Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([CH3:15])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:12]([C:10]2[C:9]([CH3:15])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)=[O:14])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: Cc1nn(-c2ccccc2)cc1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
1-Phenyl-3-methylpyrazole-4-carboxylic acid (2.2 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.3 g) and diethyl cyanophosphate (2.7 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (2.4 g), melting point: 155–156° C.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([F:43])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:37][C@@H:38]([OH:42])[C:39]([OH:41])=[O:40])[NH:22][C:23]([C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH:26]=3)=[O:24])=[CH:16][CH:15]=2)[CH:13]=1.CCN(CC)CC.CC(C)=O>>[C:1]([O:4][CH2:5][O:41][C:39](=[O:40])[C@H:38]([OH:42])[CH2:37][N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([Cl:7])[CH:9]=[CH:10][C:11]=2[F:43])=[CH:15][CH:16]=1)[NH:22][C:23]([C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[CH:26]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCBr
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
Bromomethyl acetate (11.9 mL, 121 μmol) was added to a mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (40.0 mg, 76 μmol) and Et3N (21.1 mL, 152 μmol) in acetone (1.0 mL, 14 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated and the residue was dissolved in AcOH (2 mL), filtered, and purified by reverse phase prep HPLC. The desired fractions were frozen and lyophilized to yield the title compound (8.5 mg, purity 98.5%) as a TFA salt. MS m/z [M+H]+ calc'd for C29H24ClF2N3O7, 600.13. found 600.1.
Reaction SMILES: C([Mg]Br)C.C[O:6][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[C@@H:14]([CH3:21])[CH2:13][C:12]([O:24][CH3:25])([O:22][CH3:23])[C@@H:11]3[OH:26])[CH:8]=1.[H-].[Na+].C(S)C>O1CCCC1.CN(C)C=O>[CH3:25][O:24][C:12]1([O:22][CH3:23])[C@H:11]([OH:26])[C:10]2[C:15](=[CH:16][N:17]=[C:18]3[C:9]=2[CH:8]=[C:7]([OH:6])[CH:20]=[CH:19]3)[C@@H:14]([CH3:21])[CH2:13]1
Reactant: COc1ccc2ncc3c(c2c1)[C@@H](O)C(OC)(OC)C[C@@H]3C
Agent: CC[Mg]Br
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1(OC)C[C@H](C)c2cnc3ccc(O)cc3c2[C@H]1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
A solution of ethylmagnesium bromide in tetrahydrofuran (1.0M, 8.90 mL, 8.90 mmol, 1.10 equiv) was added by syringe to a solution of (7S, 10R)-7,8,9,10-tetrahydro-2,9,9-trimethoxy-7-methyl-10-phenanthridinol (15, 2.46 g, 8.10 mmol, 1 equiv) in tetrahydrofuran (5 mL) at -78° C. The reaction flask was transferred to an ice bath for 10 min, then was cooled to -78° C. A 100-mL flame-dried Schlenk-type flask was charged with sodium hydride (1.17 g, 48.7 mmol, 6.00 equiv) and N,N-dimethylformamide (20 mL) was added slowly over 5 min. The resulting slurry was cooled to 0° C. and ethanethiol (1.80 mL, 24.3 mmol, 3.00 equiv) was added dropwise over 15 min by syringe, causing a vigorous exotherm. After the exotherm had subsided, the slurry was warmed to 23° C. and was stirred at that temperature for 10 min. The tetrahydrofuran solution of the magnesium alkoxide prepared above was added to the slurry via cannula over 5 min. Tetrahydrofuran was then removed in vacuo and the reaction mixture was heated at reflux for 1.5 h. The resulting thick brown slurry was cooled to 23° C. and was partitioned between saturated aqueous ammonium chloride solution (500 mL) and ethyl acetate (500 mL). The aqueous layer was separated and extracted further with ethyl acetate (500 mL) and 20% methanol in dichloromethane (500 mL). The aqueous layer was neutralized by the addition of aqueous hydrochloric acid solution (1% v/v, 400 mL) and was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (2.5% methanol-dichloromethane initially, grading to 5% methanol-dichloromethane) to afford (7S, 10R)-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-2,10-phenanthridinediol (16) as a yellow solid (1.66 g, 71%).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].C(O)(=O)C.N1CCCCC1>ClCCl>[C:14]([C:13]([C:12](=[O:17])[CH3:11])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O

