Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH2:15][NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CCOC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCNCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Ethyl 4-aminobutanoate hydrochloride (1.77 g) and 2,4-dimethoxybenzaldehyde (1.75 g) were dissolved in ethanol (50 ml), and the solution was heated under reflux for 1 hr. The mixture was allowed to be cooled to room temperature, sodium triacetoxyborohydride (2.2 g) was added thereto, and the mixture was stirred for 1 hr, and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (40 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.77 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32](Cl)=[O:33].C[CH2:36][N:37](CC)[CH2:38]C.N(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:32](=[O:33])[CH2:31][N:37]([CH3:38])[CH3:36])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: CCN(CC)CC
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
To a solution of 4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in CH2Cl2 (2 mL) was added 2-chloroacetyl chloride (29 μL, 0.36 mmol) and Et3N (0.1 mL, 0.7 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. After the solvent was removed, the residue was dissolved in DMF. To the DMF solution was added (CH3)2NH (64 μL, 1.2 mmol) and K2CO3 (166 mg, 1.2 mmol). The reaction mixture was heated to 70° C. and stirred at 70° C. until the reaction was complete. After it was cooled, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(2-(2-(dimethylamino)acetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (58 mg, 51%) as a yellow foam. The free base was converted to the HCl salt to give the title compound (31 mg, 50%) as a yellow solid and as a mixture of rotamers: mp 135-140° C.; 1H NMR (500 MHz, CD3OD) δ 7.75-7.71 (m, 1H), 7.59-7.55 (m, 1H), 7.49-7.37 (m, 6H), 7.05-7.01 (m, 1H), 6.49-6.45 (m, 1H), 6.28-6.26 (m, 1H), 5.24 (s, 2H), 4.87 (br s, 1H), 4.69 (br s, 1H), 4.44-4.41 (m, 2H), 4.11-4.07 (m, 1H), 3.85-3.82 (m, 1H), 3.70 (2×s, 3H), 3.06-2.92 (m, 2H), 2.97-2.94 (2×s, 6H); ESI MS m/z 471 [M+H]+; HPLC (Method B) 97.0% (AUC), tR=13.2 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:27](=[O:29])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[Na+].BrBr>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:11][C:10]=1[C:27]([OH:29])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 78.8 %

Procedure:
1-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-ethanone [prepared as per WO 2004/072051] (2.02 g, 5.2 mmol) was dissolved in 1,4-dioxane (30 ml), a solution of sodium hydroxide (2.08 g, 52.0 mmol) in water (30 ml) was added and the mixture was stirred and treated dropwise with bromine (0.8 ml, 15.6 mmol). The resulting mixture was stirred at room temperature for 16 hours. The 1,4-dioxane was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 30% ethyl acetate in petroleum ether afforded 2,4-bis-benzyloxy-5-tert-butyl-benzoic acid (1.6 g, 79%) as a pale yellow oil. 1H NMR (DMSO-d6) 12.18 (1H, br s), 7.69 (1H, s), 7.52 (4H, t), 7.45-7.33 (6H, m), 6.93 (1H, s), 5.24 (2H, s), 5.23 (2H, s), 1.32 (9H, s). MS: [M+H]+ 391.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=2[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.[CH3:32][N:33]1[C:37]2[CH:38]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:40]=[CH:41][C:36]=2[NH:35][C:34]1=[O:51].[Li+].[Cl-].O>O1CCOCC1.C(OCC)(=O)C>[Cl:31][C:29]1[CH:28]=[CH:27][C:4]2[N:5]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=[C:2]([C:39]3[CH:40]=[CH:41][C:36]4[NH:35][C:34](=[O:51])[N:33]([CH3:32])[C:37]=4[CH:38]=3)[C:3]=2[CH:30]=1
Reactant: Cn1c(=O)[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(C)c4c3)c3cc(Cl)ccc32)cc1
Temperature: 100 °C
Yield: 77.4 %

Procedure:
5,7-Dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.416 g, 0.878 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.241 g, 0.878 mmol) were dissolved in 1,4-dioxane (5 mL) and LiCl (0.112 g, 2.63 mmol), and then CsOH (0.442 g, 2.63 mmol) was added followed by water (0.5 mL). The mixture was purged with nitrogen, then [tetrakis(triphenylphosphine)]palladium(0) (0.1 g, 0.088 mmol) was added and the flask was lowered into an 80° C. oil bath and heated at 100° C. for 5.5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed twice with water then once with brine. The organic layer was dried over MgSO4, then filtered and concentrated onto silica gel. Chromatography eluting with 50-100% ethyl acetate in hexanes gave 7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.4 g, 0.68 mmol) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCI
