Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]([NH2:18])=[N:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH2:19]=O.Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:13]([NH2:18])=[N:14][N+:15]([O-:17])=[O:16])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: NC(=N[N+](=O)[O-])NCCNCc1ccc(Cl)nc1
Agent: Cl
Solvent: O
Product: NC(=N[N+](=O)[O-])N1CCN(Cc2ccc(Cl)nc2)C1

Procedure:
A mixture consisting of 1-{2-(6-chloro-3-pyridylmethylamino)ethyl}-2-nitroguanidine (1 g), a 37% aqueous solution of formalin (0.35 g), catalytic amount of hydrochloric acid, and water (20 ml) was stirred at 50° C. for one hour. After cooling, the solvent was removed from the reaction mixture under reduced pressure, leaving crystals that were then washed with chloroform to obtain the 1-(6-chloro-3-pyridylmethyl)-3-{1-(nitroimino)-aminomethyl}-imidazolidine. mp 170°-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([OH:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>[OH-].[Na+]>[C:15]([O:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[NH:5][C:6](=[O:14])[C:7]1=[O:13])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2cc(Cl)ccc2n(O)c1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)On1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of 0.4 g (1.9 mmol) 6-chloro-1-hydroxyquinoxaline-2,3(1H,4H)-dione in 15 ml 0.5N sodium hydroxide was added with stirring 1 ml acetic anhydride. Stirring was continued at 25° C. for 1 h to give a precipitate. Recrystallization (dimethylformamide-water) gave 0.2 g (42%) 1-acetoxy-6 -chloroquinoxaline-2,3(1H,4H)-dione. M.p. 219° C. 1H-NMR (DMSO-d6): 12.5 (1H, broad s), 7.2 (3H, m), 2.50 (3H, s). MS (m/e). 254 (M+, 30%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:21][CH2:20]3)[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[CH:28][C:29]=1[C:30]([F:33])([F:32])[F:31].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:20][CH2:21]3)[C:14]=2[NH:18][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[CH:28][C:29]([C:30]([F:31])([F:32])[F:33])=[C:24]([F:23])[CH:25]=2)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C3CC3)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Temperature: 40 °C

Procedure:
A reaction vial was charged with (R)-2-(5-amino-6-cyclopropyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (23.0 mg, 0.0000766 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (26 mg, 0.00011 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (73 mg, 0.00019 mol), N,N-diisopropylethylamine (33 μL, 0.00019 mol) and methylene chloride (2 mL, 0.03 mol) and the reaction was stirred at 40° C. over night. the solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc(Cl)cc1
Product: NCc1c(N)nc(-c2ccc(Cl)cc2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=377.8 (M+), was prepared from 4-chloro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.Cl.[CH3:14][O:15][NH2:16]>C(O)C>[CH3:14][O:15][N:16]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[CH2:2][Br:1]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=C(CBr)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To 4.00 g of 2-bromo-1-(2,4-dichlorophenyl)ethanone in 20 ml of ethanol, 1.25 g of methoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was mixed with 20 ml of water and extracted with ethyl acetate (20 ml×2). The resulting organic layers were combined, washed with water (20 ml×1) and then dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.85 g of the desired crude product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>C(O)(C)(C)C.CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: C=O
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(F)c1CCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert.-butanol (1 ml, synthesis quality, 99%) was added to 2-fluoro-6-nitrotoluene (776 mg, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. The solution was stirred for 5 min at room temperature and for 30 min at 70° C. (oil bath temperature). It was then left to cool down to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (20 ml). The aqueous phase was post-extracted with EtOAc (2×20 ml). Drying the organic phases over Na2SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product (1.11 g) which was purified by column chromatography (20 g SiO2, 12×2 cm, solvent: PE 40 ml, PE/EtOAc 10:1 110 ml, 8:1 270 ml, 6:1 210 ml, 5:1 60 ml, 4:1 50 ml). 2-(2-fluoro-6-nitrophenyl)ethanol (653 mg, 71%) was obtained as a yellow solid.
Reaction SMILES: Br.Br.[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:3]1([CH3:21])[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCNCCN(Cc3ccccc3)CC2)cc1