Procedure:
2.3 g (17.5 mmol) of 4-formylbenzonitrile, 1.98 ml (19.29 mmol) of 2,4-pentanedione, 1 ml (26 mmol) of acetic acid and 0.34 ml (3.5 mmol) of piperidine in 40 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from diethyl ether. 3.18 g (85% of theory) of the title compound are obtained as a pale brown solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16][NH:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Br)[N:26]=1.C(N(CC)C(C)C)(C)C.CC(N(C)C)=O>C(OCC)(=O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:18]([F:21])([F:19])[F:20])[CH2:17][CH2:16][N:15]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[N:26]=3)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:8]=1
Reactant: Brc1cccc(Br)n1
Reactant: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCN(c3cccc(Br)n3)C2)c1
Yield: 92.3 %

Procedure:
A mixture of 3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidine (3.0 g), 2,6-dibromopyridine (2.22 g), N,N-diisopropylethylamine (2.2 g) and dimethylacetamide (15 ml) was reacted at 160° C. in a sealed tube for 1 hour. Upon the completion of the reaction, the mixture was added with ethyl acetate, washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 2-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-6-bromopyridine (4.0 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[C@@H:5]([CH2:24][CH3:25])[C:4]1=[O:26])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C@@H:5]([CH2:24][CH3:25])[C:4]1=[O:26])[CH3:2]
Reactant: CC[C@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 93 %

Procedure:
(3S)-1,3-Diethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-1,3-diethyl-6-fluoro-4-(4-hydroxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (93%). [α]D25=+295° (c=0.0098 G/ML, CHCl3); MS (ESI) m/z 343 ([M+H]+); MS (ESI) m/z 341 ([M−H]−); HRMS: calcd for C19H19FN2O3, 342.1380; found (ESI_FT), 343.14475.
Reaction SMILES: B(Br)(Br)Br.[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26]C)=[CH:15][CH:16]=2)[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:29])[CH2:10][C:9]1([CH3:37])[CH3:36])(=[O:7])[CH3:6].O>ClCCl>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])=[CH:15][CH:16]=2)[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:29])[CH2:10][C:9]1([CH3:37])[CH3:36])(=[O:7])[CH3:6]
Reactant: COc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 4 h

