Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([C:12]2[C:20]3[C:19](=O)[NH:18][CH:17]=[N:16][C:15]=3[O:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N>O>[Cl:3][C:19]1[C:20]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:13][O:14][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2occ(-c3ccccc3)c12
Agent: N
Solvent: O
Product: Clc1ncnc2occ(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add 9.5 ml (101.8 mmol) phosphoryl chloride to 1.8 g (approx. 6.8 mmol) 5-phenylfuro[2,3-d]pyrimidin-4(3H)-one at RT and heat the mixture for 1 h under reflux. Cool the resultant black mixture to RT and carefully add dropwise at <10° C. to a well-stirred solution of 70 ml conc. ammonia solution and 50 ml water cooled to 0° C. (pH>9). At the end of addition, heat the black suspension to RT and stir for a further 15 min. Filter off the black solid with suction, resuspend with water three times, filter with suction again, and dry at high vacuum. Dissolve the solid in dichloromethane and column-filter on silica gel (solvent: dichloromethane). 1371 mg (80.6% of theor.) of the target compound is obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.ClCCl.C(OCC)(=O)C>[Br:31][CH2:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1cccc(CCC(=O)O)c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CCCBr)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.5 g (8.56 mmol) of 3-(3-cyanophenyl)propionic acid and 1.19 ml (8.56 mmol) of triethylamine were dissolved in 42 ml of tetrahydrofuran. 0.819 ml (8.56 mmol) of ethyl chloroformate was added to the solution under cooling with ice, and they were stirred for 20 minutes. Precipitates thus formed were removed by the suction filtration. 3 g of ice and 0.648 g (17.12 mmol) of sodium borohydride were added to the filtrate under cooling with ice, and they were stirred for 1 hour. 20 ml of 1 N aqueous hydrogen chloride solution was added to the reaction mixture, and they were stirred at room temperature for one hour. After the treatment with ethyl acetate as the extractant in an ordinary manner, an oily residue was obtained, which was dissolved in 86 ml of dichloromethane. 5.68 g (17.12 mmol) of carbon tetrabromide and 2.69 g (10.27 mmol) of triphenylphosphine were added to the solution, and they were stirred at room temperature for one hour. The reaction mixture was treated with ethyl acetate as the extractant in an ordinary manner to obtain the crude compound, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)CCC.[F-].[K+]>CN(C)C=O.C(Cl)Cl.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:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1cnc(-c2ccco2)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A solution of 2-amino-5-bromopyrazine (500 mg, 2.87 mmol) in N,N-dimethylformamide (15 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol), N,N-diisopropylethylamine (1.25 mL, 7.18 mmol), lithium chloride (426 mg, 10.06 mmol), and 2-(tributylstannyl)furan (905 μL, 2.87 mmol). The resulting reaction mixture was heated at 120° C. for 4 h. After such time, the reaction was cooled to 25° C., treated with a saturated aqueous potassium fluoride solution (10 mL), and then stirred at 25° C. overnight for 16 h. The solution was then diluted with methylene chloride (25 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 98/2 to 96/4 methylene chloride/methanol) afforded 5-furan-2-yl-pyrazin-2-ylamine (356 mg, 77%) as a brown solid: mp 80.2–83.8° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2)[C:4]([OH:6])=[O:5].[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>[OH-].[Na+].O>[C:22]([NH:2][CH:3]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2)[C:4]([OH:6])=[O:5])(=[O:24])[CH3:23]
Reactant: NC(C(=O)O)C1c2ccccc2CCc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C(=O)O)C1c2ccccc2CCc2ccccc21
Reaction time: 0.33 h
Yield: 47.2 %

Procedure:
α-Amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid, hydrochloride (5.0 g, 16.5 mmol) is dissolved in 1N sodium hydroxide (70 mL) and 50 mL of water, cooled in an ice bath, and treated with acetic anhydride (2.3 mL, 25 mmol) keeping pH at 10 to 10.5. The mixture is stirred for an additional 20 minutes, then the pH is adjusted to 3 to 4 with concentrated hydrochloric acid. A precipitate is collected, washed with water, diethyl ether, and dried in a vacuum oven (50° C./10 mm Hg). The dried solid is recrystallized from ethyl acetate-hexane to give 2.41 g of the title compound; mp 220°-223° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:22])(=[O:21])[N:11]([CH2:18][O:19][CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[OH-].[Na+]>CO.O>[CH3:20][O:19][CH2:18][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:10]([C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])(=[O:22])=[O:21]
