Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[N:22]=[N+]=[N-])([CH3:4])[CH3:3]>CO.[Pd]>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[NH2:22])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC1C(N)CC1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-(((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl)-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)-1-azidocyclobutane (980 mg, 2.45 mmol), prepared as described in Step D above, was dissolved in 20 mL of methanol and an excess of palladium on carbon was added to the solution under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature and atmospheric pressure under hydrogen for 0.5 h. The catalyst was removed by filtration and washed with 10 mL of methanol. The filtrate was concentrated in vacuo to give 850 mg (93%) yield of the title compound; MS DCI-NH3M/Z: 374 (M+H)+, 391 (M+NH4)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C1(C)C=CC=CC=1>[CH:11]1([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH2:3][C:4]2([CH3:18])[CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C(=O)OC
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 48.6 %

Procedure:
A mixture of 1000 grams (39.3 mmol) of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, 27.8 grams (236 mmol) of dimethyl oxalate and 100 ml of toluene is heated at reflux. Methanol and toluene are removed from the reaction mixture by fractional distillation. The reaction is then filtered and the liltrate is concentrated to obtain a solid. Fractional crystallization of the solid from 9:1 isopropanol:methylene chloride followed by recrystallization from heptane affords 6.5 grams (48% yield) of the title compound as a white solid melting at 124°-126° C.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:21]2[N:25](C(OC(C)(C)C)=O)[C:24]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]=3[N:22]=2)=[N:11][C:12]([NH:15][C:16](=[O:20])[CH2:17][C:18]#[N:19])=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[CH2:17][C:18]#[N:19])=[N:11][C:10]=1[C:21]1[NH:25][C:24]2[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]=2[N:22]=1
Reactant: Cc1ccc2nc(-c3nc(NC(=O)CC#N)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(-c3nc(NC(=O)CC#N)cnc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
tert-Butyl 2-(3-(bis(tert-butoxycarbonyl)amino)-6-(2-cyanoethanamido)pyrazin-2-yl)-6-methyl-1H-benzo[d]imidazole-1-carboxylate (isolated from Step 2) was dissolved in DCM (5 mL) and TFA (28.29 mg, 19.11 μL, 0.2481 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (8 mg, 10.5% Yield). 1H NMR (400.0 MHz, CDCl3) δ 2.4 (3H, s), 3.95 (2H, s), 7.15 (1H, d), 7.42-7.49 (1H, m), 7.52-7.58 (1H, m), 8.0 (1H, br s), 8.62 (1H, s), 10.55 (1H, s), 12.8 (1H, vbr s); MS (ES+) 308.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[C:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: COc1ncccc1CN1CCC(C#Cc2sccc2S(C)(=O)=O)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ncccc1CN1CCC(CCc2sccc2S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
450 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[3-(methylsulfonyl)-2-thienyl]-1-ethynyl]piperidine and 250 mg of 10% palladium-carbon powder (water-containing product) were suspended in 10 ml of ethanol. After replacing the atmosphere of a container with hydrogen, the mixture was stirred at room temperature under normal pressure for 8 hours. The reaction solution was filtered, and the filtrate was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH2:12]([O:14][C:15](=[O:23])[CH2:16][C:17]([CH2:19][O:20][CH2:21][CH3:22])=O)[CH3:13].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:5]([C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=2)[C:28]([C:27]([O:26][CH2:24][CH3:25])=[O:32])=[C:29]([CH3:30])[NH:31][C:17]=1[CH2:19][O:20][CH2:21][CH3:22])=[O:23])[CH3:13]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOCC(=O)CC(=O)OCC
Reactant: COc1ccc(C=O)cc1F
Solvent: CCO
Product: CCOCC1=C(C(=O)OCC)C(c2ccc(OC)c(F)c2)C(C(=O)OCC)=C(C)N1
Yield: 35 %

