Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C:9]2([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[C:17]([O:20][CH3:21])([O:18][CH3:19])[C:13]3([C:14](=[O:16])[CH:15]=1)[CH:11]([C:12]3([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:10]2.Cl[Si:35]([CH3:38])([CH3:37])[CH3:36].C([N-]C(C)C)(C)C.[Li+]>CCOC(C)=O.CCCCCC>[CH3:6][O:7][C:8]1[C:9]2([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[C:17]([O:18][CH3:19])([O:20][CH3:21])[C:13]3([C:14](=[O:16])[C:15]=1[Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:11]([C:12]3([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:10]2
Reactant: C[Si](C)(C)Cl
Reactant: COC1=CC(=O)C23C(CC1(CC=C(C)C)C2(OC)OC)C3(C)CCC=C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC1=C([Si](C)(C)C)C(=O)C23C(CC1(CC=C(C)C)C2(OC)OC)C3(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
A THF (1 mL) solution of 26 (16 mg, 41 μmol, 1 equiv.) was cooled to −78° C. in a 10-mL recovery flask, and chlorotrimethylsilane (0.21 mL, 1.6 mmol, 40 equiv.) and a freshly prepared THF solution of lithium diisopropylamide (0.50 M, 1.6 mL, 0.82 mmol, 20 equiv.) were added sequentially. The resulting yellow solution was stirred at −78° C. for 45 min and then allowed to warm to room temperature over 3.5 h. The golden yellow solution was then quenched at −20° C. with saturated aqueous NaHCO3 and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. Flash column chromatography (30 mL SiO2, 95:5 to 8:2 hexane:EtOAc) afforded 10.7 mg (23.2 μmol, 57% yield) of 28 as a colorless oil along with 3.9 mg (10 μmol, 24% recovery) of 26. TLC Rf 0.62 (8:2 hexane:EtOAc). 1H NMR (600 MHz; C6D6): δ 5.54 (t, J=7.1 Hz, 1H), 5.47 (t, J=7.2 Hz, 1H), 3.37 (s, 3H), 2.99 (s, 3H), 2.97 (s, 3H), 2.77-2.71 (m, 2H), 2.42 (dd, J=15.0, 7.0 Hz, 1H), 2.41-2.34 (m, 1H), 2.06 (dd, J=13.3, 6.6 Hz, 1H), 1.84 (td, J=12.3, 5.2 Hz, 1H), 1.74 (s, 3H), 1.73-1.68 (m, 4H), 1.68 (m, 4H), 1.62 (s, 3H), 1.54 (s, 3H), 0.84 (t, J=7.0 Hz, 1H), 0.48 (s, 9H). 13C NMR (126 MHz; C6D6): δ 198.9, 184.3, 131.1, 130.9, 129.2, 125.5, 123.1, 110.0, 74.1, 64.0, 53.5, 52.3, 51.0, 50.6, 41.8, 38.0, 31.7, 28.2, 26.6, 25.92, 25.87, 17.82, 17.80, 16.4, 0.9. HRMS-ESI (m/z): [M+H]+ calculated for C27H44O4Si, 461.3082. found, 461.3094.
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[N:16][N:17]([C:2]2[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:18]=1
Reactant: COC(=O)c1cnc(F)c(C)c1
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-n2cc(Cl)cn2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (800 mg, 4.73 mmol, Step-1 of Amine-36), 4-chloro-1H-pyrazole (509 mg, 4.97 mmol), and cesium carbonate (3.08 g, 9.46 mmol) in DMF (16 mL) stirred at 60° C. for 1 hour. After cooling to rt, the mixture is diluted with EtOAc (150 mL) and washed with water (100 mL×3). The organic phase is filtered through silica gel, and the filtrate is concentrated to give 1.19 g (>99% yield) of the title compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([OH:20])=O)[C:15](=[S:21])[NH:14][C:13](=[O:22])[CH:12]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].N1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:20])[C:15](=[S:21])[NH:14][C:13](=[O:22])[CH:12]=1
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)NCCNC(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
To a solution of 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (40 g, 124 mmol) in DMF (300 mL) was added tert-butyl (2-aminoethyl)carbamate (40 g, 250 mmol) and pyridine (30 mL), and the mixture was stirred at room temperature for 15 minutes. The solution was cooled to 0° C. and it was purged with nitrogen gas for 3 times. After 10 minutes, a 50% solution of T3P in DMF (109 mL) was added drop-wise at 0° C., and stirring was continued for 1 hour, whereupon the water/ice bath was removed and stirring was continued for 4 hours. The reaction solution was slowly poured into a stirring solution of aqueous HCl solution (2500 mL, 0.5 M), and the suspension was stirred at room temperature for 1 hour. The formed solid was filtered, and the filter cake was washed with 0.5M HCl solution (500 mL) followed by water (500 mL). The solid was dried in the vacuum oven at 50° C. for 20 hours to give 54.6 g of light beige powder. This solid was suspended in EtOAc (500 mL), heated to 70° C. under a stream of nitrogen gas with stirring for 1 hour, and then at room temperature for 18 h. The suspension was cooled down to 0° C., and the solid was filtered, the filter