Reactant: COCN(c1ccccc1)S(=O)(=O)c1ccsc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCN(c1ccccc1)S(=O)(=O)c1ccsc1C(=O)O
Yield: 76.8 %

Procedure:
To a homogenous mixture of 3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid methyl ester (3 g, 8.75 mmol) in methanol and water was added aqueous, sodium hydroxide solution (2N, excess) at room temperature. Upon completion of the reaction, the mixture was cooled and extracted once with diethyl ether. The aqueous layer will then acidified with aqueous, HCl (2N, excess) before re-extracting twice with ethyl acetate. The organic layer was washed once with brine solution and dried over anhydrous sodium sulfate. The ethyl acetate solution was decanted and evaporated under reduced pressure to give the desired 3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid (2.2 g, 79%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[CH:6]2.C[S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[CH:6]2
Reactant: COc1cc2cncnc2cc1C
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ncncc2cc1O
Temperature: 140 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
6-Methoxy-7-methyl-quinazoline (94 mg) was dissolved in N,N-dimethylformamide (5 ml) to prepare a solution, sodium thiomethoxide (376 mg) was added to the solution, and the mixture was stirred at 140° C. for one hr. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-hydroxy-7-methyl-quinazoline (64 mg, yield 73%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:25]=[CH:24][C:11]2[C:12]([CH:21]([CH3:23])[CH3:22])=[N:13][C:14]3[CH:15]=[CH:16][NH:17][C:18](=O)[C:19]=3[C:10]=2[CH:9]=1)=O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:28].[OH-].[Na+]>C(#N)C>[Cl:28][C:18]1[N:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:10]1[CH:9]=[C:8]([C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)[CH:25]=[CH:24][C:11]=1[C:12]([CH:21]([CH3:22])[CH3:23])=[N:13]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NNC(=O)c1ccc2c(C(C)C)nc3cc[nH]c(=O)c3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nnc(-c2ccc3c(C(C)C)nc4ccnc(Cl)c4c3c2)o1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of N′-acetyl-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridine-9-carbohydrazide (30 mg, 0.089 mmol) in ACN (1.0 mL) was added POCl3 (1.0 ml). The resulting suspension was stirred at 100° C. in a sealed vial for 3 hr. The solution was diluted with additional acetonitrile (10 mL), and then added to cooled 6N NaOH (20 mL). The resulting mixture was extracted with EtOAc (1×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford crude 1-chloro-6-isopropyl-9-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[c]-1,6-naphthyridine that was used directly without further purification. LRMS (ESI) calc'd for (C18H15ClN4O) [M+H]+, 339.1; found 339.1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>C1(C)C=CC=CC=1>[C:26]1([NH:25][C:10](=[O:11])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=3[Cl:1])[CH:6]=[CH:7][C:8]=2[N+:14]([O-:16])=[O:15])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 62.6 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (5.68 g, 0.015 mole) in toluene (35 ml) was added aniline (2.8 g, 0.30 mole). The temperature immediately rose to 45° C. The reaction was then heated to reflux for twelve hours. The cooled reaction was poured into dilute hydrochloric acid solution. The residual solids were filtered, washed with warm water and dried to give 4.1 g of a gray solid m.p. 190°-4° C. Recrystallization from methanol gave 3.8 g, m.p. 191°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[C:22]([F:30])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:31])[CH:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[C:22]([F:30])[CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:33]\[OH:34])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCCO)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OCCO)c(F)c1

Procedure:
In analogy to example 151, step 3, 5-{3-(4-chloro-2-methyl-phenyl)-3-[3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-propionyl}-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=459.3 [M+H]+.
