Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:21][C:22]1[CH2:23][C:24](=[C:36]=O)[C:25]2[O:32][C:29]3([CH2:31][CH2:30]3)[CH2:28][C:27]([CH3:34])([CH3:33])[C:26]=2[CH:35]=1.C(OCC)(=O)C>CCCCCC>[Br:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH2:1])[C:25]2[O:32][C:29]3([CH2:31][CH2:30]3)[CH2:28][C:27]([CH3:34])([CH3:33])[C:26]=2[CH:35]=1
Reactant: CC1(C)CC2(CC2)OC2=C1C=C(Br)CC2=C=O
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=Cc1cc(Br)cc2c1OC1(CC1)CC2(C)C

Procedure:
Following general procedure N and using A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and 1.6M solution of n-butyl lithium in hexanes (11.8 mL, 19 mmol)], 6-bromo-8-carbonyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 40, 2.06 g, 7 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as a clear oil (1.36 g, 66%).
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16]>O1CCCC1>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13]
Reactant: CC[Mg]Br
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: C1CCOC1
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 35 °C

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 50 ml of a tetrahydrofuran solution containing 0.018 mol of ethyl magnesium bromide was charged to the reaction vessel. Meanwhile, 0.018 mol of bromopentafluorobenzene was charged to the dropping funnel. Then, bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 10 minutes at room temperature with the stirring of the tetrahydrofuran solution in the reaction vessel, and the reaction solution was heated to 35° C. for 1 hour. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a light yellow tetrahydrofuran solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 93.9 mol % based on bromopentafluorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OCCN3CCCC3)ccc2o1
Reaction time: 48 h
Yield: 58.2 %

Procedure:
Anhydrous tetrahydrofuran (15 ml) was added to a mixture of 5-hydroxybenzofuran-2-carboxylic acid methyl ester (1.10 g, 5.7 mmol), triphenylphosphine (1.50 g, 5.7 mmol), and 1-(2-hydroxyethyl)-pyrrolidine (0.66 g, 5.7 mmol) under a nitrogen atmosphere. Diisopropyl azodicarboxylate (1.15 ml, 5.8 mmol) was slowly added to the solution at room temperature. After 2 days, the solvent was removed and the residue was dissolved in a 2:1 mixture of Et2O:EtOAc (150 ml). The solution was washed with 1.0M aqueous NaOH. The product was extracted into 1.0 M hydrochloric acid and the combined acid extracts were washed with Et2O. The extracts were cooled and the pH of the extracts was adjusted to pH 12 with 50% aqueous NaOH. The basic solution was extracted with CH2Cl2 and the organic layer was dried over anhydrous MgSO4, and concentrated to give 5-(2-pyrrolidin-1-yl-ethoxy)benzofuran-2-carboxylic acid methyl ester (0.96 g) as an amber colored solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:13]([NH:17][S:18]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[C:29]([F:42])[CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][S:18]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:2]3[CH:3]=[C:4]4[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[C:29]([F:42])[CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]cc(C=O)c3c2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 88 using 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde and N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. MS (ESI): mass calcd. for C24H22FN3O3S, 451.14; m/z found, 452.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:8][N:9]=[C:10]([NH2:12])[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].O.[CH2:14]([O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]1[O:17][CH2:16]1.[ClH:27]>C(O)C>[ClH:27].[OH:17][CH:15]([CH2:14][O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][NH:7][C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][CH2:1][CH2:8][NH:9][C:10](=[NH:12])[NH2:11]
Reactant: CCCCC(CC)COCC1CO1
Reactant: NC(N)=NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCC(CC)COCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 78 °C
Reaction time: 4 h

Procedure:
In a four-necked 200-mL flask equipped with a reflux cooling tube, a dropping funnel, a thermometer and a stirring blade, 9.4 g (53.7 mmol) of L(+)-arginine, 50.0 g of water and 50.0 g of ethanol were placed, and the mixture was heated to 78° C. while being stirred under a nitrogen atmosphere. Subsequently, the inside of the reaction system was maintained at 78 to 80° C., 10.0 g (53.7 mmol) of 2-ethylhexyl glycidyl ether was added dropwise thereto. Thereafter, the mixture was aged for 4 hours at 78 to 80° C., and then was returned to room temperature. Subsequently, 9.8 g (53.7 mmol) of a 6 mol/L aqueous solution of hydrochloric acid was added thereto to neutralize the mixture. Water and ethanol were completely distilled off from the reaction solution under reduced pressure, and thus 21.6 g of N-[2-hydroxy-3-(2-ethylhexyl)oxypropyl]-L-arginine hydrochloride was obtained as a white solid. This compound corresponds to the compound 2 of Table 1.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9](=[O:20])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=1F)[C:4]([O:6][CH2:7][CH3:8])=[O:5]>O1CCOCC1>[F:18][C:12]1[CH:11]=[C:10]2[C:15](=[C:14]([F:16])[C:13]=1[F:17])[N:1]=[CH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]2[OH:20]
Reactant: CCOC(=O)C(=CN)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O