Procedure:
15.4 g of 3-fluoro-4-methoxybenzaldehyde, 17.4 g of γ-ethoxyacetoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 80 ml of ethanol are heated to the boil overnight, the mixture is cooled, and after filtration and rinsing with cold ethanol, 2-ethoxymethyl-6-methyl-4-(3'-fluoro-4'-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in 35% yield of theory, in the form of white crystals of melting point 120°C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:14]1=[O:42])=[O:11])=O)(C)(C)C.[ClH:43]>CO>[ClH:43].[NH2:8][CH2:9][C:10]([NH:12][CH:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:14]1=[O:42])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Agent: Cl
Solvent: CO
Product: NCC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
The intermediate obtained in Step C (109 mg, 0.196 mmol) was dissolved in 2 mL of methanol and treated with 0.1 mL of concentrated hydrochloric acid. The reaction mixture was stirred at room temperature for 16 hours then solvents were removed under vacuum and the residue redissolved in water and washed with ethyl acetate. The aqueous layer was separated and the solvent removed under vacuum to yield 87 mg (0.17 mmol, 88%) of the title compound. 1H NMR (200 MHz, CD3OD): 2.10 (m,1H), 2.48 (m,3H), 3.68 (s,2H), 4.37 (m,1H), 4.84 (d,14 Hz,1H), 5.22 (d,14 Hz,1H), 6.9-7.7 (m,12H). FAB-MS: calculated for C26H25N7O2 467; found 468 (M+H,100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+]([O-])=O)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[O:17]([CH3:19])[Li].Cl>CO>[CH3:19][O:17][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [Li]OC
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 55.8 %

Procedure:
methyl 3,5-dinitrobenzoate (1.5 g, 6.63 mmol, 1 eq) in 10 ml anhydrous MeOH under Ar was heated to reflux at 85° C. LiOMe (1.0 M in MeOH, 13.3 ml, 13.3 mmol, 2 eq) was added to the refluxing solution. After 4 h the reaction was cooled to room temperature, and the mixture was adjusted to pH {tilde over ( )} 3 with concentrated HCl. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 (×2), water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.7705 g (3.70 mmol, 56% yield) of methyl 3-methoxy-5-nitrobenzoate.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1>C(O)C.[Pd]>[NH2:22][C:18]1[CH:17]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:25]([F:28])([F:27])[F:26])=[N:5]3)[CH2:15][CH2:14]2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(N)c2)CC1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a suspension of (2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-nitro-phenyl)-piperazin-1-yl]-ethanone (1.03 g, 2.59 mmol) in ethanol (50 mL) is added 10% Pd/C (100 mg). The reaction mixture is stirred under hydrogen (1 atm) for 2 h, and then filtered over Celite, washed with ethanol, and evaporated under pressure to give 1-[4-(3-amino-phenyl)-piperazin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.95 g, 99%). 1H-NMR (400 MHz, DMSO-d6): δ=2.21 (s, 3H), 3.01-3.09 (m, 2H), 3.11-3.18 (m, 2H), 3.53-3.69 (m, 4H), 4.90 (br, 2H), 5.30 (s, 2H), 6.06-6.11 (m, 1H), 6.13-6.20 (m, 2H), 6.50 (s, 1H), 6.85-6.91 (m, 1H). MS: m/z=368 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=O.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH2:7][CH2:6]3)=[CH:10][C:2]=2[O:1][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cc1ccccc1C(=O)c1cc2c(cc1O)CCC2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cc3c(cc2c1-c1ccccc1C)CCC3
Reaction time: 0.5 h

Procedure:
A solution of (6-hydroxy-2,3-dihydro-1H-inden-5-yl)(2-methylphenyl)methanone (2.0 g) in DMF (50 ml) was combined with sodium hydride (60%, in oil) (400 mg) with cooling in ice. After stirring at the same temperature for 30 minutes, the mixture was combined with ethyl bromoacetate (1 ml), and stirred for 1 hour. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was dissolved in toluene (50 ml), and combined with DBU (2 ml). The reaction solution was heated under reflux overnight, and then combined with water, and extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by a column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:3) to obtain a crude product of ethyl 3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-carboxylate. The resultant crude product of ester was dissolved in a solvent mixture of THF (50 ml) and methanol (30 ml), combined with a 1 N solution of sodium hydroxide (30 ml), and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was combined with water and extracted with ethyl acetate after acidifying with diluted hydrochloric acid. The extract was washed with water, and then dried over magnesium, and the solvent was distilled off under reduced pressure. The resultant residue was purified by recrystallization from ethyl acetate to obtain the title compound (0.9 g, yield: 39%) as a colorless crystal.
Reaction SMILES: CC1C(=CC(=CC=1)N=C=O)[N:4]=[C:5]=[O:6].C(O)C[CH:16]([OH:18])[CH3:17]>>[N-:4]=[C:5]=[O:6].[N-:4]=[C:5]=[O:6].[NH2:4][C:5]([O:18][CH2:16][CH3:17])=[O:6].[NH2:4][C:5]([O:18][CH2:16][CH3:17])=[O:6]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: CC(O)CCO
Product: CCOC(N)=O
Product: [N-]=C=O

