Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[CH:14][C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
A solution of methyl p-formylbenzoate (12.33 g), malonic acid (16 g) and piperidine (1 ml) in pyridine (100 ml) is refluxed for two hours. The reaction mixture is poured into ice-water, and the precipitated white powder is collected by filtration, and washed with water, and dried to give 4-methoxycarbonyl cinnamic acid (14.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:5]=2[CH:4]=1.[Br:18]Br>ClCCl>[Br:18][C:8]1[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:17]=[CH:16][C:6]=2[C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc2c(-c3ccccc3)coc2c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc2c(-c3ccccc3)c(Br)oc2c1

Procedure:
To a solution of 25 g (0.112 mole) of 6-methoxy-3 -phenylbenzofuran in 400 ml of dichloromethane is added over 1 hour dropwise with stirring 17.9 g (0.112 mole) of bromine in 20 ml of dichloromethane. The solution is washed with 200 ml of 10% aqueous sodium acetate, dried and evaporated to provide 2-bromo-6-methoxy-3-phenylbenzofuran as a dark oil.
Reaction SMILES: [N:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH:1]([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)cc1)C(N)=O)C(C)C
Yield: 54.5 %

Procedure:
Fmoc-N-Me-Val-N-Me-Tyr(Bzl)—NH2 (802 mg, 1.29 mmol) was dissolved in a mixed solution of MeOH (6 ml) and ethyl acetate (6 ml), mixed with 20% palladium hydroxide-carbon (150 mg), followed by stirring in a hydrogen atmosphere at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol=10:1) to give the titled compound (216 mg, 55%).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>>[C:2]1([CH2:8][CH2:9]/[CH:10]=[CH:30]/[C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: COC(=O)c1ccc(/C=C/CCc2ccccc2)cc1

Procedure:
Using the conditions in example 1(A), (3-phenylpropyl)triphenylphosphonium bromide and methyl 4-formylbenzoate are condensed, providing methyl (E)-4-(4-phenyl-1-butenyl)benzoate as a colorless oil after chromatographic separation from the later-eluting (Z) isomer. This is reduced with lithium aluminum hydride in THF in the usual fashion to provide (E)-4-(4-phenyl-1-butenyl)phenylmethanol as a colorless oil. Oxidation with pyridinium dichromate in the usual fashion provides (E)-4-(4-phenyl-1-butenyl)benzaldehyde as a colorless oil after chromatography.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:19][C:11]1[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([NH:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[N:7][CH:6]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(I)nc1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(NCCN2CCOCC2)nc1
Temperature: 70 °C