Procedure:
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane (1.3.13.31), sodium hydride and benzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[N:6][C:7]=1I.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[N:6][C:7]=1[C:13]#[N:14]
Reactant: Nc1ccc(C(F)(F)F)nc1I
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1nc(C(F)(F)F)ccc1N
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 86.31 %

Procedure:
12.5 g (0.434 mol, 1 eq) of 5-amino-6-iodo-2-(trifluoromethyl)pyridine was dissolved in 125 mL of dry DMF and degasified with nitrogen for 5 min. 6.1 g (0.519 mol, 1.2 eq) of zinc cyanide and 5 g (0.1 eq) of Pd(PPh3)4 were added and heated at 100° C. for over night. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The crude product obtained was purified by 60-120 silica gel using 15% of ethyl acetate in pet ether to get 7 g (86.31%) of pale yellow solid. 1H NMR (CDCl3, 400 MHz): 4.85 (2H, bs), 7.25 (1H, d), 7.62 (1H, d). MS 188 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)=O.[OH-].[Na+]>O>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(-c2nc3ccccc3o2)nc1
Temperature: 210 °C
Yield: 78.5 %

Procedure:
A mixture of o-aminophenol (10.9 g, 0.1 mole), picolinic acid (12.3 g, 0.1 mole) and polyphosphoric acid (275 g) is heated under a nitrogen atmosphere at 210° C for 3 hours. The mixture is then cooled to 160° C and slowly poured into 1 liter of water. The mixture is neutralized with 50% sodium hydroxide solution yielding 15.4 g of the title compound as a crystalline solid, melting point 105°-107° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].CS(O[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CS(C)=O>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCCO
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.2 g) is heated at 70° C. for 10 minutes in dimethyl sulfoxide (50 ml), to which is added 1,4-butanediol (4.5 g). The mixture is heated for one further hour. To this reaction mixture is added dropwise a solution of 3-(octadecyloxy)propyl methanesulfonate obtained in Reference Example 1 (4.06 g) in dimethyl sulfoxide (15 ml), and the mixture is stirred at 70° C. for one hour. The reaction mixture is poured into cold water, and the mixture is subjected to extraction with a mixture of hexane and ethyl acetate. The extract is washed with water and then dried, and the solvents are then distilled off under reduced pressure. The residue is subjected to purification by means of silica gel column chromatography to obtain the above-titled compound (2.2 g).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(CC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidine-1-carboxylate (Intermediate 234, 0.55 g) in DCM (5 mL) and the mixture was stirred at room temperature for 1.5 hours. The mixture was evaporated to dryness and the residue was dissolved in a small amount of methanol and loaded onto a 20 g SCX-2 SPE cartridge, washed with methanol then eluted with 2M ammonia in methanol to give (R)-2-[2-(3-fluorophenyl)-ethyl]pyrrolidine (0.39 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[O:7]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1
Reactant: O=C(CCCCBr)Nc1ccc(COC(=O)CCCCBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCCBr)OCc1ccc(N2CCCCC2=O)cc1