Procedure:
About 348 parts of toluene diisocyanate are mixed with 90 parts of 1,3-butylene glycol and reacted at 30° C. to form a diurethane diisocyanate. About 260 parts of hydroxyethyl methacrylate are added to the resultant diurethane diisocyanate and the mixture heated at 50° C. until the --NCO content is zero.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)c2OC
Yield: 45 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (75 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (89 mgs) were converted to the title compound as an off-white solid (66 mgs). 1H-NMR (CDCl3): δ 10.30 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J=15.7 Hz, 2H), 7.44-7.41 (m, 2H), 7.28-7.25 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.54 (s, 1H), 3.80 (s, 3H), 2.32 (broad S, 2H), 3.15-1.5 broad absorptions, 6H), 1.15 (t, J=7.3 Hz, 3H). LC/MS, found 504.17 (M+H)+; MP:183-185° C.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=2)C(=O)C2=CC=CC=C12.[ClH:24]>CO.O1CCCC1>[ClH:24].[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1cccc(CN)n1

Procedure:
A solution of hydrazine hydrate (0.77 g) in methanol (5 ml) was added dropwise to a suspension of 6-phthalimidomethyl-2-pyridinecarbonitrile (3.74 g) in a mixture of methanol (10 ml) and tetrahydrofuran (15 ml) at ambient temperature with stirring. After the mixture was stirred for two hours, diluted hydrochloric acid (prepared by concentrated hydrochloric acid (1.38 ml) and water (6.91 ml)) was dropped to the mixture. After stirring for three hours, the solvent was evaporated in vacuo. The residue was mixed with water (20 ml) and an insoluble material was filtered off. The filtrate was evaporated in vacuo to give 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.40 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>ClCCl.CN(C=O)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][C:18]=1[NH:23][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: COc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N)c(NC(=O)c2cc(Br)ccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Method 6—Step a A mixture of 5-Bromo-2-fluoro-benzoic acid (1.50 g, 6.85 mmol), 4-methoxy-benzene-1,2-diamine dihydrochloride (1.77 g, 8.49 mmol), HATU (2.73 g, 7.19 mmol) and TEA (2.88 mL, 20.76 mmol) in dichloromethane (20 mL) and DMF (5 mL) was stirred at room temperature overnight, then water was added (50 mL), mixture was stirred for 2 h and left standing at room temperature overnight. The precipitate obtained was filtered off and dried to afford 1.45 g of the title compound (50%).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][S:8][CH2:7][C:6]1(O)[C:10]([OH:12])=[O:11])=[O:4]>C(OC(=O)C)(=O)C>[S:8]1[CH2:7][C:6]2[C:10]([O:12][C:3](=[O:4])[C:5]=2[CH2:9]1)=[O:11]
Reactant: COC(=O)C1CSCC1(O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2=C1CSC2
Yield: 26 %

Procedure:
A solution of 3-hydroxy tetrahydro thiophene-3,4-dicarboxylicacid-4-methylester (2.87 g, 14.9 mmol) in acetic anhydride (20 ml) was refluxed for 4 h. The reaction mixture was filtered and concentrated under reduce pressure. The solid residue was triturated with acetone, dried with Na2SO4 and concentrated in vacuo. The solid product was recrystallized from benzene to give 2,5-dihydrothiophene-3,4-dicarboxylic anhydride in 26% yield.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[C:4](=[O:12])[O:3]1.[OH-:13].[Na+].C>O>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:12])=[C:10]([CH:2]=[O:13])[CH:9]=1
Reactant: O=C1OC(Br)c2cc(Br)ccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cc(Br)ccc1C(=O)O
Temperature: 80 °C
Yield: 89 %