Procedure:
BBr3 (0.69 ml) was added dropwise to a solution of 1-acetyl-6-(2-methoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.64 g) in dichloromethane (40 mL). After stirring for 4 h, TLC indicated complete conversion. Water was added to the reaction mixture and stirring was continued for 15 min. The mixture was washed with 5% aq. NaHCO3 and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting product was used without further purification.
Reaction SMILES: CC([O-:5])(C)C.[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11](CC(=O)[NH:14]2)=[CH:10][CH:9]=1.CI.[Cl-].[NH4+].CO[C:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1.O>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:24]([CH3:25])([CH3:26])[C:27](=[O:5])[NH:14]2)=[CH:10][CH:9]=1
Reactant: COC(C)(C)C
Reactant: CC(C)(C)[O-]
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC1(C)C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of potassium tert-butylate (12.8 g, 114 mmol) in dry THF (80 ml) at 0° C. under an argon atmosphere was added portionwise 6-bromoindolin-2-one (5.0 g, 22.9 mmol) followed by copper(I) bromide-dimethylsulfide complex (470 mg, 2.29 mmol). MeI (6.82 g, 3.00 ml, 48.0 mmol) was added dropwise within 45 minutes, keeping temperature of the reaction mixture below 8° C. The reaction mixture was warmed to room temperature and kept at this temperature for 16 hours. The reaction mixture was cooled to 0° C. again and saturated aqueous ammonium chloride solution was cautiously added. The mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as light yellow solid (5.17 g).
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Sn:23]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:22]=1.CI>CCCCCC.O1CCCC1>[F:16][C:17]1[C:18]([CH3:1])=[N:19][CH:20]=[C:21]([Sn:23]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(F)c1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a mixture of 2,2,6,6-tetramethyl-piperidine (0.30 mL, 1.8 mmol) and 10 mL tetrahydrofuran at −78° C. was dropwise added 2.5 M of n-butyllithium in hexane (0.80 mL). The reaction vessel was then placed into a 0° C. ice bath and stirred for 60 minutes. The reaction vessel was then cooled to −78° C., and 3-fluoro-5-tributylstannylpyridine (504.7 mg, 1.307 mmol) was added as a solution in tetrahydrofuran (2 mL). The reaction mixture was stirred at −78° C. for 90 minutes, and then methyl iodide (0.15 mL, 2.4 mmol) was added. After an additional 30 minutes, the reaction was quenched with saturated aqueous NH4Cl, and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (2 g silica, solvent gradient: 0-30% ethyl acetate in heptanes) to yield 381.8 mg (50% pure, 37% yield) of 3-fluoro-2-methyl-5-(tributylstannyl)pyridine. LCMS (ESI): M+H=402.2.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[S:22][CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:25]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][Si](C(C)(C)C)(C)C)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[S:22][CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:25]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1csc(-c2ccc3cc(O[Si](C)(C)C(C)(C)C)c(C45CC6CC(CC(C6)C4)C5)cc3c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.29 g (15.2 mmol) of ethyl 2-[7-(1-adamantyl)-6-tert-butyldimethylsilyloxy-2-naphthyl]-4-thiophenecarboxylate and 60 ml of THF were introduced into a round-bottomed flask. A solution of 15.2 ml (16.6 mmol) of tetrabutylammonium fluoride in THF (1.1N) was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane, filtered and dried. 6.12 g (93%) of ethyl 2-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]-4-thiophenecarboxylate of melting point 199°-200° C. were recovered.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[Li]CCCC.CO[C:40]([CH3:48])([CH3:47])[C:41](N(OC)C)=[O:42].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[O:67]1CCC[CH2:68]1>>[OH:67][CH2:68][C:40]([CH3:47])([CH3:48])[C:41]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:42]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C(C)(C)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)CO)c3n2)cc(OC)c1OC
Reaction time: 0.01 h
Yield: 11 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (233 mg, 0.410 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to −78° C. and treated with nBuLi (2.29M in hexanes, 0.25 ml, 0.57 mmol) dropwise. The solution was stirred for 30 seconds and then 2,N-dimethoxy-2,N-dimethyl-propionamide (198 mg, 1.23 mmol), dissolved in THF (5 ml), was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then at room temperature 30 minutes. The reaction mixture was quenched with saturated aqueous NaHSO4 and then partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a brown oil. The oil was purified by silica gel chromatography using 10-50% EtOAc in hexanes as eluant providing a yellow solid. The yellow solid was dissolved in THF (5 ml) and treated with TBAF (1M in THF, 5.3 ml, 5.3 mmol) and refluxed for 6 hours. The reaction mixture was partitioned between EtOAc/1N HCl. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow solid. The crude product was purified by preparative thin layer chromatography using 10% [5% NH4OH:MeOH]/DCM as eluant providing 30 mg (11%) of 3-hydroxy-2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a pale yellow solid. MP 227-229° C., M+H=386.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[C:12]1([O:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:12]1([O:18][C:19](=[O:20])[NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1
Yield: 92.2 %

Procedure:
A solution of the commercially available 2-amino-4-trifluoromethylpyridine (20.86 g, 128.7 mmol) in 250 mL CH2Cl2 was treated with phenylchloroformate (17.81 mL, 141.5 mmol) and pyridine (22.85 mL, 283 mmol). During addition of the pyridine a yellow precipitate formed and a considerable exotherm was observed. After 0.5 h the homogeneous reaction was diluted with 1 L Et2O and washed with 1N bisulfate buffer (pH 2) and sat. NaHCO3. The organic layer was dried with Na2SO4 and evaporated to yield a gray solid. Trituration with Et2O:hexanes (1:5) gave the title compound as white crystals (33.5 g, 92% Yield). 1H-NMR (DMSO-d6) 11.28 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.12 (bs, 1H), 7.40 to 7.48 (m, 3H), 7.22 to 7.31 (m, 3H); MS [M+H]+=283.1; LCMS RT=3.51.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH2:9][OH:10])[CH2:5][CH:6]([CH3:8])[CH3:7].[C:11](#N)[CH3:12].C(I)C.C1C[O:20]CC1>>[CH2:11]([O:10][C:9](=[O:20])[C@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[NH2:3])[CH3:12]
Reactant: CC#N
Reactant: CC(C)C[C@H](N)CO
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCOC(=O)[C@@H](N)CC(C)C
Temperature: 55 °C
Yield: 30 %

