Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[F:30])C1C=CC=CC=1>C(O)C.C1COCC1.C(OCC)(=O)C.[Pd]>[F:30][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:24]=[N:25][N:26]=[CH:27]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(F)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(O)c(F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[(4-Benzyloxy-3-fluoro-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB033019, 2.83 g, 7.09 mmol) was dissolved in a mixture of ethanol (50 mL), THF (50 mL) and ethyl acetate (50 mL) by heating and palladium on charcoal (150 mg, 5% Pd) was added. The mixture was stirred under hydrogen-atmosphere (balloon) for 18 h, filtered through a 3 cm layer of celite and concentrated under reduced pressure. The residue was suspended in 2-propanol (30 mL), the mixture was heated to reflux for 5 minutes. After cooling room temperature the white precipitate was filtered off and dried under high vacuum. Yield: 2.13 g (97%). 1H-NMR (400 MHz, d6-DMSO) δ=4.93 (s, 2H), 6.75 (d, J=9.0 Hz, 2H), 6.82-6.89 (m, 2H), 7.07-7.12 (m, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.77 (s, 2H), 9.95 (s, 1H, —OH).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20](=[O:26])[N:21]([CH3:25])[C:22]=1[CH2:23]Br)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[N:8]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:17]2[C:22]([N:21]([CH3:25])[C:20](=[O:26])[N:19]([CH3:27])[C:18]2=[O:28])=[CH:23]1
Reactant: Nc1ccccc1N
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3ccccc3N)cc2n(C)c1=O
Yield: 96.3 %

Procedure:
1,2-Phenylenediamine (1.320 g, 12.2 mmol) in absolute EtOH (25 mL) was stirred in a 50 mL round bottom flask. The mixture was warmed on an oil bath until homogenous, and then 4a (2.055 g, 6.1 mmol) was added with the aid of a powder funnel and EtOH (5 mL). The solution was stirred vigorously at refluxed for 1 h, during which a white precipitate formed. The reaction was then cooled in an ice bath, filtered, and the precipitate washed with cold ethanol to yield 5a (2.0357 g, 96.5%) as a white powder. 1H NMR (600 MHz, DMSO-d6) δ 7.37-7.31 (m, 2H), 7.25-7.19 (m, 3H), 7.08-7.02 (m, 1H), 6.92 (s, 1H), 6.83 (dd, J=1.3, 7.8, 1H), 6.75 (d, J=8.1, 1H), 6.48-6.43 (m, 1H), 5.08 (s, 2H), 3.33 (s, 3H), 3.19 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 159.07, 150.89, 144.76, 133.51, 130.42, 129.49, 129.36, 129.05, 128.64, 127.89, 127.13, 123.10, 115.65, 115.46, 105.49, 102.23, 31.50, 27.40. MS (ES+) (m/z): [M+1]+ calculated for C20H19N4O2, 347.39. found 347.05.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=[O:16])[CH:8]=2)[CH:3]=1.[Br:18]Br.O>C(Cl)(Cl)Cl.CS(C)=O>[Br:18][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:15]([OH:17])=[O:16])=[CH:6][CH:5]=2)[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]=1[OH:1]
Reactant: BrBr
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc2c(Br)c(O)c(C(=O)O)cc2c1
Reaction time: 1 h
Yield: 97 %

Procedure:
2-Hydroxy-3,6-di-hydroxycarbonylnaphthalene (11.8 g) was dissolved in chloroform (300 g) and dimethyl sulfoxide (100 g), followed by ice-cooling. Then, a solution of bromine (8.0 g) and chloroform (50 g) was added dropwise at not more than 5° C. over 2 hours. After continuously stirring for 1 hour, this solution was poured into water (1500 g) dropwise. The deposit was filtered and then washed with water and dispersed in a small amount of methanol. The dispersion was concentrated under reduced pressure at room temperature and then dried under vacuum to obtain 15.1 g of 1-bromo-2-hydroxy-3,6-di-hydroxycarbonylnaphthalene as a whitish brown crystal (DSC analysis value: 145.2° C.).
Reaction SMILES: C([Li])CCC.[O:6]1CCC[CH2:7]1.Br[C:12]1[C:13]([O:22][CH3:23])=[N:14][CH:15]=[N:16][C:17]=1[C:18]([F:21])([F:20])[F:19].C(OCC)=O>O>[CH3:23][O:22][C:13]1[C:12]([CH:7]=[O:6])=[C:17]([C:18]([F:21])([F:20])[F:19])[N:16]=[CH:15][N:14]=1
Reactant: C1CCOC1
Reactant: COc1ncnc(C(F)(F)F)c1Br
Agent: [Li]CCCC
Solvent: CCOC=O
Solvent: O
Product: COc1ncnc(C(F)(F)F)c1C=O
Reaction time: 3 h
Yield: 15.8 %