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, n-pentyl iodide 0.79 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 15 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.97 g.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1N(C)CCN1C.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl.C1C[O:38]CC1>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[C:9]([CH:14]=[O:38])=[C:10]([B:25]([OH:26])[OH:24])[CH:11]=[CH:12][CH:13]=1
Reactant: C1CCOC1
Reactant: COc1ccccc1C1N(C)CCN1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(B(O)O)c1C=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of t-butyl lithium (9.0 mL, 1.7 M in pentane) was added to a stirred solution of 2-(2-methoxyphenyl)-1,3-dimethylimidazolidine (2.0 g, 9.8 mmol) in THF (5 mL) at −10° C. under N2 and stirred at 0-5° C. for 2 hours. The reaction mixture was cooled to −50° C. and triisopropylborate (3.5 mL, 15 mmol) was added. The solution was slowly warmed to 0° C. in 3 hrs. HCl (120 mL of 2N) was added at 0° C. and let it stirred for 30 min. The mixture was warmed to room temperature and was diluted with ethyl acetate. The organic layer was washed ( 2× HCl (1 N), brine), dried ( sodium sulfate) and concentrated to afford yellow crude product which purified by reverse phase HPLC chromatography. Upon removal of solvent 3-methoxy-2-formylphenylboronic acid crystallized as a light yellow solid, 1.3 g (yield 75%). ESI-MS m/e 177 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:14]([NH2:16])[CH3:15]>ClCCl>[CH2:14]([NH:16][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:15]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Alternatively, 2-chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) in anhydrous dichloromethane (250 mL) with Amberlyst A-21 ion-exchange resin (17 g) was treated with a 2M ThF solution of ethylamine (45 mL). The mixture was stirred at rt under nitrogen overnight. After filtration, the filtrate was concentrated to give N-ethyl-2-chloro-5-nitrobenzamide (9.0 g, 39 mmol, 86% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][S:10][C:9]1=[N:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-:17].[NH4+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][S:10][C:9]1=[N:13][C:14](=[O:17])[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#CN=C1SCCN1Cc1ccccc1
Agent: Cl
Agent: [NH4+]
Product: NC(=O)N=C1SCCN1Cc1ccccc1

Procedure:
6.36 g (50 moles) of 3-benzyl-2-cyanimino-thiazolidine are boiled with 80 ml of a 10% hydrochloric acid for 10 minutes. A clear solution is obtained, which is cooled down and alkalized with a 25% aqueous ammonium hydroxide solution to yield 5.65 g of 3-benzyl-2-carbamoylimino-thiazolidine, melting at 143° to 145° C. After crystallization from ethanol the melting point is raised to 148° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[H][H].[Cl:12][CH2:13][CH:14]=[CH2:15]>O>[Cl:12][CH2:13][CH:14]=[CH:15][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7]
Reactant: [H][H]
Reactant: C=CCCl
Reactant: OCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: OCCCCCOC=CCCl
Temperature: 60 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
In a reaction vessel containing 10.42 g of 1,5-pentanediol was put 2.20 g of 60% sodium hydride (in oil), and the mixture was stirred until the evolution of hydrogen gas ceased, to which 3.83 g of 3-chloro-1-propene was added dropwise under ice cooling. The reaction mixture was slowly warmed and stirred at 60° C. for 3 hours, which was then poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 1.50 g of 5-(3-chloro-1-propenyloxy)pentanol (yield, 21%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:27])=O)C.C([NH:30][CH2:31][CH2:32][NH:33][CH2:34][CH3:35])C.[CH2:36](O)[CH3:37]>>[CH2:36]([N:33]([CH2:34][CH3:35])[CH2:32][CH2:31][NH:30][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:27])=[O:3])[CH3:37]
Reactant: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O
Reactant: CCNCCNCC
Reactant: CCO
Product: CCN(CC)CCNC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
