Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH3:29])=[N+:20]([O-])[C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.[C:37]([O:40]C(=O)C)(=[O:39])[CH3:38]>>[C:37]([O:40][CH2:29][C:19]1[C:18]([CH2:17][N:15]2[C:14](=[O:30])[N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:10]3=[N:16]2)=[CH:23][CH:22]=[C:21]([C:24]([F:27])([F:26])[F:25])[N:20]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]
Product: CC(=O)OCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C

Procedure:
A solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (60 mg, 0.12 mmol) in acetic anhydride (2 mL) in a sealed tube was stirred at 130° C. for 6 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO3, water, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 45 mg of the crude product as a light brown foam. A portion of the product (15 mg) was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 7.5 mg of the title compound as a yellow powder. HPLC/MS: retention time=2.90 min, [M+H]+=554.1.
Reaction SMILES: [CH2:1]([O:9][CH2:10][C:11]([OH:13])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[CH2:1]([O:9][CH2:10][C:11]([Cl:17])=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COCCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenethyloxy-acetic acid (3.89 g, 18.9 mmol) was dissolved in a mixture of 50 ml dichloromethane and 2.6 ml DMF. Oxalyl chloride ([79-37-8], 1.76 ml, 20.8 mmol) was slowly added, and the mixture was stirred at r.t. overnight. Phenethyloxy-acetyl chloride [221019-38-1] was obtained after evaporation of the solvent, and was sufficiently pure for the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[I:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11](O)=[O:12]>C(Cl)(Cl)Cl>[I:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([Cl:2])=[O:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1I
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1I
Yield: 85.3 %

Procedure:
To a suspension of PCl5 (33.0 g, 158 mmol) in 30 mL CHCl3 was added, with magnetic stirring, 3-iodo-p-anisic acid (40.0 g, 144 mmol) in small portions. The solution was heated at reflux for b 1 h under a gentle nitrogen sweep, during which time the solution became homogenous. The solvent was evaporated under reduced pressure, then the residue was distilled under high vacuum. The fraction distilling at 152-156° C. (5 mm Hg; lit.10 bp 183-185° C., 12-13 mm Hg) was collected, which rapidly solidified as a pink solid. Recrystallization from 200 mL hexane/CH2Cl2 afforded the desired product as white needles (36.4 g, 85.5%); mp 58° C.; 1H NMR (CDCl3) δ 3.99 (s, 3 H), 6.88 (d, 1 H, J=8.7 Hz), 8.13 (dd, 1 H, J=8.7, 2.4 Hz), 8.52 (d, 1 H, J=2.4 Hz); EI-MS m/z 296 (M+, 42), 261 (100).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:13]([C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](O)=[O:25])[CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[N:9]2)=[CH:4][CH:3]=1.C(O)C>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
A solution of 2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid (74.9 kg, 175.9 mol), (1S, 2R)-ephedrine hemihydrate (32.5 kg, 186.5 mol), 200 proof ethanol (290 Kg) and water (17 L) were stirred and heated to about 35° C. for 35 minutes. The solution was filtered and then cooled to about 20° C. until the onset of crystallization. The reaction was further cooled to 0–5° C. for about 2 hours. The intermediate ephedrine salt was filtered and washed with a cold (0–5° C) solution of 200 proof ethanol (206 Kg) and water (10 L). The ephedrine salt was dissolved in 377 L of dichloromethane and stirred with 125 L water and 9.7 kg 37% hydrochloric acid. The aqueous layer was removed. The organic layer was washed with water (125 L). The organic layer was distilled to 60% of the original volume. Carbonyldiimidazole was dissolved in CH2Cl2 (128 L) and slowly transferred to the reaction solution. The reaction was complete after 20 minutes. The reaction was washed two times with water (250 L each). The CH2Cl2 solution was distilled atmospherically, the volume being replaced-with of 200 proof ethanol (500 Kg). The ethanol solution was cooled at a rate of 20±5° C. per hour to 0–5° C. The solution was then held at 0–5° C. for 16 hours. The product was filtered and washed with 200 proof ethanol (100 kg). The product was dried for 16 hours under vacuum at 60° C. This afforded 26.0 Kg of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone as a white solid (36% yield). 1H-NMR: δ 8.87 (d, J=8.8, 1H), 8.61 (m, 2H), 7.93 (d, J=7.0, 1H), 7.74 (m, 4H), 6.05 (m, 1H), 3.62 (m, 1H), 3.28 (dd, J=7.0, 17.2, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J=6.2, 6H); Cl (MS) M+1 at 408, 100%; [α]D20=+135° (c=1, dichloromethane).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1
Reactant: SCc1ccc(Br)cc1
Reactant: C#Cc1cccc(C)c1C
Agent: [Na]
Product: Cc1cccc(/C=C\C(SC(/C=C\c2cccc(C)c2C)c2ccc(Br)cc2)c2ccc(Br)cc2)c1C

