Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:38]I>C1(C)C=CC=CC=1.CCOCC.C(#N)C>[I:38][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCOCCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: ICCCOCCc1ccccc1
Temperature: 50 °C

Procedure:
To 3-(2-phenylethoxy)-1-propanol (2 g; 11 mmol) dissolved in toluene (50 ml), acetonitrile (50 ml), imidazole (2.2 g; 33 mmol) and triphenylphosphine (2.8 g; 11 mmol) is added iodine (2.8 g; 11 mmol). The reaction mixture is heated for 1 hour at 50° C., then it is cooled, diluted with Et2O, washed with 1N HCl, NaS2O3 solution, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to dryness. The residue is purified by column chromatography using 10% ether/90% petroleum ether to obtain 1-iodo-3-(2-phenylethoxy)propane which is used directly in Step D.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]12[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C.CCOC(C)=O>[CH3:21][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]12[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Nc2ccc(-c3ccc[nH]3)cc2C12CCCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
A mixture of 5′-(1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.46 g, 1.7 mmol) and potassium carbonate (5 eq, 1.18 g, 8.6 mmol) in DMF (2 mL) at room temperature was treated with a solution of iodomethane (3 eq, 0.32 g, 5.1 mmol) in DMF (1 mL). The solution was stirred 16 h at room temperature, then poured into water (10 mL). EtOAc (15 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (15 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the subtitled compound (0.44 g, 76%) as a white powder, mp 148-9° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.62 (m, 3H), 1.62-1.82 (m, 5H), 1.83-1.94 (m, 2H), 3.11 (s, 3H), 6.08 (m, 1H), 6.42 (m, 1H), 6.79 (m, 1H), 6.97 (d, 1H, J=8.1 Hz), 7.51 (dd, 1H, J=8.1, 1.8 Hz), 7.70 (d. 1H, J=1.7 Hz), 11.20 (br s, 1H). Anal. Calcd for C18H20N2O1: C, 77.11; H, 7.19; N, 9.98. Found: C, 76.44; H, 7.21; N, 9.96.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:21][CH3:22])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH:30][C:11](=[O:12])[C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: CC1CCCCC1N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCOc1c(OC)cc(C(=O)NC2CCCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a mixture of 15 ml of THF and 0.45 g of 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride were added 0.24 g of 2-methylcyclohexylamine and 0.27 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue obtained was washed with methyl tert-butyl ether and hexane to obtain 0.49 g of N-(2-methylcyclohexyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 19 of the present invention) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[N:3]=1.[OH-].[Li+:13]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([O-:11])(=[O:10])=[O:9])[N:3]=1.[Li+:13]
Reactant: O=S(=O)(O)c1cccc(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])c1cccc(Cl)n1
Yield: 89.5 %

Procedure:
Into a 200 ml egg-plant type flask, 785.2 mg (4.06 mmol) of 2-chloropyridine-6-sulfonic acid was charged, then dissolved with an addition of 2 ml of water and neutralized with an aqueous lithium hydroxide solution. The solvent was distilled off under reduced pressure, and after an addition of 100 ml of 2-propanol, the mixture was heated. Insoluble matters were removed by filtration, and the solvent was distilled under reduced pressure to obtain 725 mg (89.5%) of lithium 2-chloropyridine-6-sulfonate as crystalline solid. Purification was conducted by recrystallization from 2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][C:9](=O)[CH:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(CN2CCNC(=O)C2c2ccccc2)cc(OC)c1OC
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: COc1cc(CN2CCNCC2c2ccccc2)cc(OC)c1OC

Procedure:
1-(3',4',5'-Trimethoxy benzyl)-2-phenyl-3-keto piperazine prepared according to Example 13, is reduced by following the procedure described hereinabove in Example 8a whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-(3',4',5'-trimethoxy benzyl-2-phenyl-3-keto piperazine is used. The resulting 2-phenyl piperazine compound is obtained in the form of a yellow oil boiling at 185°-195°C./0.08 mm. Hg.
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][CH:4]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[CH2:5]C(OC)=O.FC(F)(F)C([O-])=O.C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1>C(#N)C.O.Cl>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([CH:4]2[CH2:5][NH:1][C:2](=[O:20])[CH2:3]2)[CH:15]=1.[ClH:16]
Reactant: COC(=O)CC(CC(N)=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C1CC(c2cc(Cl)ccc2[N+](=O)[O-])CN1