Procedure:
Sodium hydride (60% dispersion in oil: 4.5 g, 0.11 mol) was added to a stirred solution of L-leucinol (12.8 ml, 0.10 mol) in a mixture of dry acetonitrile (24 ml) and dry THF (200 ml) at room temperature under argon. The mixture was heated at reflux for 2 h, cooled to 55° C. and ethyl iodide (8.2 ml, 0.10 mol) added carefully. The reaction mixture was heated at reflux overnight and allowed to cool to room temperature. Ice cold brine (100 ml) was added carefully and the mixture extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was distilled under reduced pressure to give L-leucinyl ethyl ether (4.5 g, 30%) as a colourless oil which was used directly in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:5][CH:4]=1)=O.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[C:20]2[S:16][C:17](=[O:22])[NH:18][C:19]2=[O:21])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(-c2ccccc2Cl)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(-c3ccccc3Cl)cc2)S1

Procedure:
To a solution of 4-formyl-(2′-chloro-1,1′-biphenyl) (0.12 g, 0.55 mmol) and 2,4-thiazolidinedione (0.08 g, 0.65 mmol) in toluene (10 mL) were added piperidine (0.008 mL, 0.073 mMol) and benzoic acid (0.011 mg, 0.08 mmol), and the reaction was refluxed for 4 h with continuous removal of water. The solvent was then distilled off and the oily residue obtained was purified by chromatography on silica-gel using hexane: ethyl acetate (3:1) as the eluent to yield titled product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2>O>[N+:1]([C:14]1[CH:13]=[CH:12][C:11]([F:10])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2)([O-:4])=[O:2]
Reactant: Fc1cccc2cccnc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c2ncccc12
Reaction time: 0.5 h

Procedure:
15 ml of nitric acid were added with stirring at -5° C. to 30 ml of concentrated sulfuric acid and then 16 g of 8-fluoroquinoline were added thereto with stirring over 30 minutes at -5° to 0° C. The mixture was stirred at 0° C. for three hours and was then allowed to return to room temperature. The mixture was stirred at room temperature for two hours and was then poured into a mixture of water and ice. The mixture was vacuum filtered and the product was suspended in water. The mixture was made alkaline by addition of 10% sodium carbonate solution and was extracted with methylene chloride. The organic phase was dried and evaporated to dryness under reduced pressure to obtain 12 g of 5-nitro-8-fluoro-quinoline melting at 132°-133° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([N:18]4[CH2:22][CH2:21][C:20]5([CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23]5)[CH2:19]4)[CH:15]=[C:16]([CH3:17])[C:10]=3[N:9]=2)=[C:6](I)[CH:5]=[CH:4][N:3]=1.[ClH:30].[O:31]1CCOCC1>O>[Cl:30][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:31])[C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([N:18]3[CH2:22][CH2:21][C:20]4([CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23]4)[CH2:19]3)[CH:15]=[C:16]([CH3:17])[C:10]=2[N:9]=1
Reactant: Cl
Reactant: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(I)ccnc5Cl)[nH]c4c3)C2)C1
Reactant: C1COCCO1
Solvent: O
Product: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4c3)C2)C1
Temperature: 85 °C
Yield: 15 %

Procedure:
To a suspension of 2-(2-chloro-4-iodo-pyridin-3-yl)-6-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-4-methyl-1H-benzoimidazole (450 mg, 0.86 mmol) in H2O (1.5 mL) was added a solution of HCl in dioxane (4 M, 20 mL, 80 mmol). After it was heated at 85° C. for 5 h, the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by chromatography (100:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (53 mg, 15%). 1H NMR (MeOH-d4) δ 1.18 (t, J=8 Hz, 3H), 1.87-2.07 (4H), 2.54 (s, 3H), 2.60-2.91 (6H), 3.19-3.39 (4H), 6.46 (s, 1H), 6.50 (s, 1H), 6.57 (d, J=6 Hz, 1H), 7.51 (d, J=6 Hz, 1H). ESI-MS m/z 412 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 114 %

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1.0 g, 5.85 mmol) in 15 mL of DMSO was added 1-methylhexahydro-1H-1,4-diazepine (0.8 mL, 6.42 mmol) and potassium carbonate (2.4 g, 17.4 mmol). The reaction mixture was heated at 80° C. for 16 h at which time the reaction was diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to give 1-methyl-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (1.77 g, 6.67 mmol) as a yellow solid containing residual DMSO. ESIMS (M+H)+=266