Procedure:
A solution of 2,3-dimethylphenylacetylene (0.02 mol), 4-bromobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dimethylstyryl-4-bromobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C1(C)C(S(O)(=O)=O)=CC=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13]
Reactant: OCCOCCOCCOCCO
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: OCCOCCOCCOCCOC1CCCCO1
Reaction time: 3.5 h

Procedure:
To a 20 mL solution of methylene chloride containing tetraethylene glycol (15 mmol, 2.91 g) and toluenesulfonic acid (20 mg) was added dropwise via syringe 3,4-dihydro-2H-pyran (12 mmol, 1.0 g, 1.1 mL). The reaction mixture was stirred for 3.5 h, and the solvent was removed by rotary evaporation. Mono-tetrahydropyran 1 was isolated by flash chromatography on silica eluting with 1:1 tetrahydrofuran/methylene chloride, affording 1.82 g of a clear, colorless oil (44% yield). 1H NMR (400 MHz, CDCl3): δ4.61 (dd, 1H, J1 =J2 =4 Hz), 4.6-4.8 (m, 2H), 3.69 (t, 2H, J=7 Hz).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:20]=1[C:21]([NH2:23])=[O:22].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:23][C:21](=[O:22])[C:20]4[C:19](=[CH:27][C:26]([O:28][CH3:29])=[CH:25][C:24]=4[O:30][CH3:31])[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 155 °C
Yield: 88.8 %

Procedure:
A mixture of 4-(4-acetylpiperazin-1-yl)benzaldehyde (1.34 g, 5.77 mmol) and 2-amino-4,6-dimethoxybenzamide (1.03 g, 5.24 mmol) in DMA (30 mL) was treated with p-TsOH (0.100 g, 0.524 mmol) and NaHSO3 (0.578 g, 5.55 mmol). The mixture was heated at 155° C. for 6 hours, cooled to room temperature, diluted with water (400 mL), and filtered to give brown solids. The filtrate was extracted with EtOAc (3×100 mL), concentrated, and combined with the brown solids from the filter cake. The combined solids were purified by silica gel chromatography, eluting with 92:7:1 CHCl3/MeOH/concentrated NH4OH to afford 2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one as a yellow solid (1.9 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl>C(OCCO)C>[CH3:19][C:14]1[N:13]=[C:12]([NH2:11])[N:17]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)nc(N)n1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
4-Nitroaniline (B1) [9.22 g, 0.07 mol] and 2-amino-4-chloro-6-methylpyrimidine (E1) (9.30 g, 0.07 mol) were dissolved in 2-ethoxyethanol (330 mL). To the resulting solution were added a few drops of c.HCl, and the resulting mixture was refluxed for 30 min, and then allowed to cool to room temperature overnight. After this time, the reaction mixture was filtered, and the resulting solid was basified by addition of aqueous ammonia solution, and then crystallized from H2O:EtOH to afford amine E2 as an amorphous bright-yellow solid (7.33 g). Concentration of the filtrate, followed by basification and reprecipitation as before, afforded a further quantity (0.78 g, overall yield 51%). 1H NMR [(CD3)2SO]: 2.14 [s, 3H, ArCH3], 6.00 [s, 1H, ArNHAr], 6.37 [s, 2H, ArNH2], 8.00 [ddd, J=10.24, 5.05, 2.96 Hz, 2H, ArH], 8.12 [ddd, J=10.24, 4.95, 2.90 Hz, 2H, ArH], 9.75 [s, 1H, ArH]. LCMS (APCI+): 246 (100%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][N+:4]([O-:6])=[O:5].[Cl:8][C:9]([C:20](=O)[CH3:21])=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1>C(O)C>[Cl:8][C:9]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:3]([N+:4]([O-:6])=[O:5])=[C:2]([CH3:7])[NH:1][C:20]=1[CH3:21]
Reactant: CC(=O)C(Cl)=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(N)=C[N+](=O)[O-]
Solvent: CCO
Product: CC1=C(Cl)C(c2cccc([N+](=O)[O-])c2)C([N+](=O)[O-])=C(C)N1