Procedure:
5.8 g of the product from Example 10 are initially introduced into 25 ml of dioxane. 4.8 g of potassium tert.-butylate are added in portions at room temperature.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>>[C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:22][CH3:23])=[O:2]
Reactant: CCO
Reactant: CCC(CCCCCC1=CCCC1=O)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CC)CCCCCC1=CCCC1=O

Procedure:
Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 154) with thionyl chloride and then treatment of the acid chloride with ethanol in the manner described in Example 264 give an amber oil. The oil is placed on a magnesia-silica gel column and eluted with 3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122° C. (0.06 mm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:7])[CH3:6].CCN(CC)CC>C(Cl)Cl>[C:10]([NH:9][CH2:8][C@@H:4]([C@H:5]([OH:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:18])(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Yield: 89.5 %

Procedure:
In a 100 ml autoclave was put a solution of 2.5 g (10 mmol) of methyl-2-(N-benzoylamino)methyl-3-oxobutyrate and 173 mg (0.102 mmol) of Ru2Cl4((R)-BINAP)2.NEt3 in 17.5 ml of methylene chloride, and the mixture was stirred at 50° C. under a hydrogen pressure of 10000 kPa for 20 hours. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography to furnish 2.25 g (90%) of the title compound. Optical purity: 98%e.e.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([CH2:19][CH3:20])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]1=[O:21])[CH:2]=C.[BH4-].[Na+].C[OH:25]>>[CH2:19]([C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH2:2][OH:25])[C:5]1=[O:21])[CH3:20]
Reactant: CO
Reactant: C=CCN1CCCCC(CC)(c2cccc(OC)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Product: CCC1(c2cccc(OC)c2)CCCCN(CCO)C1=O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of 1-allyl-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described in Example 49, Step A) (0.9 g, 3.1 mmol) in MeOH (20 mL) at −78° C. was saturated with 03 for 20 min. The solution was warmed to −40° C. for 10 min then NaBH4 (0.36 g, 9.4 mmol) was added and the reaction mixture was stirred at 25° C. for 1 hr. The MeOH was removed in vacuo, and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[C:10]2[N:11]([CH3:15])[C:12](=O)[NH:13][C:9]=2[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[N:11]([CH3:15])[C:10]2[C:5]([N:4]([CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH3:3])=[N:6][CH:7]=[CH:8][C:9]=2[N:13]=1
Reactant: CCCN(CCC)c1nccc2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)c1nccc2nc(Cl)n(C)c12

Procedure:
A solution of 0.91 g (3.66 mmol) of 4-dipropylamino-3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 30 mL of phosphorous oxychloride was heated at 100° C. overnight and concentrated in vacuo. The thus obtained residue was quenched with water, adjusted with aqueous sodium bicarbonate to pH 5, and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The thus obtained residue was triturated with acetonitrile, filtered, and the filtrate, which contained the desired product, was concentrated in vacuo. The residue thus obtained (0.18 g, 18%) was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[CH2:10][CH3:11].C(N(CC)CC)C>O1CCCC1>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCI
Reactant: Fc1ccc(S)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSc1ccc(F)cc1
Yield: 86.2 %

Procedure:
A solution of 4-fluorobenzenethiol (10 g, 78 mmol) and iodoethane (7.57 mL, 94 mmol) in tetrahydrofuran (100 mL) was treated with triethylamine (13.05 mL, 94 mmol) at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated, washed with hexane and dried under vacuum to provide the title compound (10.5 g, 81%).
Reaction SMILES: [C:1](I)([F:4])([F:3])[F:2].[CH2:6]([N:13]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:14]1[C:26]([OH:28])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OO>CS(C)=O.O>[CH2:6]([N:13]1[C:17]([C:1]([F:4])([F:3])[F:2])=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:14]1[C:26]([OH:28])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cn(Cc2ccccc2)c(C(=O)O)c1-c1ccc(F)cc1
Reactant: FC(F)(F)I
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2ccc(F)cc2)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Reaction time: 16 h