Procedure:
Adapting literature known protocols (Loudon, et al., J. Org. Chem., 1984, 49(22), 4272-4276; Loudon and Boutin, J. Org. Chem., 1984, 49(22), 4277-4286; Nicolaou, et al., Bioorg. Med. Chem. 1998, 6(8), 1185-1208; and Ji et al., Tetrahedron Lett., 2009, 50(45), 6166-6168), 4-(5-chloro-2-nitro-phenyl)pyrrolidin-2-one (18f) is prepared from methyl 5-amino-3-(5-chloro-2-nitro-phenyl)-5-oxo-pentanoate (18e) (2.87 g, 10.0 mmol) in a mixture of acetonitrile (MeCN) (15 mL) and water (15 mL) through an acidic Hoffmann-rearrangement with [I,I-bis(trifluoroacetoxy)iodo]benzene (phenyl iodosyl bis(trifluoroacetate, PIFA) (4.25 g, 10.0 mmol) followed by partial spontaneous intramolecular lactamization of the intermittent amine at room temperature. The reaction may be monitored by TLC and/or analytical LC/MS to completion. The reaction mixture is diluted with 2.0 M hydrochloric acid (HCl). The aqueous phase is extracted with diethyl ether (Et2O) (3×) to remove ether-soluble iodobenzene dichloride which is discarded. The aqueous phase is frozen and the solvents lyophilized off to yield an intermediate hydrochloride. The hydrochloride is diluted with water and the aqueous phase is adjusted to pH 8-9 with 2.0 M aqueous sodium hydroxide (NaOH). The aqueous phase is extracted with ethyl acetate (EtOAc) (3×). The combined organic extracts are either partially evaporated under reduced pressure followed by heating directly at reflux for about 6 hours to yield the crude title compound (18f). Alternatively, the solvent is evaporated under reduced pressure using a rotary evaporator, the residue is diluted with toluene or benzene and the solution is heated at reflux for about 6 hours. The crude material (18f) may either be used directly in the next step or may be further purified by silica gel chromatography using EtOAc, methanol (MeOH), dichloromethane (DCM), and/or hexanes or by re-crystallization.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:12][N:13]([CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:18]
Reactant: CN(C)CCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (1.0 g, 6.58 mmol), 3-dimethylamino-1-propanol (1.01 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0° C. in THF (20 mL) was added dropwise diisopropyl azodicarboxylate (1.99 g, 9.87 mmol). After stirring for 16 h at room temperature the solution was concentrated and the residue purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as an oily solid (1.25 g, 5.2 mmol). MS(ESI): 238.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][O:12]S(=O)[O:10]2)=[N:7][CH:8]=1)[CH3:2].O[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:10])[CH2:13][O:12][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2COS(=O)O2)nc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
0.5 g (0.0023 mol) 5-ethyl-2-(2-oxo-[1,3,2]-dioxathiolan-4-yl)-pyridine was added into solution of 0.343 g (0.0027 mol) p-hydroxy benzaldehyde dissolved in 5 mL DMF. Reaction mixture was heated at 80° C. for 14 hr. Subsequent work up furnished 0.3 g (47%) the desired product.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=O)[C:17]=2[O:16][CH2:15]1.[O-]CC.[Na+]>C(O)C>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22](/[CH:23]=[CH:13]/[C:3]3[N:4]=[C:5]4[CH:12]=[CH:11][CH:10]=[CH:9][N:6]4[C:7](=[O:8])[C:2]=3[Br:1])[C:17]=2[O:16][CH2:15]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)c(/C=C/c2cccc3c2OCO3)nc2ccccn12

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.5 g, 6.271 mmol) and 1,3-benzodioxole-4-carbaldehyde (1.12 g, 7.463 mmol) in the presence of sodium ethoxide (640 mg, 9.401 mmol) in absolute ethanol (100 ml) as described in Intermediate 1 to give 1.5 g of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 4.48 (s, 2H), 6.83-6.89 (m, 2H), 7.05-7.10 (m, 2H), 7.19 (t, J=6.9 Hz, 1H), 7.69 (d, J=9.3 Hz, 1H), 7.78-7.85 (m, 1H), 7.97 (d, J=15.6 Hz, 1H), 8.94 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.[CH3:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[C:18]([NH:20][CH:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:5][CH:6]([CH3:11])[CH3:7])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=1
Reactant: Cc1cc(N)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C=O)nc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Nc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of methyl 6-formylnicotinate (200 mg, 1.21 mmol) in toluene (8 mL) containing activated molecular sieves was added 2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-amine (316 mg, 1.33 mmol). The reaction mixture was heated to 90° C. and stirred overnight. The reaction mixture was concentrated and the residue dissolved in tetrahydrofuran (8 mL). The solution was cooled to 0° C. Zinc chloride (3.64 mL of a 1.0M solution in diethyl ether, 3.64 mmol) was added, followed by isobutylmagnesium bromide (1.82 mL of a 2.0M solution in THF, 3.64 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL). The mixture was diluted with dichloromethane (30 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (30 mL) two more times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinate (290 mg, 51%). 1H NMR (400 MHz, CDCl3, δ): 9.20 (s, 1H), 8.25 (d, 1H), 7.62 (d, 4H), 7.50 (d, 2H), 7.45 (d, 1H), 7.20 (d, 2H), 6.30 (s, 2H), 4.62 (m, 1H), 3.95 (s, 3H), 3.5 (s, 3H), 1.87 (s, 6H), 1.73 (d, 3H), 1.26 (m, 3H), 1.10 (m, 6H).
Reaction SMILES: [O:1]1[CH2:12][C@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCCCCC>[CH2:5]([O:4][CH2:3][C@H:2]([OH:1])[CH2:12][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH:13]1[CH2:14][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: Oc1ccccc1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O[C@@H](COCc1ccccc1)COc1ccccc1OCC1CC1
Temperature: 25 °C

