Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH2:12]([Sn](CCCC)(CCCC)CC=C)[CH2:13][CH2:14]C.CN(C)C=O.[F-].[K+]>C(N(CC)CC)C>[CH2:14]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[CH:13]=[CH2:12]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1CCC2=O
Temperature: 20 °C

Procedure:
15 g of 4-bromo-1-indanone, 24 ml of tributyl allyl stannane, 150 ml of dimethylformamide, 0.82 g of tetrakis triphenyl phosphine palladium and 7.89 g of triethylamine are taken to 120° C. for one hour. After cooling to 20° C., the reaction mixture is poured over 300 ml of an aqueous solution of potassium fluoride, agitated, and filtered on celite; the filtrate is extracted with isopropyl ether. The insoluble part is taken up with ethyl acetate and filtered on celite. The reunited organic phases are washed with water saturated with sodium chloride, dried and brought to dryness under reduced pressure. The residue is chromatographed on silica with hexane-ethyl acetate (9-1) and 11.84 g of expected product is recovered.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([NH2:16])=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CO[C:21](OC)(N(C)C)[CH3:22].Cl.[CH:29]([NH:32][NH2:33])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:32]([CH:29]([CH3:31])[CH3:30])[N:33]=[C:21]([CH3:22])[N:16]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(C)NN
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Temperature: 95 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (9.040 g, 0.02780 mol) in Toluene (150 mL) was added dimethylacetamide-dimethylacetal (12.38 mL, 0.08340 mol). The reaction was stirred at 95° C. for 4 hours. The toluene was then removed in vacuo and the crude was carried forward without further purification. The crude material was redissolved in acetic acid (90 mL). Isopropylhydrazine hydrochloride (3.689 g, 0.03336 mol) was added and the reaction was stirred at room temperature overnight. The acetic acid was then removed in vacuo. The crude material was triturated in isopropyl alcohol, and filtered to give 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as a light yellow solid (10.422 g). MS(ESI+) 405.0/407.0
Reaction SMILES: [C:1]1([CH2:6][NH:7][C:8]([NH2:10])=[S:9])[S:5][CH:4]=[CH:3][CH:2]=1.[Br:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(O)C>[BrH:11].[C:1]1([CH2:6][NH:7][C:8]2[S:9][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)NCc1cccs1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: Br
Product: c1ccc(-c2csc(NCc3cccs3)n2)cc1
Yield: 78.1 %

Procedure:
N-thenylthiourea (2.0 grams, 0.0116 moles) and α-bromoacetophenone (2.3 grams, 0.0116 moles, Aldrich Chem. Co.) in 15 ml absolute ethanol were heated to reflux temperature for 90 minutes under nitrogen. The reaction mixture was cooled and the ethanol removed under vacuum. On dissolving the residue in hot isopropyl alcohol and diluting with diethyl ether, an oil was formed. The diethyl ether was decanted, the oil dissolved in a small amount of ethanol and cooled. The resulting solids were filtered and dried over phosphorus pentoxide, yielding 3.20 grams (78%) of 2-thenylamino-4-phenyl-thiazole hydrobromide, m.p. 115°-118° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:36])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-acetylphenyl isocyanate (196 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 278 mg (84.0%) of the desired product as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]1([C:22]2[C:31]([OH:32])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:32][C:31]1[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccccc2nc1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccccc3)c2cc1OC
Temperature: 145 °C
Reaction time: 7 h
Yield: 67.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (222 mg), 2-phenylquinolin-3-ol (107 mg), and 4-dimethylaminopyridine (340 mg) were suspended in o-dichlorobenzene (11 ml), and the suspension was stirred at 145° C. for 7 hr. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (134 mg, yield 68%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH2:19][OH:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([N:21](S(C3SC(Cl)=CC=3)(=O)=O)[S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48].[OH-].[Na+]>ClCCl.CO>[Cl:30][C:27]1[S:26][C:25]([S:22]([NH:21][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][OH:20])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:47](=[O:49])[CH3:48])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(hydroxymethyl)-1H-indazol-3-yl]-5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-2-thiophenesulfonamide (for a preparation see Intermediate 72) (53 mg, 0.082 mmol) was suspended in dichloromethane (0.5 mL) and triethylamine (0.115 mL, 0.823 mmol). Acetic anhydride (0.008 mL, 0.09 mmol) was added to the suspension and it stirred for 1 h. LCMS showed starting material remaining so dichloromethane (0.3 mL) and acetic anhydride (3.88 μL, 0.041 mmol) were added to the solution and stirred for 2 h. LCMS showed only a small amount of starting material remaining so the reaction mixture was concentrated in vacuo to leave an off-white residue, which was dissolved in methanol (3 mL) and treated with NaOH (1.546 mL, 3.09 mmol). The reaction was stirred at room temperature for 1 h and then was concentrated in vacuo, and acidified with 5% citric acid. The solution was extracted with ethyl acetate and the organic layer was washed twice with water (25 mL) and once with brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo. The yellow residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (17 mg, 43%) as a colourless glassy solid. LCMS (System A) RT=0.91 min, ES+ve m/z 505/507 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[N:13]1([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Nitrobenzoyl chloride (5 g, 27 mmol) in tetrahydrofuran (10 mL) was added slowly to a solution of morpholine (5 g, 88 mmol) and triethylamine (2.7 g, 27 mmol) in tetrahydrofuran (50 mL), and stirred at room temperature for four hours. Ethyl acetate (200 mL) was added to the mixture and the combined mixture was washed with water (25 mL), 1N HCl (25 mL), water (25 mL), saturated sodium bicarbonate (25 mL), water (25 mL) and brine (25 mL). The mixture was dried (Na2SO4), filtered and concentrated under vacuum and the residue used without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][CH3:8])=[O:6])[CH3:4].Br[CH:10]([CH3:14])[C:11]([OH:13])=[O:12].[OH-].[Na+]>O1CCOCC1.O>[C:5]([CH:3]([NH:2][C@H:10]([C:11]([OH:13])=[O:12])[CH3:14])[CH3:4])([O:7][CH3:8])=[O:6]
Reactant: CC(Br)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(C)N[C@@H](C)C(=O)O
Reaction time: 0.5 h