Procedure:
CF3I (10 g) gas was bubbled through a solution of 1-benzyl-3-(4-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylic acid (4.0 g, 12.94 mmol) in DMSO (40 mL) and FeSO4.7H2O (2.15 g, 7.76 mmol) at RT for 5 min. 30% Aqueous H2O2 (8.7 mL, 77.64 mmol) was then added at 0° C. and stirring was continued at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (1×100 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 60-120 mesh); it eluted with 10-12% EtOAc in petroleum ether to yield ACI-09 (1.7 g, 35%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[ClH:23].[H][H]>[OH-].[OH-].[Pd+2].CCO>[ClH:23].[ClH:23].[NH2:8][CH2:7][C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]2
Reactant: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Temperature: 25 °C
Reaction time: 66 h
Yield: 96 %

Procedure:
A 2.5 L Parr reaction vessel was charged with 5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzonitrile (25.00 g, 84.09 mmol), EtOH (8.40 mL, 0.1M), and Pearlmans catalyst (5 g, 20% weight) and purged with nitrogen. Concentrated HCl (70.08 ml, 840.9 mmol) was added to the mixture. The vessel was charged with nitrogen gas (to 30 psi×3) and hydrogen (to 50 psi×3), and the reaction was stirred at ambient temperature for 66 hours. The mixture was filtered through a Celite pad and the pad was washed with EtOH. The filtrate was concentrated under reduced pressure, and the residue was azeotroped with EtOH and toluene to provide light brown solid to provide 30.2 g (96.0%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.72 (d, J=8.61 Hz, 1H), 7.42 (d, J=2.35 Hz, 1H), 7.33 (dd, J=3.13 Hz, 8.61 Hz, 1H), 7.29 (dd, J=2.35 Hz, 8.61 Hz, 1H), 7.12 (dt, J=3.13 Hz, 8.61 Hz, 1H), 6.83 (dd, J=4.70 Hz, 8.61 Hz, 1H), 4.54 (t, J=5.48 Hz, 2H), 4.25 (br s, 2H), 3.98 (t, J=5.48 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C:22]2([C:25]#[N:26])[CH2:24][CH2:23]2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[CH3:28].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)CC.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>[C:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C:22]3([C:25]#[N:26])[CH2:24][CH2:23]3)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)(=[O:29])[CH3:28]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: CC(=O)c1ccc(B(O)O)cc1
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: CCCO
Product: CC(=O)c1ccc(-c2ccc([C@H](N[C@@H](CC(C)C)C(=O)NC3(C#N)CC3)C(F)(F)F)cn2)cc1
Temperature: 150 °C