To 1.0 g. (0.0027 mole) of 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared as in Example 9) was added to 0.63 g. (0.0054 mole) of diethylethylenediamine in 25 ml. of ethanol. This mixture was heated at reflux for 3.5 hours. Then ice-chilling caused the formation of a white solid that was filtered off and re-crystallized from ethanol to give 0.9 g. of product with a m.p. 115°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>O1CCOCC1>[CH2:11]([N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[C:2]([Br:1])[CH:3]=[CH:4]2)=[N:8]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Brc1ccc2cn(Cc3ccccc3)nc2c1
Reaction time: 0.33 h

Procedure:
6-Bromoindazole (3.63 g, 18 mmol) was suspended in dioxane (15 mL) and benzyl bromide (2.65 mL, 22 mmol, 1.2 eq.) was added. The reaction was heated to reflux overnight, then allowed to cool to 80° C. after which point ethyl acetate (50 mL) added. The cake was broken up with a spatula and after stirring for 20 min, the solids were filtered off and washed with ethyl acetate, giving glossy white crystals of the hydrobromide salt of 2-benzyl-6-bromoindazole. These were suspended in ethyl acetate (100 mL) and shaken with saturated NaHCO3 (150 mL) until dissolution. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were concentrated to an off-white powder which was recrystallized from 66% ethanol (40 mL). Washing with water and drying in vacuo gave 2-benzyl-6-bromoindazole (3.30 g, 62%) as shiny white plates.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 87.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2CO3 (5.2 g, 0.04 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]-ethanone (6.6 g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for 5hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent was concentrated to yield initially an oil, which solidified upon standing. The solid was triturated with hexane and collected to afford 7.7 g of the product as a waxy solid. The compound was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with dichloromethane/methanol (5%). Concentration of the appropriate fractions yielded 5.1 g of off-white solid 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone, which when recrystallized from ethyl alcohol yielded 3.2 g (36%) of feathery-white needles, m.p.=88°-90° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([NH2:12])[CH2:11][CH2:10][CH2:9]1>O>[CH:8]1([NH:12][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][CH2:2]2)[CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cnccn1
Reactant: NC1CCC1
Solvent: O
Product: C1=CN(NC2CCC2)CC=N1
Temperature: 110 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 2-chloropyrazine (26.12 g, 228.0 mmol) and cyclobutylamine (40.00 mL, 468.5 mmol) was heated in a pressure reaction flask with stirring to 110° C. for 16 hours. The brown reaction was allowed to cool to room temperature and was diluted with water (750 mL). The aqueous solution was extracted with ethyl acetate (2×250 mL). The combined organic solutions were washed with water (1×250 mL), saturated NaHCO3 (1×250 mL) and brine (2×250 mL). The organic solution was dried (MgSO4), filtered, and concentrated. The crude product was purified by MPLC (20% ethyl acetate-40% ethyl acetate/hexanes) to afford N-cyclobutylaminopyrazine (EX-115A) in 93% yield: 1H NMR (300 MHz, DMSO) δ 7.97–7.96 (m, 1H) 7.82–7.79 (m, 2H), 5.12 (br s, 1H), 4304.18 (m, 1H), 251–239 (m, 2H), 1.97–1.73 (m, 4H); 13C NMR (75 MHz, DMSO) δ 149.3, 137.6, 128.3, 126.9, 42.2, 26.7, 10.7; HRMS (ES) calcd for C8H12N3 150.1031, found 150.0992.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:18][CH3:19])=[N:6][C:7]2[N:8]([CH:11]=[C:12]([C:14]([NH:16][NH2:17])=[O:15])[N:13]=2)[C:9]=1[CH3:10])[CH:2]=[CH2:3].[C:20](OCC)(OCC)(OCC)[CH3:21]>>[CH2:1]([C:4]1[C:5]([O:18][CH3:19])=[N:6][C:7]2[N:8]([CH:11]=[C:12]([C:14]3[O:15][C:20]([CH3:21])=[N:17][N:16]=3)[N:13]=2)[C:9]=1[CH3:10])[CH:2]=[CH2:3]
Reactant: CCOC(C)(OCC)OCC
Reactant: C=CCc1c(OC)nc2nc(C(=O)NN)cn2c1C
Product: C=CCc1c(OC)nc2nc(-c3nnc(C)o3)cn2c1C

Procedure:
A mixture of 3.58 g of 6-allyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbohydrazide and 25 cm3of triethyl orthoacetate was heated at 150°-180° C. for 16 hours. The mixture was then cooled and evaporated to dryness and the resulting crude product purified by flash chromatography to obtain 1.47 g of 6-allyl-7-methoxy-5-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.C1(N)CCCCC1>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: NC1CCCCC1
Solvent: CC(C)O
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 46 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-chloro-2'-nitro-4-biphenylyl)-4-oxo-butyric acid. Yield: 46% of theory. Melting point of the cyclohexylamine salt: 171°-172° C. (from isopropanol).