Procedure:
N-(2-iodopyrimidin-5-yl)-2-methyl-5-nitrobenzamide (60 mg, 0.156 mmol), 2-morpholinoethanamine (˜200 mg, 1.5 mmol), and DIEA (0.041 mL, 0.234 mmol) were taken up in IPA (2.5 mL) in a 16×100 mm resealable pyrex tube and heated at 70° C. for 4 h. The mixture was concentrated and purified by preparative TLC (2.5% MeOH/CH2Cl2) to afford 2-methyl-N-(2-(2-morpholinoethylamino)pyrimidin-5-yl)-5-nitrobenzamide.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29]>ClCCl>[C:28](=[O:29])([O:19][CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:30][CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)COC(=O)Cl
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)OCc1nc2ccccn2c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
0.1 g (0.403 mmol) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl) methanol were solubilised in 3 ml of dichloromethane with magnetic stirring. 0.084 ml (0.604 mmol) of triethylamine and 0.059 ml (0.443 mmol) of isobutyl chloroformate were added. The mixture was stirred at r.t. for 15 min before being concentrated in vacuo. The residue was taken up in 10 ml of diisopropyl ether and a solid was isolated by filtration. The solid was purified by preparative HPLC and 0.084 g (yield=59%) of isobutyl ((3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methyl) carbonate were obtained as a pale yellow solid. LC-MS: m/z=349 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.70 (d, J=6.8 Hz, 1H), 7.79-7.65 (m, 3H), 7.60-7.45 (m, 4H), 7.23 (td, J=6.8, 1.1 Hz, 1H), 5.42 (s, 2H), 3.91 (d, J=6.6 Hz, 2H), 1.95-1.80 (m, 1H), 0.86 (d, J=6.7 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:13][C:14]1[CH:19]=[C:18]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:12])[CH2:6][CH2:7][O:8]3)=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCOc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1
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: C1COCCO1
Solvent: O
Product: O=C1CCOc2cc(-c3cccc(F)c3)ccc21
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-2H-chromen-4-one (1.5 g, 6.6 mmol), 3-fluorophenylboronic acid (1.39 g, 9.9 mmol) and sodium carbonate (2.1 g, 19.8 mmol) in dioxane (20 mL) and water (1 mL) was added Pd(PPh3)4 (382 mg, 0.3 mmol) at rt. The solution was heated at 100° C. overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc/DCM=10:1:2) to give 1.4 g (88%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 2.86 (2H, t, J=6.6 Hz), 4.60 (2H, t, J=6.6 Hz), 7.11-7.14 (1H, m), 7.18 (1H, d, J=1.5 Hz), 7.23-7.29 (2H, m), 7.32-7.45 (2H, m), 7.98 (1H, d, J=8.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13].C(O)C.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.[OH-].[K+]>O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: ClCC1CO1
Reactant: CC(C)C1C(=O)Nc2ccc(O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C1C(=O)Nc2ccc(OCC3CO3)cc21
Yield: 50 %

Procedure:
18 g. 5-Hydroxy-3-isopropylindolinone are dissolved in 150 ml. ethanol, 22 ml. epichlorohydrin are added thereto, the mixture is mixed with 5.3 g. potassium hydroxide in 5 ml. water and the reaction mixture is stirred for 2 days at ambient temperature. After the addition of 200 ml. water, the reaction mixture is extracted with ethyl acetate and the extract purified over a column of silica gel with methylene chloride/methanol (95:5 v/v). There are obtained 11 g. of the title compound; yield 50% of theory; m.p. 122°-125° C., after recrystallisation from diethyl ether.
Reaction SMILES: C(O)=O.[C:4]1([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26]=O.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[CH3:26][N:12]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)[CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CCNC2CCN(Cc3ccccc3)CC2)cc1
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: CN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
136 ml of formic acid was added to 210 g of 4-(2-phenylethylamino)-1-benzylpiperidine. Since the temperature of the mixture increased to about 90° C., the mixture was ice-cooled. To the reaction mixture was added 64 ml of 37% formalin at 50-60° C.; the ice bath was removed; and the mixture was stirred for 1 hour. To the resulting reaction mixture were added 1 liter of ethanol and 120 ml of concentrated hydrochloric acid, followed by concentration under reduced pressure. To the residue was added 1 liter of ethanol. The resulting insolubles were collected by filtration and then washed with ethanol to obtain 251.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-benzylpiperidine dihydrochloride as a white powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][CH:9]([CH3:41])[CH2:10][CH2:11][NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:40])OC4C=CC=CC=4)[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14].CC(C)CCNC(N1C2C(=CC(OC3C=CN=C(NC(N4CCC(N5CCCC5)CC4)=O)C=3)=CC=2)C=C1)=O>CN(C)C=O>[CH3:41][CH:9]([CH3:8])[CH2:10][CH2:11][NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:40])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14]
Reactant: OC1CCNCC1
Reactant: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Agent: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(O)CC4)c3)ccc21
Reaction time: 2 h
Yield: 60.8 %