Procedure:
0.1 mol of 2-amino-1-nitro-prop-1-ene and 0.1 mol of 2-chloro-1-(3-nitrophenyl)-but-1-ene-3-one were heated in boiling ethanol, analogously to Example 18. 3-Chloro-1,4-dihydro-2,6-dimethyl-5-nitro-4-(3-nitrophenyl)pyridine of melting point 198° C. (decomposition) was obtained. Yield:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1c(-c2cccnc2)[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.50 ml) is added dropwise to a solution of 7.5 g 3-(2-hydroxyethyl)-2-(3-pyridyl)-indole and 10.0 ml of triethylamine in 150 ml of methylene chloride at -10°. This mixture is stirred at room temperature for 0.5 hour and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride and the extract is washed with saturated sodium bicarbonate solution, dried over MgSO4 and evaporated in vacuo to give 3-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-indole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:14].C([O-])(=O)C.[Na+].[Br:20]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:20][CH:13]1[C:3]2([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: BrBr
Reactant: O=C1Nc2ccccc2C12CCCC2
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12CCCC2Br
Yield: 105 %

Procedure:
A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm3) was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm3). After 30 min. the mixture was poured into sat. sodium hydrogen carbonate solution and extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to give the subtitled compound (0.37 g, 1.47 mmol, 96%) as an off-white solid which was used without further purification: 1H NMR (CDCl3) δ 1.8-2.27 (m, 8H), 6.79 (d, J=8 Hz, 1H), 7.30-7.39 (m, 2H), 8.63 (br s, 1H).
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[N+:6]([CH3:9])([O-:8])=[O:7].[O-]CC.[Na+].O>C(O)C>[N+:6]([CH2:9][C:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1)([O-:8])=[O:7]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 45 %

Procedure:
To a solution of cyclobutanone (10.0 g, 143 mmol) and nitromethane (12 mL) in ethanol (10 mL) was added sodium ethoxide in ethanol (2.67 M, 2.7 mL, 7.2 mmol). The mixture was stirred for 6 d at rt. Water was added and the mixture was extracted thrice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The volatiles were removed by distillation under vacuum to provide 1-(nitromethyl)cyclobutanol as a yellow liquid (8.51 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]([CH:14]1[CH2:16][CH2:15]1)#[CH:13]>C1COCC1.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:13]#[C:12][CH:14]2[CH2:16][CH2:15]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C#CC1CC1
Reactant: Clc1nc(Cl)c2occc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(C#CC2CC2)c2occc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (0.30 g, 1.6 mmol, ArkPharm), PPh3 (0.008 g, 0.03 mmol) in THF (1.2 mL) and TEA (1.764 mL). The mixture was placed under vacuum and purged with N2 three times, then Pd(PPh3)2Cl2 (0.011 g, 0.016 mmol) and CuI (0.006 g, 0.03 mmol) were added. The mixture was placed under vacuum and purged with N2 three times and then ethynylcyclopropane (0.161 mL, 1.905 mmol) was added. The mixture was placed under vacuum and purged with N2 and then the mixture was stirred at rt for about 18 h. The mixture was filtered and the filter cake was washed with EtOAc (3×20 mL). The filtrate was concentrated under reduced pressure and the residue was deposited on silica gel and purified by column chromatography (12 g silica gel, 0 to 30% EtOAc/heptane) to give 2-chloro-4-(cyclopropylethynyl)furo[3,2-d]pyrimidine (0.090 g, 26%): LC/MS (Table 2, Method c) Rt=2.11 min; MS m/z 219 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:30])([CH3:29])[CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[C:6]=2[N:7]=1.[CH:31]1([C:34]2[N:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=2)[CH2:33][CH2:32]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:18]=[C:17]([NH:19][C:40](=[O:41])[CH2:39][N:37]4[CH:38]=[C:34]([CH:31]5[CH2:32][CH2:33]5)[N:35]=[N:36]4)[CH:16]=[N:15][CH:14]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:30])([CH3:29])[CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[C:6]=2[N:7]=1
Reactant: CC(C)(COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Reactant: O=C(O)Cn1cc(C2CC2)nn1
Product: CC(C)(COC1CCCCO1)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C4CC4)nn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 1 using {2-amino-7-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}(5-aminopyridin-3-yl)methanone (see Preparation 49) and (4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetic acid (see Preparation 83) to afford the title compound as a yellow solid in 86% yield, 70 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC1CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 117.1 %