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][CH:6]=[CH:5][N:4]=1)=O.Cl.[C:15]([NH:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[C:15]([N:19]1[C:9](=[O:11])[C:8]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[CH:1]=[N:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1cccnc1C=O
Reactant: CC(C)(C)NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2ncccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In acetic acid-water (1:1) (5 ml) was dissolved ethyl 2-formyl-3-pyridinecarboxylate (1.3 g) followed by addition of t-butylhydrazine hydrochloride (1.8 g), and the mixture was refluxed with stirring for 1 hour. This reaction mixture was cooled to room temperature, adjusted to pH 5.0 with saturated aqueous NaHCO3 solution, and extracted with dichloromethane. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in acetic acid (2 ml) and refluxed for 1 hour. This reaction mixture was cooled, adjusted to pH 5.0 with saturated aqueous NaHCO3 solution, and extracted with dichloromethane. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate =1:1). White powder, 1.2 g. 1H-NMR (CDCl3) δ: 1.73(9H,s), 7.64(1H,dd,J=8.2&4.4Hz), 8.38(1H,s), 8.69(1H,d,J=8.2Hz), 9.03(1H,d,J=4.4Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:13].C([O-])(=O)C.C([O-])(=O)C.C1([I+2])C=CC=CC=1.FC(S(O)(=O)=O)(F)F>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]1[O:13][C:12]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:11][N:5]=1
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [I+2]c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2cnc(-c3c(Cl)cccc3Cl)o2)cc1

Procedure:
2,6-Dichlorobenzonitrile and 4-nitrophenyl methyl ketone can be reacted with phenyliodine (III) diacetate and trifluoromethylsulfonic acid by the method of R. S. Varma, et al, J. Heterocyclic Chem., 1998, 35(6), 1533-1534 to give 2-(2,6-dichlorophenyl)-5-(4-nitrophenyl)-1,3-oxazole. The nitrophenyl group can be reduced to the corresponding aniline with tin (II) dichloride or iron powder and ammonium chloride. Reaction of this aniline with 2,2-dichloroacetyl chloride and triethylamine can then give 2,2-dichloro-N-[4-[2-(2,6-dichlorophenyl)-5-(1,3-oxazolyl)]phenyl]acetamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN1CCCC1=O>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:7]=3)[N:9]=2)[NH:14][CH:15]=1)=[O:22]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccnc(Cl)c3)nc12
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccnc(N4CCCC4)c3)nc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of 1-[2-(2-chloro-pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.030 g, 0.095 mmol), 0.100 mL of pyrrolidine and 1.5 mL of N-methylpyrollidinone was stirred at 150° C. in a pressure tube for 3 h. The resulting black solution was partitioned between 30 mL of ethyl acetate and 40 mL of water. The organic layer was washed with three 30 mL portions of water, dried over MgSO4, filtered and concentrated to a residue. Silica gel chromatography (0->60% EtOAc/hexanes) afforded 0.020 g (61%) of 2,2-dimethyl-1-[2-(2-pyrrolidin-1-yl-pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow solid.