Procedure:
N,N-dimethylformamide (2.5 ml) and 4-hydroxypiperidine (213 mg, 2.11 mmol) were added to a mixture (243 mg) of phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-carbamate and phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate synthesized in Example 93; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by NH-silica gel column chromatography (ethyl acetate:methanol=10:1) to yield the title compound as white crystals (150 mg, 0.322 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O-:3])=[O:2].FC(F)(F)S(O[C:33]1[CH2:37][CH2:36][CH2:35][CH:34]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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:33]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:6]=2)[CH2:37][CH2:36][CH2:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(OC1=CCCC1)C(F)(F)F
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 32.2 %

Procedure:
To a solution of tert-butyl (2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (16 g, 43.9 mmol, 1.0 equiv.) in 1,4-dioxane (320 mL) were added cyclopent-1-en-1-yl trifluoromethanesulfonate (11.4 g, 52.7 mmol, 1.2 equiv.), Pd (PPh3)4 (2.54 g, 2.2 mmol, 0.05 equiv.) and a solution of Na2CO3 (5.6 g, 52.7 mmol, 1.2 equiv.) in water (160 mL) at room temperature. The reaction was then heated to 110° C. and stirred for 4 h. The reaction mixture was filtered through celite then concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to give tert-butyl (5-(cyclopent-1-en-1-yl)-2-nitrophenyl)carbamate (4.3 g, 32% yield).
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>O.C1COCC1>[CH:1]([N:4]([CH3:5])[S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:18])=[O:19])([CH3:3])[CH3:2]
Reactant: CNC(C)C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer. The flask was charged with isopropylmethylamine (0.85 g, 11.6 mmol) followed by THF (50 mL). The mixture was cooled to 0° C. by placing the flask in an ice bath. Potassium hydroxide (23.2 mmol) was dissolved in water (20 mL) and added to the flask. An addition funnel was installed and charged with 3-nitrobenzenesulfonyl chloride (11.6 mmol) in THF (40 mL). The solution was added dropwise over 20 minutes, then the ice bath was removed. TLC (dichloromethane) indicated that the reaction was complete after addition of the 2-nitrobenzenesulfonyl chloride. The reaction was concentrated under diminished pressure, water (100 mL) was added, the mixture extracted with ethyl acetate (150 mL), dried (Na2SO4), and filtered. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a plug of silica gel (400 g in a 600 mL sintered glass funnel), and eluted with dichloromethane. Fractions were taken (100 mL) until the product eluted, as determined by TLC. Fractions containing the product were collected, and the solvent was removed in vacuo to yield N-(isopropyl)-N-(methyl)-3-nitrobenzenesulfonamide as a pale yellow, crystalline solid. 2.38 g, (79%). 1H-NMR (CDCl3): δ 1.03-1.05 (d, 6H, J=6.7 Hz); 2.78 (s, 3H); 4.23-4.32 (m, 1H, J=6.7 Hz); 7.70-7.76 (t, 1H, J=8.0 Hz); 8.13-8.15 (d, 1H, J=6.8 Hz); 8.40-8.43 (d, 1H, J=8.2 Hz); 8.64 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]2[C:19]3[C:20]([CH3:32])=[C:21]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]=3[O:17][C:16]2([CH3:34])[CH3:33])=[CH:11][CH:10]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]4[O:17][C:16]([CH3:34])([CH3:33])[CH:15]([C:12]5[CH:13]=[N:14][C:9]([F:8])=[CH:10][CH:11]=5)[C:19]=4[C:20]=3[CH3:32])[CH2:27][CH2:28]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Reactant: Fc1ccccc1
Product: Cc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Yield: 50 %

Procedure:
Using fluorobenzene and 1-(3-(6-fluoropyridine-3-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 127, the title compound was obtained in the same manner as in Example 16. Yield 50%. Amorphous powder.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:18][C:17]2[CH:12]=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=2)=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(Cl)nc1C#N
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(Oc2cnc(C#N)c(C#N)n2)cc1
Yield: 41.5 %