Procedure:
5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonate (7.5 g, 54.1 mmol) and the cyclobutanemethanol tosylate (13 g, 54.1 mmol). The mixture was stirred at 50 ° C. under argon for 16 hours. Poured into water (500 ml), extracted with ethyl acetate (4×100 ml)and the combined organic fractions washed with 1M sodium hydroxide solution (100 ml), water (100 ml), saturated brine (100 ml) dried (MgSO4) and concentrated in vacuo to give 5-chloro-2-(cyclobutylmethoxy)benzaldehyde as a brown oil (13 g) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br>C(#N)C>[F:27][C:28]([F:41])([F:42])[C:29]1[CH:30]=[C:31]([CH2:32][NH:1][C@H:2]2[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: COC(=O)[C@H]1CC[C@H](N)[C@@H]1c1ccc(F)cc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccc(F)cc1
Yield: 71.7 %

Procedure:
A solution of 20 mg of amine from Example 63, 0.050 mL of DIPEA and 30 mg of 3,5-bis(trifluoromethyl)benzyl bromide in 1 mL of acetonitrile was stirred for 20 h in a sealed vial and evaporated. The residue was purified on a 1 mm preparative silica gel plate eluted with 20% ethyl acetate in hexanes to obtain 28 mg of title compound as an oil. Mass spec (NH3 /CI): 464 (M+1).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:12](#[N:15])[CH:13]=[CH2:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1>[C:12]([CH2:13][CH2:14][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)#[N:15]
Reactant: C=CC#N
Reactant: c1c[nH]c(Cn2ccnc2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#CCCn1cccc1Cn1ccnc1
Reaction time: 18 h

Procedure:
2-(Imidazol-1-ylmethyl)pyrrole (4.41 g) and acrylonitrile (6.0 ml) were dissolved in dioxan (75 ml) and benzyltrimethylammonium hydroxide (1.5 ml of 40% solution in methanol) was added. The mixture was warmed to 55° for 1 hour and then allowed to stand at room temperature for 18 hours. It was then poured into water and the mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform gave 1-(2-cyanoethyl)-2-(imidazol-1-ylmethyl)pyrrole (5.0 g) as an oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=[O:11].[O:20]1C2C(=CC=CC=2)C(=O)CC1C1C=CC=CC=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH:10]1[CH2:9][C:8](=[O:20])[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[O:11]1
Reactant: O=C(C=Cc1ccccc1O)c1ccc(Cl)cc1Cl
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Product: O=C1CC(c2ccc(Cl)cc2Cl)Oc2ccccc21

Procedure:
2-Hydroxy-2',4'-dichlorochalcone, as described in Arch. Pharm. 295, 16 (1962), was cyclized to the flavanone by the procedure described in Bull. Soc. Chem. France 674 (1973). Two recrystallizations from methanol gave 3 g of 2',4'-dichloro flavanone as pale tan crystals, m.p. 91°-92° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[C:7]([NH:9]N)[CH:8]=1.O.[NH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl>CCO>[Br:2][C:3]1[C:8]2[C:19]3[CH2:18][NH:17][CH2:22][CH2:21][C:20]=3[NH:9][C:7]=2[C:6]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:5][CH:4]=1
Reactant: NNc1cc(Br)ccc1SCCCCl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: ClCCCSc1ccc(Br)c2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 58 %

Procedure:
1-{5-Bromo-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloride (784 mg, 2.4 mmol) and 4-piperidone monohydrate.HCl (398 mg, 2.6) were dissolved in EtOH (5mL). Conc. Hcl (0.2 mL, 2.4 mmol) were added. The reaction was refluxed for 18 hrs and then cooled to rt. The ppt was collected by filtration and the residue was washed with EtOH (3mL). 9-bromo-6-[(3-chloropropyl)sulfanyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloroide (500.4 mg, 58%) was isolated as a white powder. 1H NMR (CD3OD, 300 Mhz) δ7.18 (d, 1H, 8.0 Hz), 7.12 (d, 1H, 8.0 Hz), 4.73 (s, 2H), 3.64 (t, 2H, 6.6 Hz), 3.58 (t, 2H, 6.3 Hz), 3.16 (t, 2H, 6.3 Hz), 3.02 (t, 2H, 6.6 Hz), 1.87-1.96 (m, 2H) ppm.