Procedure:
Neutralize a solution of 1.4 g of methyl L-alaninate HCl and 3.1 g of α-bromopropionic acid in a dioxane-water mixture to pH 9 with sodium hydroxide. Warm to 70° and hold for 30 minutes, keeping the pH at 8 to 9 by addition of sodium hydroxide as necessary. Cool, apply to a column of Dowex 50 (H+) ion exchange resin, wash with water, and elute with 2% pyridine in water. Combine the product fractions and freeze dry. Purify this crude by chromatography on an ion-exchange column of Dowex 50 (Na+) in 0.5M sodium citrate buffer pH 3.3. Collect the product fractions, concentrate to a small volume in vacuo, and repeat the Dowex 50 (H+) chromatography. Freeze dry the product fractions to obtain the pure N-(1-carbomethoxyethyl)-alanine.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(#N)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].P([O-])(O)(O)=O.[Na+]>[Cu](I)I.C(N(CC)CC)C>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)o1

Procedure:
A solution of 5 g of the product of Stage A, 15 ml of acetonitrile, 15 ml of triethylamine, 4.5 ml of ethynyltrimethylsilane, 170 mg of (triphenylphosphine)palladium chloride and 30 mg of copper iodide was heated at 40° C. for 2 and a half hours and then allowed to return to room temperature and was poured into an aqueous sodium dihydrogenphosphate solution. The mixture was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was evaporated to obtain after chromatography on silica (eluent: 95/5 hexane/ethyl acetate) 4.75 g of the expected product.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:3].C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:3][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:1]
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CNCCN1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-(1-methylethyl)-4-((2R)-2-piperazinylmethyl)-2-piperazinone (0.161 g, 0.670 mmol, Example 184) and triethylamine (0.290 mL, 2.083 mmol) in dichloromethane (5.82 mL) was added a solution of 2-thiophenesulfonyl chloride (0.138 g, 0.756 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (1 mL) drop-wise at room temperature. The solution was stirred for 30 min and then the mixture was concentrated. The residue was re-dissolved in CH2Cl2 and washed with water followed by brine. The organic layer was dried (Na2SO4), filtered, and concentrated to give 3-(1-methylethyl)-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-2-piperazinone (242 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:36]([O:43][CH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53]Br)=[CH:49][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([O:43][CH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:49][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: BrCc1ccc(CCCOCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCOCc2ccccc2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.08 g (3.38 mmol) di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate in tetrahydrofuran (18 mL) at −78° C., lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1.0 M in tetrahydrofuran, 6.20 mL) was added dropwise. The solution was stirred for 2 h, then 1-[3-(benzyloxy)propyl]-4-(bromomethyl)benzene (1.01 g, 2.82 mmol) dissolved in 5 mL tetrahydrofuran were added slowly. The reaction was stirred for additional 2 h and then quenched by the addition of 10 mL of 2 N aqueous hydrogen chloride. The mixture was warmed to room temperature poured into 10 mL 1 N aqueous hydrogen chloride and extracted with dichloromethane (3×30 mL). The organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27].CCOC(C)=O>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine (0.3 g, 0.89 mmol), and ethylene diamine (0.6 mL, 8.93 mmol) in dry NMP (3 mL) at 100° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extracte twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:14](O)[CH3:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:14][CH3:15])=[O:6]
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.4 %