Procedure:
2,3-Dicyano-5-chloropyrazine (0.83 g; 0.005 mole) was dissolved in 25 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 0.54 g (0.005 mole) of p-cresol, 0.21 g (0.005 mole) of sodium hydroxide, 1 ml of water and 15 ml of acetone was added dropwise over the period of 15 minutes. The mixture was stirred at 0° to 5° C. for 1 hour. After the reaction, the solvent was removed by concentration under reduced pressure. The residue was extracted with 100 ml of chloroform. The chloroform solution was washed with 30 ml of a 1 N aqueous solution of sodium hydroxide and 30 ml of water and dried over anhydrous calcium chloride. Then, the solvent was distilled off. Recrystallization of the crude product from ethanol afforded 0.49 g (yield 41%) of 2,3-dicyano-5-(p-methylphenoxy)pyrazine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: Cc1ccnc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)Cn1ccc(C)cc1=O
Yield: 77 %

Procedure:
As described for example 320a, 2-hydroxy-4-methyl-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 40:60) afforded the title compound as a colorless liquid (yield: 77%). MS: m/e=196.1 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([NH2:70])[CH:65]=2)(=[O:57])=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>CN(C=O)C>[N:49]1([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([NH:70][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:65]=2)(=[O:57])=[O:56])[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.010 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 53% yield: LCMS (ESI) m/z 507 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:13][C:12]([F:14])([F:15])[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Temperature: -80 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
3-Methoxy-5-nitrobenzotrifluoride (5 g, 23 mmol) was dissolved in anhydrous methylene chloride (100 mL) and cooled to -80° C. under a nitrogen atmosphere. To this solution was added via dropping funnel a 1M solution of BBr3 in methylene chloride (68 mL, 68 mmol). This solution was allowed to warm to room temperature and stirred for 3 days. Water was slowly added to the mixture and mixed well to quench the excess BBr3. To this mixture ether (500 mL) was added. The organic layer was separated and extracted with 2N NaOH (240 mL). The alkaline extract was neutralized with dilute HCl and extracted with diethyl ether (3×300 mL). The ether extracts were combined, washed with saturated NaCl and dried over anhydrous MgSO4. Evaporation of diethyl ether gave a brownish yellow oil which was chromatographed on a silica column to give 1.6 g (34%) of a yellow solid. 1H-NMR (CDCl3 /CD3OD; 300 MHz) δ 7.38-7.40 (m, 1H), 7.82 (t, 1H, J=2.2 Hz), and 7.95-7.96 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=[N+]([O-])c1nccn1C1CCCCO1
Yield: 83.7 %

Procedure:
A suspension of 0.113 g (1.0 mmol) of 2-nitroimidazole and 10 ml of 2,3-dihydropyran was stirred at 80° C. in the presence of 5 mg of p-toluenesulfonic acid for 1 hr. according to the procedure of Robins et al. [J. Am. Chem. Soc 83, 2574 (1961)]. The excess of 2,3-dihydropyran was removed under reduced pressure. The residue was chromatographed on silica gel by elution with ethyl acetate-benzene mixture (employing a gradient from 9:1 to 1:1) to provide 0.165 g (83.7%) of the title compound, which was recrystallized from petroleum ether, mp 50° C.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:6][CH2:7][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@@H:18]5[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]5[NH:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:3][CH2:4]2)=[O:28])[CH2:26][CH2:25]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To the solution (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, the residue dissolved in dichloromethane (15 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to afford the title compound (27 mg, 28%) as white powder. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.63-0.81 (m, 4H), 0.97 (s, 3H), 1.23-1.43 (m, 5H), 1.51-1.82 (m, 9H), 1.83-1.95 (m, 3H), 2.06-2.29 (m, 2H), 2.81-3.00 (m, 2H), 2.98-3.14 (m, 2H), 3.33-3.64 (m, 4H), 3.70-3.88 (m, 1H). MS (M+1): 389.2.