cake washed with cold (0° C.) EtOAc (100 mL) and dried in the vacuum oven at 50° C. for 9 hours to give 49.0 g of off-white solid. This solid was suspended in acetonitrile (300 mL), and stirred at 70° C. under a stream of nitrogen for 18 h. The mixture was cooled to 0° C., and the resultant solid was filtered, washed with cold acetonitrile (50 mL) and dried in the vacuum oven at 50° C. for 8 hours to give 46.5 g of off-white solid. This solid was suspended in EtOAc (350 mL), heated to 70° C. under a stream of nitrogen gas with stirring for 1 hour, and then at room temperature for 18 h. The suspension was cooled down to 0° C., and the solid was filtered, the filter cake washed with cold (0° C.) EtOAc (50 mL) and dried in the vacuum oven at 50° C. for 9 hours to give the title compound (45.4 g, 78.8%) as an off-white powder.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[O:3]1.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[Cl:12][CH2:11][CH:10]1[O:13][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH2:9]1
Reactant: CC1(C)OC(=O)C=C(CC(O)CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CC(=O)OC(CCl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
A mixture of 940 mg (4.26 mmol) of (-)-2,2-dimethyl-6-(3-chloro-2-hydroxypropyl)-1,3-dioxin-4-one (98% ee), 882 mg (6.39 mmol) of potassium carbonate and 10 ml of methanol was stirred at room temperature for 12 hours. After completion of the reaction, methanol was distilled off, and the resultant residue was neutralized with 10% HCl and then extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography (an eluent of hexane:ethyl acetate=3:1), thereby obtaining 510 mg (yield 74%) of (-)-6-chloromethyltetrahydropyran-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:23]C)=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C([O-])=O)([O-])=O.[CH2:25]([OH:27])[CH3:26].C(O)(=[O:30])C>[Fe]>[CH2:15]([C:14]1[N:1]=[C:4]2[C:5](=[C:23]=[O:30])[C:6]([O:27][CH2:25][CH3:26])=[CH:10][CH:11]=[C:12]2[N:13]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)O
Reactant: CCc1c(C(=O)[O-])ccc(NC(=O)Cc2ccccc2)c1[N+](=O)[O-]
Reactant: CCO
Agent: [Fe]
Product: CCOc1ccc2c(c1=C=O)=NC(Cc1ccccc1)=N2
Reaction time: 40 h

Procedure:
A mixture of 3-nitro-4-phenylacetylamino-ethylbenzoate (3.60 g), ethanol (47 ml), acetic acid (23 ml) and iron (6.4 g) is refluxed by heating for four hours. Solids are separated through filtration and the filtrate is concentrated. Ethanol (50 ml) and 35% hydrochloric acid (5 g) are added to the residue and the solution is stirred for 40 hours as it is refluxed by heating. The solution is neutralized with sodium bicarbonate and chloroform extraction is performed. The organic layer is concentrated under reduced pressure and then purified using silica gel column chromatography. Thus, 2-benzyl-5-ethoxy-carbonylbenzimidazole (2.30 g) is obtained. 1H-NMR (CDCl3, δ): 1.39 (3H, t, J =7.1Hz), 4.26 (2H, s), 4.37 (2H, q, J=7.1Hz), 7.22-7.36 (5H, m), 7.50 (1H, d, J=8.6Hz), 7.94 (1H, dd, J=1.5 and 8.6Hz), 8.23 (1H, d, J=1.3Hz).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CCCCCC.O>CC(C)=O>[CH:1]#[C:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C#CCC(O)CCCCC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: O
Product: C#CCC(=O)CCCCC

Procedure:
A solution of 14 g of 1-nonyn-4-ol in 100 ml of acetone is cooled to 0° and treated dropwise with 70 ml of 2.67 molar Jones reagent with stirring. The reaction mixture is poured into a mixture of hexane and water, the organic layer is separated and washed with water, dried over sodium sulfate, stripped of solvent, and the residue distilled to give the title product.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][OH:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=[O:20])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=1
Reactant: COc1cc(C(F)(F)F)c(CO)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(F)(F)F)c(C=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To a cooled (−78° C.) solution of DMSO (0.15 mL, 2.13 mmol) in dichloromethane (2 mL) was added oxalyl chloride (0.14 mL, 1.60 mmol), and the mixture was stirred for 10 minutes. 6-Methoxy-4-trifluoromethyl-3-pyridinemethanol (220 mg, 1.06 mmol) in dichloromethane (4 mL) was added to the reaction mixture. After stirring at −40° C. for 50 minutes, the mixture was treated with triethylamine (0.44 mL, 3.16 mmol), stirred for 90 minutes while warming to room temperature, and quenched with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 6-methoxy-4-trifluoromethyl-3-pyridinecarboxaldehyde (162 mg, 74.4%) as a solid. The crude product was used directly in the following Swern oxidation.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C@@H](O)S([O-])(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].CO.Cl.CO[CH:26]([O:29][CH3:30])[O:27][CH3:28]>O1CCOCC1>[CH3:19][O:18][C:16](=[O:17])[C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][CH:26]([O:27][CH3:28])[O:29][CH3:30]