Reaction SMILES: CC(C)([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:26])[C:11]3[C:16]([O:17][C:18]=2[C:19]=1[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])=[CH:15][CH:14]=[CH:13][CH:12]=3)C=C>C1(C)C=CC=CC=1>[CH3:18][C:9]([CH3:10])=[CH:8][CH2:7][C:19]12[C:6](=[O:5])[CH:7]3[CH:8]=[C:9]4[C:18]1([CH:22]([CH2:23]3)[C:21]([CH3:25])([CH3:24])[O:20]2)[O:17][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:10]4=[O:26]
Reactant: C=CC(C)(C)Oc1ccc2c(=O)c3ccccc3oc2c1OC(C)(C)C=C
Solvent: Cc1ccccc1
Product: CC(C)=CCC12OC(C)(C)C3CC(C=C4C(=O)c5ccccc5OC431)C2=O
Yield: 135.6 %

Procedure:
A solution of 3,4-bis-(1,1-dimethyl-allyloxy)-xanthen-9-one (229 mg, 0.587 mmol) in toluene (10 mL) was refluxed under argon for 2 h. The solvent was evaporated and the residue was purified by column chromatography (SiO2, EtOAc:hexanes/10-30%) to give the title compound as white solids (145 mg, 63%): 1H NMR (CDCl3, 300 MHz) δ 7.95 (dd, J=1.5, 7.8 Hz, 1H), 7.53 (ddd, J=1.5, 7.2, 8.1 Hz, 1H), 7.44 (dd, J=0.6, 7.2 Hz, 1H), 7.07 (m, 2H), 4.42 (m, 1H), 3.50 (dd, J=4.5, 6.9 Hz, 1H), 2.63 (m, 2H), 2.46 (d, J=9.3 Hz, 1H), 2.35 (dd, J=4.2, 12.6 Hz, 1H), 1.73 (s, 3H), 1.31 (m, 1H), 1.31 (s, 6H), 0.92 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 202.8, 176.3, 159.5, 136.1, 134.8, 134.7, 133.6, 126.8, 121.8, 119.0, 118.9, 118.0, 90.3, 84.6, 83.5, 48.8, 46.8, 30.4, 29.2, 25.4, 25.2, 16.8.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[C:32]1([CH2:38][C:39]([OH:41])=O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:39](=[O:41])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (30 mg, 0.068 mmol, prepared as described in Step (A) of Example 28) and benzeneacetic acid (8.5 mg, 0.062 mmol) in 0.6 ml of CH2Cl2, 1,3-diisopropylcarbodiimide (8.6 mg, 0.068 mmol) was added. The reaction was stirred at room temperature for 5.5 hrs and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 25% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 75% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (21 mg, 61%) as a white solid, m.p. 114°-122° C. (amorphous).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68]O)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]>C(Cl)Cl>[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68][O:34][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][C:30]=2[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]3[O:23][C:22]2[C:14]([F:13])=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH3:37])=[CH:16]3)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
Diethyl azodicarboxylate (0.178 g, 1.02 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.267 g, 0.787 mmol), triphenylphosphine (0.31 g, 1.18 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.176 g, 0.945 mmol) in methylene chloride (10 nm). After stirring for 15 minutes at ambient temperature, further triphenylphosphine (0.062 mg, 0.236 mmol) and diethyl azodicarboxylate (0.041 mg, 0.3 mmol) were added. After stirring for 1 hour at ambient temperature, the mixture was poured onto a column of silica and eluted with increasingly polar mixtures of ethyl acetate and methylene chloride followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the solid was filtered, washed with ether and dried under vacuum to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline 0.210 g, 60%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH:47]([CH3:50])[CH:48]=O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH:47]([CH3:50])[CH:48]=[CH:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:30][CH:29]=2)=[CH:44][CH:45]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: COc1ccc(CC=CC(C)Cc2ccc(C(C)(C)C)cc2)cc1
Yield: 51.1 %

Procedure:
Starting from p-methoxyphenethyltriphenylphosphonium bromide (3.10 g, 6.49 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.1 mL, 6.49 mmol, 1.0 equiv.) and 3-(4-tert-butylphenyl)-2-methylpropanal (1.99 g, 9.74 mmol, 1.5 equiv.), 1.07 g (44%) of the title compound as a light yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17](B(O)O)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>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>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][CH:13]=[CH:14]3)[CH:5]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(-c2ccc3[nH]ccc3c2)c1