Procedure:
A mixture of (S)-benzyl 2,3-epoxypropyl ether (8.95 g as described in Heterocycles Vol. 16, 381, 1981), o-cyclopropylmethoxyphenol (8.95 g) in 36 ml acetone and 4 ml hexane, to which is added powdered potassium carbonate (6.9 g), is stirred at reflux in nitrogen atmosphere for 74 hours. After cooling to room temperature the solid is filtered off and washed with acetone. The filtrate is concentrated under reduced pressure, the residue is dissolved in ether, the ether solution is washed 2x with water and dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness. The crude oil is distilled in vacuo, at 199°-212°/0.2 mm to yield (S)-1-benzyloxy-3-[o-(cyclopropylmethoxy)phenoxy]-2-hydroxypropane.
Reaction SMILES: [CH3:1][O:2][NH3+:3].[Cl-].[OH-].[K+].[N:7]([CH2:10][C:11](OCC)=[O:12])=[C:8]=[O:9].Cl>O>[CH3:1][O:2][N:3]1[C:11](=[O:12])[CH2:10][NH:7][C:8]1=[O:9]
Reactant: CO[NH3+]
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CON1C(=O)CNC1=O
Reaction time: 1 h
Yield: 69.2 %

Procedure:
An aqueous solution prepared by dissolving 3.34 g of hydroxylamine methyl ether hydrochloride in 20 ml of water, was cooled with ice. While stirring the solution, an aqueous solution prepared by dissolving 2.24 g of potassium hydroxide in 20 ml of water, was gradually dropwise added thereto. After completion of the dropwise addition, the reaction system was returned to room temperature and the stirring was continued for 1 hour. Then, the reaction mixture was again cooled with ice, and 2.58 g of ethyl isocyanatoacetate was gradually added. The reaction system was returned to room temperature, and the reaction solution was stirred at a temperature of from 40° to 50° C. for further 0.5 hour. Then, the reaction solution was cooled with ice, and 10 ml of 6N hydrochloric acid was added. The mixture was refluxed for 3 hours, and then cooled with ice, whereby crystals precipitated. The crystals were collected by filtration to obtain 1.8 g of 3-methoxy-2,4-dioxoimidazolidine having a melting point of from 98° to 107° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[NH:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([CH3:18])([C:27]([O:29][CH3:30])=[O:28])[CH3:26])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C(C)(C)NCCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)N(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirred suspension of 2,4-dichloro-5-nitropyrimidine (7.5 g, 38.5 mmol), anhydrous potassium carbonate (10.0 g) in dry acetone (150 mL) was added a solution of methyl 2-methyl-N-(3-methylbutyl)alaninate (5.6 g, 30.0 mmol) in dry acetone (9 mL) at 0° C. The reaction was then allowed to warm up to room temperature and stirred at rt for 16 h. The reaction mixture was filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate-hexane mixture (v:v=5:95)) to give titled product (yield: 15%). 1HNMR (300 MHz, CDCl3): δ 0.85 (s, 3H), 0.88 (s, 3H), 1.30-1.36 (m, 2H), 1.60-1.65 (m, 7H), 3.37-3.42 (m, 2H), 3.72 (s, 3H) and 8.56 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[CH2:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[CH2:10][CH2:11][N:12]([CH2:26][CH:23]2[CH2:25][CH2:24]2)[CH2:13][CH2:14]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCNCC1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a stirred solution of [4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester (0.058 g, 0.14 mmol) in ClCH2CH2Cl (0.75 mL) at room temperature under Ar was added cyclopropanecarboxaldehyde (0.012 mL, 0.156 mmol, 1.2 eq.) and HOAc (0.075 mL, 1% v/v). The mixture was stirred for 0.5 h then Na(OAc)3BH (0.041 g, 0.2 mmol, 1.5 eq.) was added. The mixture was stirred for 16 h, diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL) and saturated brine (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to give [1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester (0.061 g, 95%). MS (ESI): 471.2/472.2 (M+1).
Reaction SMILES: C[C:2]1(C)[O:6][CH:5]([CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4](=[O:16])[O:3]1.Cl>C1(C)C=CC=CC=1.C[O-].[Na+]>[OH:6][CH:5]([CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([O:3][CH3:2])=[O:16]
Reactant: CCOC(=O)CC(=O)CC1OC(C)(C)OC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)CC(O)C(=O)OC
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 4-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-oxobutanoate (480 mg, 1.97 mmol) in toluene (2.0 ml), sodium methoxide (1M in methanol) (2.1 ml) was dropwise added at 0° C. in an argon atmosphere and stirred for 30 minutes. To the mixture, 1N hydrochloric acid (2.1 ml) was dropwise added and the mixture was stirred at room temperature for 15 minutes. After evaporating off the most of the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate and washed with a saturated saline and a phosphate buffer (pH 7.0). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1) to give pure 1-methyl 6-ethyl 2-hydroxy-4-oxoadipate (366 mg, 1.67 mmol). Yield, 85 %.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[Se](=O)=[O:16]>>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:14]=[O:16])=[N:7]2
Reactant: COc1ccc2nc(C)ccc2c1Br
Reactant: O=[Se]=O
Product: COc1ccc2nc(C=O)ccc2c1Br
Yield: 75 %