Procedure:
30.0 ml (48.0 mmol) of n-butyllithium (1.6 mol/l n-hexane solution) was slowly added to 100 ml of tetrahydrofuran solution containing 10.3 g (40.0 mmol) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine at −65 to −60° C., and the resultant mixture was stirred at 30 minutes. Further, 3.6 g (48.0 mmol) of ethyl formate was added thereto at the same temperature, and the mixture was stirred for 3 hours at the same temperature. The resultant reaction solution was poured into water and was extracted with ethyl acetate. The organic phase thus obtained was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resultant solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 15.8%) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: Cc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(6-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 13 (100 mg, 0.398 mmol), 6-chloro-9H-purine (65 mg, 0.418 mmol) and DIPEA (0.347 mL, 1.99 mmol) in dioxane (3 mL) was stirred in a sealed vial for 20 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then crystallised from acetonitrile affording 118 as a white solid (35 mg, 24%). LCMS: RT 3.15 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.17-8.07 (2H, m), 7.88-7.78 (1H, m), 7.64-7.45 (6H, m), 7.06 (1H, d, J=8.26 Hz), 6.86 (1H, s), 5.50 (1H, br), 2.35 (3H, s), 1.54 (3H, d, J=6.82 Hz)
Reaction SMILES: [C:1]1([CH2:8][OH:9])([CH2:6][OH:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][C:23]1[CH:25]=[CH:26][C:20]([S:17]([O:7][CH2:6][C:1]2([CH2:8][OH:9])[CH2:5][CH:4]=[CH:3][CH2:2]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1(CO)CC=CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(CO)CC=CC2)cc1
Temperature: 26 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To an ice-cooled solution of cyclopent-3-ene-1,1-diyldimethanol (44.0 g, 343 mmol), triethylamine (34.7 g, 343 mmol) and 4-dimethylaminopyridine (4.19 g, 34.3 mmol) in dichloromethane (2 L) was added tosyl chloride (58.9 g, 309 mmol) portionwise. The reaction mixture was warmed to 26° C. After 16 h, the mixture was concentrated, and the resulting residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether)) to afford product as a brown solid (34 g, 35% yield).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.I[C:24]1C2C(=CC(/C=C3/C(=O)N(C)C4C/3=CC=CC=4)=CC=2)NN=1>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:24])[C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: CN1C(=O)/C(=C/c2ccc3c(I)n[nH]c3c2)c2ccccc21
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21