Procedure:
The mixture of 3,5-dibromo-3H-isobenzofuran-1-one (B3) (38 g, 130 mmol) in a solution of 10N NaOH (28.6 mL, 286 mmol) and water (240 mL) is heated for 2 h at 80° C. Activated charcoal (2 g) is added and the mixture is refluxed for another 1 hour. Mixture is hot filtered and acidified with 2N methanesulfonic acid (100 mL). The resulting mixture is cooled in an ice-water bath for 1 h. The solid is filtered and washed with water (4×25 mL) and vacuum dried under KOH to yield 4-bromo-2-formyl-benzoic acid (C3) (26.5 g, 89%, mp: 202° C.). Recrystallization: Dissolved 4-bromo-2-formyl-benzoic acid (C3) in hot EtOH (220 mL) and cooled the mixture in an ice-water bath for 4 h. The solid is filtered and rinsed with cold EtOH (3×20 mL). The solid is then vacuum dried over KOH to yield 4-bromo-2-formyl-benzoic acid (16.8 g, 63%, mp: 204-205° C.).
Reaction SMILES: [CH:1]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)=O.Cl.[NH2:20][CH:21]([CH:23]([OH:31])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH3:22]>>[OH:31][CH:23]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[CH:21]([NH:20][CH2:1][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)[CH3:22]
Reactant: CC(C)(C)OC(=O)COc1ccc(CC=O)cc1
Reactant: CC(N)C(O)c1ccc(O)cc1
Agent: Cl
Product: CC(NCCc1ccc(OCC(=O)OC(C)(C)C)cc1)C(O)c1ccc(O)cc1
Yield: 50.9 %

Procedure:
The ester 20 was prepared by condensation of tert-butyl 4-[formylmethyl]phenoxyacetate (10.0 g, 0.04 mole) with α-(1-aminoethyl)-4-hydroxybenzyl alcohol 13 (8.2 g, 0.04 mole) using the same method as described for the preparation of 5, 8, and 16. The ester 20 (8.18 g, 51%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[F:11][C:12]1[CH:13]=[C:14]([CH2:15][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(C[Mg]Cl)c1
Reactant: O=C1CCC2CCC(=O)N12
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(F)c1
Yield: 62.3 %

Procedure:
Analogous to the procedure described for Example 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (2 g, 14 mmol) was reacted with 3-fluorobenzylmagnesium chloride (0.25M in Et2O, 62 mL, 15.5 mmol) over 2.5 h. Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to 2:1 EtOAc:hexanes to EtOAc to 2% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided 5-[4-(3-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.1730 g). 1H NMR (CDCl3) δ7.32–7.27 (m, 1H), 7.00–6.90 (m, 3H), 6.12 (bs, 1H), 3.69 (s, 2H), 3.59 (m, 1H), 2.52 (t, 2H), 2.30 (m, 2H), 2.19 (m, 1H), 1.75 (m, 2H), 1.65 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2].C([O-])(=[O:28])C.[K+].O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([OH:28])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1nc(O)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Yield: 84.6 %

Procedure:
To a solution of 1-bromo-5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (3.2 g) in dimethylsulfoxide (DMSO) (30 ml) was added potassium acetate (2.5 g) with stirring. The mixture was heated on a steam bath for one hour. Water was then added to cause the precipitation of crude product as a white solid (2.3 g, 85% yield). Recrystallized from a mixture of acetonitrile, chloroform and methanol, m.p. >300° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][OH:22])[C:18]([CH3:24])([CH3:23])[C:17]3=[O:25])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:3][O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=4)[C:18]([CH3:23])([CH3:24])[C:17]3=[O:25])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COC(=O)C1CC2CCCC(C1)C2N1CC(CO)C(C)(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C1CC2CCCC(C1)C2N1CC(COc2ccc(C#N)cn2)C(C)(C)C1=O
Temperature: 25 °C

Procedure:
NaH (0.1 g, 60% in oil, 2.56 mmol) was added in one portion to a stirred and cooled (0° C.) solution of the product of Example 7D (0.48 g, 1.42 mmol) and 6-chloro-nicotinonitrile (0.35 g, 2.56 mmol) in tetrahydrofuran (7 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). After the addition, the solution was warmed to room temperature and stirred for another five hours. The dark brown reaction mixture was cooled (0° C.), quenched with acetic acid (0.1 mL), and partitioned with diethyl ether and water. The organic phase was washed with water and brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-80% ethyl acetate in hexanes to give the titled product as a solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]I.[NH2:8][C:9]1[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]>CN(C1C=CN=CC=1)C.O>[N:8]1([C:9]2[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:11]([CH:10]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ICCCCCI
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCCC2)c1
Temperature: 25 °C
Yield: 33 %

Procedure:
1,5-diiodopentane (0.85 ml, 1.8 g, 5.74 mmol, 3 eq) was added to a stirred solution of dimethyl 5-aminoisophthalate (0.40 g, 1.91 mmol, 1 eq) and DMAP (0.467 g, 3.82 mmol, 2.1 eq) at 100° C. under Ar. After heating overnight the reaction was cooled to room temperature and poured in water. The mixture was extracted with EtOAc (×2). The combined organic extracts were washed with water (×4), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.1736 g, 0.626 mmol, 33% yield) of the product.