Reaction time: 12 h
Yield: 24.5 %

Procedure:
2-Chloroisonicotinic acid methyl ester (1.22 g, 7.11 mmol), 1H-indole-5-boronic acid (1.15 g, 7.13 mmol), 2M-aqueous sodium carbonate solution (10 mL, 20 mmol) and tetrakis(triphenylphosphine)palladium (0.41 g, 0.35 mmol) were dissolved in toluene (140 mL), and stirred for 12 h under reflux. After completion of the reaction, ethyl acetate (200 mL) was added, and washed with aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by column chromatography to give the title compound (440 mg, 1.74 mmol, 25% Yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:11]1[CH2:15][CH:14]([CH3:16])[CH:13]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][NH:26][C:23]=4[N:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>CN(C=O)C>[CH2:29]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]1[CH2:12][CH:13]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][N:26]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:23]=4[N:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]([CH3:16])[CH2:15]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
To the suspension of sodium hydride (60% dispersion in mineral oil, 0.382 g, 9.55 mmol) in DMF (50 mL) was added drop-wise a solution of N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine (3.96 g, 9.09 mmol) in DMF (50 mL) at 0° C. The resulting solution was stirred at ambient temperature for about 10 min. SEM chloride (1.774 mL, 10.0 mmol) was added drop-wise and the solution was stirred for about 1 h. The solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc (200 mL each). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concd. The residue was purified by silica gel chromatography eluting with 10-80% EtOAc in DCM to yield N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.1 g, 60% yield) as an off-white amorphous solid. LC/MS (Table 1, Method a) Rt=3.32 min; MS m/z 566 (M+H)+.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([CH2:7][C:8](=[O:29])[CH2:9][P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:2]([O:4][C:5]([CH2:7][C:8](=[O:29])[CH:9]=[P:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
A solution of {3-(ethoxycarbonyl)-2-oxopropyl}triphenyl phosphonium chloride (21.34 g, 500 mmol) in water (450 mL) was added to a solution of sodium carbonate (3.1 g, 25.0 mmol) in 10 min (Note: A white precipitate was obtained immediately after the addition). This reaction mixture was stirred at room temperature overnight. The precipitate that obtained was filtered off through a sintered funnel. The precipitate was dissolved in dichloromethane (100 mL), dried over sodium sulfate and concentrated to yield a white solid 18.13 g (93%). This material was dried over phosphorus pentoxide overnight. 1H NMR (CDCl3) δ 1.26 (t, 3H), 3.34 (s, 2H), 3.76-3.84 (d, 1H) 4.19 (m, 2H) and 7.48-7.68 (m, 15H, PhH).
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:25]>O1CCOCC1.C(OCC)C>[ClH:25].[F:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C@H:11]2[CH2:12][C@H:9]([NH2:5])[CH2:10]2)=[CH:15][C:16]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CC(C)(C)N(C(=O)[O-])[C@H]1C[C@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@H]1C[C@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,1-dimethylethyl(trans-3-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}cyclobutyl)carbamate (3.16 g, 9.05 mmol) in 1,4-dioxane (20 mL) was added hydrochloric acid in 1,4-dioxane (4M, 25 mL, 100 mmol) in one charge. The reaction vessel was sealed and the reaction stirred at ambient temperature for 16 hours. The majority of the solvent was then removed in vacuo leaving a slurry which was diluted with diethyl ether (ca 50 mL) and the solid collected by filtration and dried in vacuo to give the title compound (2.187 g).