Procedure:
The ester from Step 1 (1 g, 2.22 mmol) was dissolved in DMF. Cs2CO3 (725 mg, 2.22 mmol) was added and the reaction mixture was heated to 50° for 18 hours. TLC shows ~50% starting material remaining. Additional Cs2CO3 (2.22 mmol) was added the reaction mixture was heated at 50° for and additional 8 hours. The mixture was dissolved in 10% citric acid and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried (MgSO4) filtered and concentrated to yield a yellow oil. Flash chromatography (EtOAc) yielded the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:31]1[C:35]([CH2:36][C:37](O)=[O:38])=[N:34][N:33]=[N:32]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:31]1[C:35]([CH2:36][C:37]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:38])=[N:34][N:33]=[N:32]1
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C2CCN(C(=O)Cc3nnn[nH]3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 17.2 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (50.7 mg, 0.122 mmol), (1H-tetrazol-5-yl)-acetic acid (15.6 mg, 0.122 mmol), triethylamine (51 uL, 0.366 mmol) and BOP (54 mg, 0.128 mmol) in 1 mL DMF were reacted as above to give a clear oil. The crude product was crystallized from methanol/acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-1H-tetrazol-5-yl-acetyl)-piperidin-4-yl]-phenyl}-amide as off-white crystals (11 mg, 17%). ES-MS calcd for C25H22F3N7O3 (m/e) 525.49, obsd 526 (M+H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH:1]([Br:5])[Br:2])=[CH:39][CH:40]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Carbon tetrabromide (78.1 g, 235.6 mmole) and triphenylphosphine (123.5 g, 471.2 mmole) were combined in 460 ml dichloromethane in a flame dried 1000 ml three neck round bottom flask under nitrogen at 0° C. The mixture was stirred 1 hour at 0° C. and was treated portionwise with 4-benzyloxybenzaldehyde (25 g, 117.8 mmole). The reaction was stirred 30 minutes at 0° C. and was washed successively with 1×100 ml water and 1×100 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were poured into 3 liters hexane. The supernatant was collected and the residue was dissolved in a minimum amount of dichloromethane. This solution was also poured into 3 liters hexane and the process was repeated one more time. The combined supernatants were filtered through a 125 ml plug of silica gel (230-400 mesh) in a 600 ml coarse filter funnel. The plug was washed with 1 liter 15% ethyl acetate/hexane and the combined eluents were concentrated in vacuo to provide 38.2 g (89%) of 2-(4-Benzyloxyphenyl)-1,1-dibromo-ethane as a white solid. Melting Point: 97°-98° C. The dibromo-olefin (20 g, 54.3 mmole) was dissolved in 200 ml dry tetrahydrofuran in a flame dried 500 ml three neck round bottom flask under nitrogen. The solution was cooled to -78° C. and was treated slowly dropwise with butyllithium (70 ml, 108.6 mmole). The reaction was stirred 1 h at -78° C. followed by 1 hour at 0° C. The mixture was cooled to -78° C. and was treated with methyl-chloroformate (4.6 ml, 60 mmole). The reaction mixture was stirred for 20 minutes at -78° C. and then for 1.5 hours at 0° C. The reaction was quenched with 1×100 ml 1:1 saturated ammonium chloride/saturated sodium chloride. The layers were separated and the aqueous layer was washed with 2×100 ml diethyl ether. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a red oil. The oil was crystallized and then recrystallized from hexane to provide 9.2 g (75%) of methyl-4-benzyloxyphenylpropiolate as orange tinged flakes. Melting Point: 78° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1CC#N.[C:14]([OH:17])(=[O:16])[CH3:15].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:15][C:14]([OH:17])=[O:16]
Reactant: Cc1c(CC#N)cccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Reaction time: 0.62 h