Procedure:
The title compound was synthesized according to the method of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one, except substituting (E)-3-((3-iodo-1H-indazol-6-yl)methylene)-1-methylindolin-2-one (545 mg, 1.36 mmol) to give the title compound as a 9:1 mixture of diastereomers (405 mg, 72%); MS ESI 416.0 [M+H]+, calcd for [C18H14IN3O+H]+ 416.03.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])([CH3:12])([CH3:11])[CH3:10].Cl.CCCCCC.CCCCCCC.[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(C1C=CC=CC=1)C>O1CCCC1>[C:9]([NH:13][S:14]([CH2:17][CH:33]([OH:32])[CH2:34][CH2:35][CH3:36])(=[O:16])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NS(C)(=O)=O
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CCCC(O)CS(=O)(=O)NC(C)(C)C
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A 2.0 M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (400 ml) was cooled to −45 to −50° C. under nitrogen atmosphere. A solution (100 ml) of N-t-butylmethanesulfonamide (55.0 g) in tetrahydrofuran was added dropwise thereto for 20 minutes. After raising the temperature to 5° C. taking 1 hour, the solution was cooled again to −65° C. To the resulting solution was added dropwise a solution of n-butyl aldehyde (28.8 g) in tetrahydrofuran (100 ml) for 30 minutes. The solution was stirred for 18 hours while raising the temperature gradually to room temperature. The resulting reaction solution was poured into an excess amount of dilute hydrochloric acid under cooling with ice to make it acidic and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain a solid crude product. Hexane (300 ml) was added thereto with stirring. Crystals thus obtained were collected by filtration, washed with hexane, and dried under reduced pressure to obtain N-t-butyl-2-hydroxy-1-pentane-sulfonamide (46.2 g) as white crystals.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4](C(C)=CC(Cl)=O)=[CH:3][CH:2]=1.[CH3:19][Mg]Br.[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[C:13]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:25](=[CH:24][C:23](=[O:22])[CH3:19])[CH3:26]
Reactant: C1CCOC1
Reactant: C[Mg]Br
Reactant: CC(=CC(=O)Cl)c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)c1ccccc1-c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
10.0 g (0.039 mole) of the crude acid chloride from (c), above, is dissolved in 200 ml of dry tetrahydrofuran and the solution placed in a 500 ml round bottom flask fitted with a septum inlet and magnetic stirrer, and held under a nitrogen atmosphere. The solution is cooled to -30° C. in a dry ice/isopropanol bath and 19.5 ml (0.039 mole) of a commercial 2 M methyl magnesium bromide solution in dry toluene is added, dropwise, over 30 minutes. After the addition is complete, the mixture is allowed to warm to room temperature and then stirred for 1 hour. The reaction is quenched by the addition of 20 ml of saturated ammonium chloride solution and the organic layer is separated. The aqueous layer is extracted twice with 20 ml portions of ether and the combined organic extracts are then dried over anhydrous magnesium sulphate and evaporated to yield the heading compound, m.p. 130° to 133° C., after recrystallisation from petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][C:3]=1[CH3:18].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH:35]([C@@H:38]1[CH2:42][O:41][C:40](=[O:43])[NH:39]1)([CH3:37])[CH3:36]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:39]2[C@H:38]([CH:35]([CH3:37])[CH3:36])[CH2:42][O:41][C:40]2=[O:43])=[O:17])=[CH:4][C:3]=1[CH3:18]
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: Cc1cc(CCCCCCCC(=O)O)ccc1F
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(CCCCCCCC(=O)N2C(=O)OC[C@H]2C(C)C)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a cooled (−10° C.) solution of 8-(4-fluoro-3-methylphenyl)octanoic acid (0.486 g, 1.926 mmol) in 15 mL of THF, were added stepwise triethylamine (0.69 mL, 4.952 mmol) and pivaloyl chloride (0.23 mL, 1.889 mmol). The reaction mixture was stirred at −10° C. for 1 h and then LiCl (0.080 g, 1.889 mmol) and (R)-4-iso-propyloxazolidin-2-one (0.237 g, 1.834 mmol) were added stepwise. After being warmed slowly to room temperature and stirred for overnight, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.547 g, 82% yield). GC-MS: tR=6.9 min; m/z 363 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:16]=[C:15]([Si:12]([CH3:14])([CH3:13])[CH3:11])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: ON=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cc(-c2ccc(Br)cc2)no1
Reaction time: 22 h

Procedure:
The product from Example 42A (0.124 g, 0.621 mmol) and trimethylsilylacetylene (0.35 mL, 2.5 mmol) were combined in tetrahydrofuran (2.2 mL), treated bleach (2.2 mL), and stirred for 22 hours. The mixture was diluted with ethyl acetate (7 mL), washed with brine (5 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (7% ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: C[C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([OH:11])[CH:7]=[CH:6][CH:5]=2.[C:12](=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[CH:19]([O:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:2][NH:3]2)[CH3:12]
Reactant: Cc1cc2c(O)cccc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc2[nH]ccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-4-hydroxyindole (5 g) in N,N-dimethylformamide (50 ml) was added anhydrous potassium carbonate 11.7 g) and methyl bromoacetate (3.54 ml) at room temperature, and the mixture was stirred at 80° C. for 2 hours. To the reaction solution was added iced water to give the title compound (5.4 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11]O)[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1.CCN(C(C)C)C(C)C.O=S(Cl)[Cl:25]>C1COCC1.CCOCC>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][Cl:25])[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2c(Cl)cc(Cl)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: ClCc1cc2c(Cl)cc(Cl)cc2o1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of the product of Step E (0.24 g; 1.1 mmol) and DIPEA (0.2 ml; 1.11 mmol) in anhydrous THF (1 ml), SOCl2 (0.1 ml; 1.13 mmol) was added drop wise at 0° C. under N2 with stirring. The mixture was allowed to warm up to room temperature and stirred overnight, then diluted to 15 ml with Et2O and washed with 0.1N HCl, 5% NaHCO3, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.25 g; 96%), as a creamy syrup, which was used in the next step without further purification. 1H-NMR (CDCl3) 4.68 (s, 2H); 6.8 (s, 1H), 7.2 (s, 1H); 7.39 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH3:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl.C1(C)C=CC=CC=1>[O:24]1[CH:14]([CH2:13][O:12][C:11]2[CH:17]=[CH:18][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=2)[CH:15]1[CH3:16]
Reactant: C/C=C/COc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1OC1COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
A solution of trans-4-[4-(tert-butoxycarbonyl)phenoxy]-2-butene (3.10 g, 12.48 mmol) in dry dichloromethane (50 ml) was treated at 22° C. with 3-chloroperoxybenzoic acid (4.30 g, 24.9 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The mixture was then diluted with toluene, washed with 5% sodium thiosulfate, saturated sodium bicarbonate and brine. After drying (sodium sulfate), evaporation of the solvent gave an oil that was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (95:5) gave 3.16 g (96%) of the title material as an oil which solidified upon standing: bp 85-90° C./0.05 torr (bulb to bulb, air bath temperature); mp 47-48° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(=O)O[CH2:29][CH2:28][O:27]1>>[OH:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Product: OCCOc1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Reaction time: 4 h
Yield: 83 %

