 4.00-4.15 (2H).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:20]3)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[NH:42][C:43](=[O:45])[CH3:44].CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1.CCOC(C)=O>[C:43]([NH:42][C:41]1[CH:40]=[C:39]([NH:38][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:20]3)[C:14]([C:35](=[O:37])[NH2:36])=[CH:13][N:12]=2)[CH:48]=[CH:47][CH:46]=1)(=[O:45])[CH3:44]
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(=O)OCc4ccccc4)C3)n2)c1
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A mixture of benzyl 3-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (582 mg, 1.16 mmol), 3′-amino-acetanilide (210 mg, 1.40 mmol) and pTsOH (220 mg, 1.16 mmol) in dioxane (10 mL) was stirred at 100 C for 4 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl. During the washing white solids precipitated out, which were collected to give the titled compound (412 mg). MS 518.5 (M+H); UV 201.6, 249.8 nm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH2:30](B(O)O)[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:30][CH2:31][CH2:32][CH3:33])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: CCCCB(O)O
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: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ccc2c(=O)n(Cc3ccccc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), n-butylboronic acid (340 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg), potassium carbonate (280 mg), toluene (6 ml) and THF (3 ml) was stirred at 100° C. under a nitrogen atmosphere for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and crystallized from hexane to give the title compound (210 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](O)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(=O)=O.Cl>S(Cl)(Cl)=O>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Oc1ccccc1
Reactant: CCCCCCCC(=O)O
Agent: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Product: CCCCCCCC(=O)Oc1ccccc1

Procedure:
The ester was prepared by slowly adding thionyl chloride (10 ml) to a mixture of pure phenol (6.5 g) and octanoic acid (10 g). The reaction mixture was warmed to drive off the sulfur dioxide and hydrogen chloride gases. The crude mixture was distilled at 95°-100° C./5 mmHg.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:25][CH2:26][CH3:27])[C:13]2[C:22]3[CH:21]=[C:20]([OH:23])[CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:24]=1)[CH3:8].I[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[C:34]([O:33][C:32](=[O:38])[NH:31][CH2:30][CH2:29][O:23][C:20]1[CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]3[N:24]=[C:11]([CH2:10][O:9][CH2:7][CH3:8])[N:12]([CH2:25][CH2:26][CH3:27])[C:13]=3[C:22]=2[CH:21]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Reactant: CC(C)(C)OC(=O)NCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2cnc3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Temperature: 65 °C
Yield: 90.9 %

Procedure:
Solid cesium carbonate (18.33 g, 56.22 mmol) was added to a solution of 2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (10.7 g, 37.5 mmol), prepared in Parts A-I, in DMF (185 mL). tert-Butyl 2-iodoethylcarbamate (11.17 g, 41.2 mmol), prepared in Parts J and K, was added, and the reaction mixture was heated at 65° C. for 18 hours. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic fraction was washed with water (4×100 mL) and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide a black oil. The oil was purified by column chromatography on silica gel (eluting with 98:2 dichloromethane:methanol) to yield 14.6 g of tert-butyl[2-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamate as a tan, waxy solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH3:20])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:34]([F:46])=[CH:33][C:32]=1[N:47]1[C:59](=[O:60])[C:58]2[S:57][C:56]3[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=3[C:50]=2[CH:49]=[N:48]1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.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]>[F:46][C:34]1[CH:33]=[C:32]([N:47]2[C:59](=[O:60])[C:58]3[S:57][C:56]4[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=4[C:50]=3[CH:49]=[N:48]2)[C:31]([CH2:30][O:29][C:26](=[O:28])[CH3:27])=[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[N:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH3:20])[CH:14]=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:35]=1
Reactant: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 85 °C
Reaction time: 4 h
Yield: 27.1 %

Procedure:
A mixture of (S)—N-(1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)propan-2-yl)acrylamide 107d (150 mg, 0.37 mmol), 108c (200 mg, 0.40 mmol), Pd(dppf)Cl2(27 mg, 10 mol %) and K3PO4(235 mg, 1.11 mmol) in acetonitrile (20 mL) and water (5 ml) was stirred at 85° C. for 4 h under nitrogen. The reaction mixture was cooled to rt and concentrated. The residue was purified by prep-TLC (DCM/MeOH=30/1) to give 108d (70 mg crude) as yellow solid
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:5](Cl)=[O:6].COC([C:20]1C=CC=[CH:22][N:21]=1)C(O)=O.S(Cl)(Cl)=O.CNC.[OH-].[Na+]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:5]([N:21]([CH3:22])[CH3:20])=[O:6]
Reactant: COC(C(=O)O)c1ccccn1
Reactant: COC(C(=O)Cl)c1ccccn1
Agent: CNC
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(C(=O)N(C)C)c1ccccn1
Reaction time: 4 h

Procedure:
Alternatively, 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide is prepared by the following procedure. 2-Methoxy-2-(2-pyridyl)acetyl chloride hydrochloride, 22 g. [prepared by reacting 2-methoxy-2-(2-pyridyl)acetic acid in benzene with thionyl chloride] in 100 ml. of chloroform is added dropwise and with cooling to 50 g. of dimethylamine in 100 ml. of chloroform. The mixture is stirred for four hours, then 50 ml. of 5% aqueous sodium hydroxide is added and the chloroform solution is dried and concentrated to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[O-:7][S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[F:15][C:16]([F:26])([F:25])[CH2:17][I+]C1C=CC=CC=1>C(Cl)Cl>[O-:10][S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:17][C:16]([F:26])([F:25])[F:15])[CH:3]=1
Reactant: FC(F)(F)C[I+]c1ccccc1
Reactant: Cn1ccnc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccn(CC(F)(F)F)c1

Procedure:
1-Methylimidazole (0.82 g, 10 mmol) was added to methylene chloride (20 ml), and (2,2,2-trifluoroethyl)(phenyl)iodonium triflate (4.54 g, 10 mmol) was added thereto while stirring in an ice bath. Thereafter, the mixture was stirred at room temperature for 3 hours. Methylene chloride was removed by distillation, and the residue was then dried using a vacuum pump while being heated. Thus, 1-methyl-3-(2′,2′,2′-trifluoroethyl)imidazolium triflate of interest was obtained in a substantially quantitative manner.