Reactant: COC(OC)OC
Reactant: COC(=O)C(CC1CCCCC1)C[C@@H](O)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H](CC1CCCCC1)CC(OC)OC
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a slurry of sodium (S)-4-cyclohexyl-1-hydroxy-3-methoxycarbonyl-butane-1-sulfonate (400.0 g, 1.26 mol) and methanol (2 L) was added 4.0 M HCl in 1,4-dioxane (400 mL) and the reaction mixture was stirred for 15 min. Trimethoxymethane (340 mL, 3.11 mol) was added and reaction mixture was heated at 50° C. overnight, and then cooled to room temperature. White solids were filtered off and discarded. Most of the solvent was removed from the filtrate by rotary evaporation. Ethyl acetate (800 mL) was added resulting in more precipitation. The white precipitate was removed by filtration. Solvent was removed from the filtrate by rotary evaporation and then under high vacuum at room temperature overnight to yield the title compound (211 g) as a thick oil. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 4.25 (t, 1H), 3.57 (s, 3H), 3.18 (s, 6H), 2.43 (m, 1H), 1.55-1.81 (m, 2H), 1.50-1.72 (m, 5H), 1.20-1.48 (m, 2H), 1.05-1.21 (m, 4H), 0.71-0.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1.[I:20]I>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([I:20])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1
Reactant: CCCCCc1ccc(-c2cccc(F)c2F)cc1
Reactant: II
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(I)c(F)c2F)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2′,3′-Difluoro-4-pentylbiphenyl (612 g, 0.243 mol), and dry tetrahydrofurane (400 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, pressure-equilibrated dropping funnel and thermometer. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was cooled down to −78° C. on the dry ice/acetone bath and then 2.5 mol/dm3 of n-butyllithium solution in hexane (100 ml 025 mol) was added dropwise, keeping the reaction temperature below −70° C. After addition of all n-butyllithium the mixture was stirred for additional 2 hours at −78° C. Next iodine solution in tetrahydrofurane (63.5 g, 0.25 mol) was added dropwise maintaining the temperature below −70° C. After addition of the iodine solution the cooling bath was removed and the mixture was stirred to reach the room temperature. Organic solvents were evaporated and the thick oily residue was diluted with hexane and treated with water solution of sodium sulfite to remove the remaining iodine. Phases were separated and hexane was evaporated. The residue was distilled under reduced pressure 1 mmHg collecting the fraction boiling at 174-175° C. The colourles liquid product 71 g was obtained with 78% of theor. yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].Br[CH2:41][CH2:42][CH3:43]>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:41][CH2:42][CH3:43])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCCBr
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(C(=O)OCC)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc21
Reaction time: 0.25 h
Yield: 703.6 %

Procedure:
To a suspension of NaH (0.23 g, 1.9 mmol) in DMF (5 mL) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid ethyl ester (0.03 g, 0.05 mmol), obtained in step (vi) of Example 124, at 0° C., and stirred for 15 min. Bromopropane (0.23 g, 1.9 mmol) was added to this at the same temperature and the reaction was stirred for another 1 h. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 10% ethyl acetate and pet ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-propyl-1H-indole-2-carboxylic acid ethyl ester (0.2 g, yield: 38%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=1[NH2:26].Cl>C(O)(C)C>[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=1[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1ccc(N)c(F)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (200 mg, 0.622 mmol), (prepared as described for the starting material in Example 2c) and 2-fluoro-4-methylaniline (94 mg, 0.764 mmol) in isopropanol (5 ml) containing 6.2M hydrogen chloride in isopropanol (110 μl) was stirred at 80° C. for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum. The solid was purified by column chromatography, eluting with methylene chloride/methanol (90/10) followed by 5% ammonia in methanol/methylene chloride (10/90). Evaporation of the fractions containing the expected product gave 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (170 mg, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c(Br)c(Br)n2Cc2ccc(F)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 513 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Na+].