Procedure:
A mixture of 4-oxo-4-phenylbutanoic acid (5.00 g), ethanol (2.59 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.46 g), and 4-(dimethylamino)pyridine (171 mg) in N,N-dimethylformamide (25 mL) was stirred for 1.5 hours at room temperature. The mixture was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (75 mL), and the organic layer was washed with water (75×3 mL), saturated sodium bicarbonate (75 mL), and brine (75 mL), dried over magnesium sulfate, and evaporated to give ethyl 4-oxo-4-phenylbutanoate as a colorless oil (4.19 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.I[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.N>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(I)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62, starting with 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and reacting with 1-iodo-4-fluorobenzene (yield: 0.0881 g, 78%). mp 175-177° C. 1H NMR (300 MHz, DMSO d6) δ 3.27-3.36 (3H, obstructed by H2O), 3.88 (bs, 2H), 6.98-7.09 (m, 4H), 7.34 (m, 2H), 7.65 (m, 2H), 7.71 (m, 2H), 8.06 (m, 3H). MS (DCI/NH3) m/z 453 (M+H)+, 470 (M+NH4)+. Anal. calc. for C24H18F2N2O3S: C, 63.71; H, 4.01; N, 6.19. Found: C, 63.61; H, 4.26; N, 6.03.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-n2cncn2)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of N-(3-bromo-5-nitrophenyl)acetamide (5 g, 19.3 mmol) in DMF (50 ml) were added 1,2,4-triazole (3.3 g, 48.25 mmol, 2.5 eq.), copper(I) oxide (0.56 g, 3.86 mmol, 0.2 eq.) and cesium carbonate (12.5 g, 38.6 mmol, 2 eq.) and the mixture was heated at 90° C. for 48 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 86% yield (4.1 g). LC-MS (ESI): Calculated mass: 247.21; Observed mass: 248.0 [M+H]+ (rt: 0.257 min).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.S(=O)(=O)(O)O>O1CCCC1>[C:8]1([CH2:7][O:6][CH2:5][CH:4]=[O:3])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COCc1ccccc1)OCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=CCOCc1ccccc1
Temperature: 25 °C

Procedure:
A stirring mixture of 100 g of benzyloxyacetaldehyde diethyl acetal, 500 ml of tetrahydrofuran and 400 ml of 2N sulfuric acid is heated at reflux temperature for 45 minutes. The resulting solution is cooled to room temperature, concentrated in vacuo to 400 ml volume and diluted with 1000 ml of chloroform. The organic layer is washed with water, cold saturated sodium bicarbonate, saturated sodium chloride and dried. The filtrate is evaporated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100° C.) to give 59.0 g of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])(O)[CH2:4][CH2:3]1.CC[N:28]([CH:32]([CH3:34])C)[CH:29]([CH3:31])C.[OH:35][CH2:36][CH2:37]C1CCNC1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:28]4[CH2:29][CH2:31][CH:34]([CH:36]([OH:35])[CH3:37])[CH2:32]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:4][CH2:3]1
Reactant: OCCC1CCNC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: CC(O)C1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-hydroxyethyl-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.62 (m, 1H), 3.71-3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.30 (m, 2H), 1.13 (m, 3H). m/z: 452 [M+H]
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25]C)=[C:17]2[C:27](=[O:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=[O:30])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:28]2[C:27](=[O:39])[C:17]3[C:16](=[C:15]([O:14][CH3:1])[C:24]4[N:23]=[CH:22][CH:21]=[N:20][C:19]=4[C:18]=3[OH:25])[C:29]2=[O:30])=[CH:37][CH:36]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
Into a flask containing 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 246 (10 mg, 0.019 mmol, 1 equiv.) was added CH2Cl2 (1 mL) and under a nitrogen atmosphere was added triethylsilane (200 μL) followed by trifluoroacetic acid (200 μL). The reaction was allowed to stir for 1.5 hours and concentrated in vacuo until thoroughly dried. To the oil was added Hexanes/Ethyl ether (20 mL, 1/1 ratio) and sonicated. The resulting solid was filtered, washed in hexanes and air dried to give 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 249 (67%, 4.6 mg, 0.015 mmol). 1H NMR (300 MHz) CDCl3 δ 9.07 (d, J=1.8 Hz, 1 H), 8.97 (d, J=1.8 Hz, 1 H), 7.23-7.27 (m, 2 H), 6.96-7.05 (s, 2 H), 4.87 (s, 2 H), 4.46 (s, 3 H). 19F NMR (300 MHz) CDCl3 δ 62.77 MS: 354.0 (M+1)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)C(C)C)(C)C.[C:20](OC([O-])=O)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>ClCCl.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
26.25 g of 3-Bromobenzylamine hydrochloride was suspended in 250 ml of dichloromethane, and the mixture was cooled to 0° C. 33.5 g of N,N-diisopropylethylamine and 28.3 g of t-butyl dicarbonate were added. After stirring was continued at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off, to give 31.28 g of the title compound.