Procedure:
First, 19.2 g (60 mmol) of the HQ obtained in section (M) mentioned above was put in an 1-liter three-necked flask, and dissolved by the addition of 500 ml of sulforane. To this solution, 7.92 g (90 mmol) of ethylene carbonate was added, and the mixture was heated under a nitrogen atmosphere. Then 0.1 g of K2C03 was added at the reflux temperature of sulforane, and reflux was continued for 4 hours with stirring. After the reaction was completed, the reaction mixture was filtered and the filtrate was cooled. The white solid that was precipitated was collected by filtration and dried. In this way, 18.38 g (yield, 83% of 4-(2-hydroxyethoxy)-p-quaterphenyl (HEQ) was obtained. The liquid-crystal transition temperature of HEQ was 335° C.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.CO.C(Cl)Cl>CS(C)=O>[CH:24]1([NH:27][C:2]2[C:3]([CH3:23])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1NC1CC1
Temperature: 100 °C
Yield: 84.1 %

Procedure:
Prepared similar to that described in Example 131 using rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 62.4 mg, 0.201 mmol) and cyclopropanamine (Alfa Aesar, Ward Hill, Mass.; 0.042 mL, 0.603 mmol) in DMSO (1.0 mL), heating at 100° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished rac-2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (58.8 mg, 0.169 mmol, 84% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (1H, br. s.), 7.99 (1H, d, J=7.4 Hz), 7.53-7.64 (2H, m), 7.36 (1H, t, J=7.7 Hz), 7.18 (1H, d, J=1.8 Hz), 6.98 (1H, br. s.), 3.46-3.58 (1H, m), 3.05-3.20 (2H, m), 2.88-2.98 (1H, m), 2.51 (3H, br. s.), 1.24 (3H, d, J=6.5 Hz), 0.88-1.00 (2H, m), 0.68-0.78 (2H, m). m/z (ESI, +ve) 348.2 (M+H)+. Separation of this material by supercritical-fluid chromatography (Chiralpak AS-H (250×21 mm, 5 μn), 60% liquid CO2/40% MeOH (+20 mM NH3), 70 mL/min) separately afforded: 2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, first-eluting enantiomer (160; 19.6 mg, 0.056 mmol) as a yellow solid; and 2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, second-eluting enantiomer (161; 19.2 mg, 0.055 mmol) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3](=O)[C:4](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+]>>[CH2:8]([O:7][C:5](=[O:6])[C:4]#[C:3][C:2]([F:30])([F:31])[F:1])[CH3:9]
Reactant: CCOC(=O)C(C(=O)C(F)(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C#CC(F)(F)F
Yield: 82.9 %

Procedure:
A mixture of ethyl 4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate (270 g, 617 mmol) and potassium carbonate (54 g, 490 mmol) is heated from 160° C. to 225° C. in 3 h at 2-3 mbar vacuum. The title compound is distilled and recovered in a cold trap to yield the title compound (85 g, 83%) as a slightly yellow oil. ES/MS m/e 167 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[N:28]([CH2:35][C@:36]([OH:40])([CH3:39])[CH2:37][OH:38])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:10][CH:11]=1)[C:3](=[O:4])[O:38][CH2:37][C@@:36]([OH:40])([CH3:39])[CH2:35][N:28]1[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=[C:27]1[Cl:26]
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CN(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
N-Methyl-N-(4-trifluoromethoxyphenyl)-carbamoyl chloride (1.33 g, 5.23 mmol), N,N-diisopropylethylamine (1.2 ml, 6.97 mmol) and 4-dimethylaminopyridine (85 mg, 0.70 mmol) were added to a suspension of (R)-2-chloro-1-(2,3-dihydroxy-2-methyl)propyl-4-nitroimidazole prepared in Example 10 (0.82 g, 3.48 mmol) in toluene (10 ml) followed by stirring at 100° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, and the solution was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl N-methyl-N-(4-trifluoromethoxyphenyl)carbamate (1.04 g, yield 65%) as a light yellow amorphous form.