Procedure:
The title compound was prepared from 5-bromo-6-methoxy-2-methylquinoline (6b) and selenium dioxide using methods as described in the literature for similar compounds (Mathes et al., 1957) in 75% yield. 1H NMR (DMSO-d6, HMDSO), δ: 4.07 (3H, s); 7.92 (1H, d, J=9.0 Hz); 8.03 (1H, d, J=9.2 Hz); 8.29 (1H, d, J=9.2 Hz); 8.58 (1H, d, J=9.0 Hz), 10.09 (3H, s).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][Si:21]([CH3:23])([CH3:22])[C:24]#[C:25][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Add copper (I) iodide (45.0 mg, 0.24 mmol), bis(triphenylphosphine)palladium (II) dichloride (147.4 m g, 0.21 mmol) and triethylamine (2.37 mL, 16.8 mmol), to a solution of 1-bromo-3-trifluoromethoxybenzene (0.62 mL, 4.15 mmol) and trimethylsilylacetylene (0.78 mL, 5.4 mmol), in ethyl acetate (4 mL) and stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify by silica gel chromatography, eluting with hexanes to give the title compound (1.07 g, 100%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1.CO>C1COCC1.C(Cl)Cl>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=2)[N:20]=1
Reactant: CN(c1cc(N)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cc(Nc2nc(Cl)ccc2C(N)=O)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Reaction time: 21 h
Yield: 58.1 %

Procedure:
A 1 M THF solution of LiHMDS (0.762 mL, 0.762 mmol) was added dropwise to a suspension of 2,6-dichloronicotinamide (54.0 mg, 0.283 mmol) and N-(5-amino-2-(morpholine-4-carbonyl)phenyl)-N-methylmethanesulfonamide (68.2 mg, 0.218 mmol) in THF (0.5 mL) at 0° C. After 21 h at room temperature, LCMS analysis showed that the reaction was less than 50% complete. Additional portions of LiHMDS (0.054 mL) were added at 22, 23, and 24 h time points. After a total of 28 h, the mixture was quenched by saturated NH4Cl (2 mL) and extracted with EtOAc (3×2 mL). The combined extracts were loaded onto a silica gel cartridge and dried in vacuo. The dry cartridge was then connected to an ISCO cartridge and eluted with 30-100% EtOAc in hexanes, then 10% MeOH in CH2Cl2 to give a brown powder (59.3 mg, 58% yield). LCMS: (M+H)+=468.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, s), 8.38 (1H, br. s.), 8.21 (1H, d, J=8.28 Hz), 7.95 (1H, d, J=2.26 Hz), 7.85 (1H, br. s.), 7.55 (1H, dd, J=8.41, 2.13 Hz), 7.30 (1H, d, J=8.28 Hz), 7.01 (1H, d, J=8.03 Hz), 3.64-3.78 (2H, m), 3.45-3.59 (4H, m), 3.23 (2H, m), 3.16 (6H, s).