Procedure:
To a solution of N2-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-leucinamide (100 mg, 0.26 mmol) in toluene (1.5 mL) and n-propanol (0.4 mL) was added under a stream of nitrogen, 4-(acetyl)phenylboronic acid (55 mg, 0.33 mmol ), Pd(PPh3)4 (15 mg, 0.013 mmol) and Na2CO3 (2 M, 0.5 mL). The mixture was degassed with a rapid stream of nitrogen bubbling through the mixture and the mixture was heated to 150° C. in a Smith Creator microwave reactor (Personal Chemistry AB, Uppsala, Sweden) for 800 sec. The mixture was cooled, diluted with EtOAc and washed with water. Chromatography (50% EtOAc/Hexane) gave the title compound.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:23]([NH2:25])[CH3:24].O>CS(C)=O>[CH2:23]([NH:25][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:24]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CCN
Solvent: O
Solvent: CS(C)=O
Product: CCNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 70% v/v ethanamine in water (26.1 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-(ethylamino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.23 (br. s, 1H), 7.84-7.89 (m, 1H), 7.50-7.56 (m, 1H), 7.26-7.33 (m, 2H), 7.06-7.11 (m, 1H), 6.93 (br. s, 1H), 3.48-3.58 (m, 2H), 3.38-3.45 (m, 2H), 2.82-2.89 (m, 2H), 2.50 (s, 3H), 1.30 (t, J=1.0 Hz, 3H). m/z (ESI, +ve) 322.1 (M+H)+.
Reaction SMILES: [N+](CP(=O)([O:8][CH2:9][CH3:10])OCC)#[C-].C([Li])CCC.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27]C(=O)[CH2:25]2)=[CH:20][CH:19]=1.Cl>CCOCC>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[CH2:27][C@H:10]([CH:9]=[O:8])[CH2:25]2)=[CH:20][CH:19]=1
Reactant: [C-]#[N+]CP(=O)(OCC)OCC
Reactant: O=C1CC(c2ccc(Br)cc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C[C@H]1C[C@H](c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of diethyl isocyanomethylphosphonate (0.86 mL, 5.3 mmol) in anhydrous ether (45 mL) at −78° C. under nitrogen was added n-butyl lithium (2.13 mL, 2.5 M in hexane) and the resulting mixture was stirred at −78° C. for 1 hr. Then, 3-(4-bromo-phenyl)-cyclobutanone (1 g, 4.4 mmol) in anhydrous ether (15 mL) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred 16 hours. Concentrated hydrochloric acid (9.5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 5 hrs. The mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel eluting with 2-3% ethyl acetate in hexanes to provide 3-(4-bromo-phenyl)-trans-cyclobutanecarbaldehyde (281 mg, 27%) as the faster eluting isomer (A1) and 3-(4-bromo-phenyl)-cis-cyclobutanecarbaldehyde (508 mg, 48%) as the slower eluting isomer (A2). A1: 1H NMR (300 MHz, CDCl3) δ 2.37 (m, 2 H), 2.72 (m, 2 H), 3.16 (m, 1 H), 3.53 (p, J=6 Hz, 1 H), 7.09 (d, J=9 Hz, 2 H), 7.44 (d, J=9Hz, 2 H), 9.95 (s, 1 H),; (DCl/NH3) m/z 239 (M+H)+; A2: 1 H NMR (300 MHz, CDCl3) δ 2.35 (m, 2 H), 2.55 (m, 2 H), 3.21 (m, 1 H), 3.52 (p, J=6 Hz, 1 H), 7.07 (d, J=9 Hz, 2 H), 7.42 (d, J=9 Hz, 2 H), 9.73 (s, 1 H); (DCl/NH3) m/z 239 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:22])[N:20]=2)[CH:17]=1
Reactant: NCc1c(F)cccc1Cl
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1c(F)cccc1Cl)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-chloro-6-fluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:14].[CH2:15](O)[CH3:16]>>[ClH:14].[CH2:15]([O:12][C:11](=[O:13])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1])[CH3:16]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
L-Tyrosine (1.00 kg, 5.52 tool) is suspended in 2B anhydrous ethanol (5.0 L). Anhydrous hydrogen chloride is introduced into this suspension initially at ambient temperature for 2.5 hours at which time the temperature rises to 56° C. The resulting clear solution is refluxed for 5 hours with continued introduction of a slow stream of hydrogen chloride. The solution is allowed to cool overnight and completion of precipitation of product is induced by the addition of t-butyl methyl ether (12.0 L). The crystals are collected by filtration and the filtrate is washed with more t-butyl methyl ether (2×500 mL). The solid is first air-dried and then vacuum-dried for 36 hours (40° C., 3 Torr) to yield L-tyrosine ethyl ester monohydrochloride, m.p. 165°-166° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC.[F-].[K+]>O1CCCC1.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>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(OCC)c1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 4,6-dichloro-2-methyl-5-nitropyrimidine (3.12 g), tributyl(1-ethoxy-vinyl)tin (5.3 mL) and dichlorobis(triphenylphosphine)palladium(II) (0.53 g) in tetrahydrofuran (60 mL) was stirred at 85° C. under an argon atmosphere in a reaction vessel equipped with a reflux condenser for 4 hours. The reaction mixture was cooled to room temperature. To the mixture was added 0.5 mol/L aqueous potassium fluoride solution (20 mL), and the resulting mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and the organic layer was separated. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1−4/1). The product was dissolved in ethyl acetate. To the solution were added 0.5 mol/L aqueous potassium fluoride solution (20 mL) and water (20 mL), and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4-chloro-6-(1-ethoxyvinyl)-2-methyl-5-nitropyrimidine (3.65 g). This material was dissolved in acetone (30 mL). To the solution was added p-toluenesulfonic acid monohydrate (2.28 g), and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1−4/1) to give the title compound (2.32 g).