Procedure:
150 g of 2-Methyl-3-nitro phenylacetonitrile is added to 750 ml pure water and 600 ml acetic acid. 675 ml sulfuric acid is added drop wise to the reaction mixture and refluxed for 6-7 hours. After completion of reaction, 2000 ml water is added to it and stirred for 30-45 minutes, filtered and dried to give 2-Methyl-3-nitro phenylaceticacid (130-135 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](Br)[CH:17]=[N:18][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH2:26][C:27]1[N:28]([CH3:36])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22](=[O:25])[CH:23]=[CH2:24].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](/[CH:24]=[CH:23]/[C:22](=[O:25])[N:21]([CH3:20])[CH2:26][C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:17]=[N:18][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(Br)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)NC(=O)CN2C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
A solution of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b]pyrazine-4-carboxylic acid tert-butyl ester (494 mg, 1.5 mmol) in propionitrile (12 mL) was treated with N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-acrylamide (685 mg, 3 mmol) and diisopropylethylamine (788 μL, 4.5 mmol) and purged with Argon for 10 min. Pd(OAc)2 (34 mg, 0.15 mmol) and P(o-Tol)3 (92 mg, 0.3 mmol) was added and the Argon purge was repeated. The mixture was heated to 100° C. and stirred for 6 hours under Argon. Upon cooling, solvent was removed and the residue was purified by Flash chromatography (silica, 1-3% MeOH in CH2Cl2) to afford the title compound (480 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 10.81 and 10.73 (rotamers, 2s, br, 1H), 8.46 and 8.41 (rotamers, 2s, 1H), 7.58 (d, J=15.4 Hz, 1H), 7.51 (m, 3H), 7.23 (d, J=15.4 Hz, 1H), 7.11 (m, 1H), 7.03 (m, 1H), 6.45 and 6.20 (rotamers, 2s, 1H), 5.06 and 4.87 (rotamers, 2s, 2H), 4.32 and 4.28 (rotamers, 2s, 2H), 3.74 and 3.71 (rotamers, 2s, 3H), 3.16 and 3.05 (rotamers, 2s, 3H), 1.44 and 1.42 (rotamers, 2s, 9H). MS (ESI) m/e: 476.2 (M+H)+, 420.2 (M-tert-Bu)+.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:21])[CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1>C(O)C.C(COC)OC>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]([OH:21])[CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: O=C1CC(c2ccc3c(c2)OCO3)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: O[C@@H]1C[C@H](c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Sodium borohydride (1.5 g) was added in portions with stirring at 10-15° C. to a solution of 3-(benzo[1,3]dioxol-5-yl)-indan-1-one (10 g) in a mixture of ethanol (75 mL) and dimethoxyethane (75 mL). The mixture was stirred at rt for 1 h and then evaporated in vacuo. The resulting oil was treated with water and diethyl ether, and the organic phase was separated and washed with water and 0.1 N HCl, dried (MgSO4) and evaporated in vacuo to give cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol as a brown oil (10 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[N:18]2[C:19]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:20][O:21][C:16]3=[C:17]2[C:12](=[CH:13][CH:14]=[CH:15]3)[NH:11]1>C(#N)C.C(O)(=O)C>[Br:1][C:15]1[C:16]2[O:21][CH2:20][C:19]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:18]3[C:10](=[O:9])[NH:11][C:12]([C:17]=23)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)NCC1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a mixture of N-[(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide in acetonitrile (5 mL) and acetic acid (3 mL), and cooled to 0° C. The reaction was stirred for 1 h, concentrated to remove residual acetic acid, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide (0.040 g. 60%). LCMS calculated for C17H16BrN4O3 (M+H)+: m/z=403.1, 405.1. found: 402.9, 405.0.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:16]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[N+:17]=[N-:18]>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[N:18]=[N:17][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=2)[C:5]=1[OH:13])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Combine a solution of sodium ethoxide (5.5 mL, 21 wt % in ethanol) and diethyl malonate (2.50 mL, 16.5 mmol) in ethanol (26 mL) with a solution of 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (4.40 g, 16.3 mmol) in ethanol (6 mL) and heat to 80° C. After 7 hours, cool to RT. Concentrate mixture in vacuo and dissolve the viscous oil in H2O (20 mL). Add aqueous 1N HCl until solution reaches pH 2-3. Collect the white precipitate by filtration and dry under reduced pressure to give the title compound: MS (IS) 384.0 (M+H), MS (ES−) 382.1 (M−H); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.92 (s, 2H), 5.41 (s, 2H), 4.15 (q, 2H, J=7.3), 1.22 (t, 3H, J=7.3).