[I-:17]>CC(=O)CC.CCOCC>[I:17][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)C1(CCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)C1(CCCCI)CC1
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.6 g, 45.7 mmol) in 2-butanone (50 mL) was added NaI (8.23 g, 54.5 mmol). The reaction mixture was stirred under reflux overnight, diluted with Et2O (100 mL), washed with a mixture of H2O (100 mL) and aqueous Na2S2O4 (0.5 M, 10 mL) and brine (50 mL). The organic phase was dried (Na2SO4) and evaporate in vacuo to give tert-butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate (14.8 g, 94% pure by GC, 94%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=3.18 (t, J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.62-1.45 (m, 4H), 1.43 (s, 9H), 1.12 (dd, J=6.7 Hz, 3.8 Hz, 2H), 0.60 (dd, J=6.6 Hz, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=173.9, 80.0, 33.8, 33.3, 28.9, 28.2 (3×), 24.2, 15.5 (2×), 7.2. HRMS calcd for C12H21IO2 (M+): 324.0587. found: 324.0587.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][O:49]S(C)(=O)=O)[CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>C1COCC1>[CH:48]([OH:49])=[O:66].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)[CH:46]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1COCCN1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCN5CCOCC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
To a solution of Intermediate 124c (0.13 mmol) in THF (2.5 mL) was added DIPEA (90 μL, 0.52 mmol) and morpholine (45 μL, 0.52 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title compound (26 mg, 26%). LCMS (Method 5): Rt 3.70 min, m/z 736 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.2 Hz), 0.58 (3H, d, J=6.2 Hz), 1.20 (9H, s), 1.34-1.54 3H, m), 1.63-1.68 (2H, m), 1.72-1.86 (2H, m), 1.89-1.97 (1H, m), 2.01-2.07 (2H, m), 2.37 (4H, t, J=4.4 Hz), 2.69 (2H, t, J=6.7 Hz), 3.08-3.18 (2H, m), 3.49 (4H, t, J=4.6 Hz), 4.19 (2H, t, J=6.7 Hz), 4.80 (1H, dt, J=8.6, 5.6 Hz), 5.49 (1H, t, J=4.3 Hz), 6.22 (1H, s), 7.11 (1H, d, J=8.6 Hz), 7.16 (1H, dd, J=9.8, 2.2 Hz), 7.19-7.25 (1H, m), 7.28-7.33 (3H, m), 7.59 (1H, s), 7.62 (1H, d, J=9.6 Hz), 7.84 (1H, d, J=1.9 Hz), 7.96 (1H, s), 8.02 (1H, s), 8.14 (0.6H, br s).
Reaction SMILES: [H-].[Na+].Cl.[C:4]1([C:10]2[N:11]=[C:12]([C:15]3[N:16]=[CH:17][N:18]4[C:23](=[O:24])[N:22]([CH2:25]C#C)[N:21]=[N:20][C:19]=34)[NH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[CH3:30]I>CN(C=O)C>[CH3:25][N:22]1[C:23](=[O:24])[N:18]2[CH:17]=[N:16][C:15]([C:12]3[N:13]([CH3:30])[CH:14]=[C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:11]=3)=[C:19]2[N:20]=[N:21]1
Reactant: [H][H]
Reactant: C#CCn1nnc2c(-c3nc(-c4ccccc4)c[nH]3)ncn2c1=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)nc1-c1ncn2c(=O)n(C)nnc12
Reaction time: 8 h
Yield: 41.1 %

Procedure:
Sodium hydride (60% in mineral oil, 19 mg, 0.467 mmol) was added in portions to a solution of 8-(4-phenyl-1H-imidazol-2-yl)-3-(prop-2-ynyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one hydrochloride (70 mg) in DMF (3 mL) and the mixture was sonicated several times until hydrogen evolution ceased. Methyl iodide (66 μL, 1.065 mmol) was added and the mixture was stirred overnight. The resulting solution was poured into ice and was then left at 4° C. for 5 hours. The precipitate was filtered and washed successively with water and diethyl ether. 10 mg of crude product obtained from a previous experiment was combined, and the crude mixture was absorbed on silica. The crude product was purified by flash chromatography using DCM:MeOH (95:5) as eluent to give the title compound as a bright yellow solid (25 mg, 23%). The NMR spectrum of the product showed that it contained ˜5/6% of either starting material or the regioisomer of the product. δH (DMSO-d6): 8.92 (1H, s), 7.89 (1H, s), 7.89-7.92 (2H, m), 7.38-7.42 (2H, m), 7.22-7.26 (1H, m), 3.98 (3H, s), 3.87 (3H, s).