Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:30][C@H:27]1[CH2:26][CH2:25][C@@H:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:29][CH2:28]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@H]1CC[C@@H](C(=O)OCC)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with cis-4-amino-cyclohexanecarboxylic acid ethyl ester following general procedure B to afford 8-methoxy-4-(cis-4-ethoxycarbonyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (198 mg). Thus obtained amino-ester (175 mg, 0.44 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish cis-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-cyclohexane-carboxylic acid ethyl ester (138 mg). LCMS: m/z 508[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Br:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)=[O:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[Br:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:3]2[C:2]=1[NH:1][C:17](=[O:19])[N:6]([CH:7]1[CH2:8][CH2:9][CH2:10]1)[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Br)cccc1C(=O)NC1CCC1
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 326.4 %

Procedure:
A mixture of 2-amino-3-bromo-N-cyclobutylbenzamide (2.127 g, 7.90 mmol) and triphosgene (0.797 g, 2.69 mmol) in DCM (80 mL) was heated at reflux (using a water-cooled reflux condenser) for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was taken up in toluene (80 mL) and heated at 110° C. for 1.5 h. Additional triphosgene (0.040 g, 014 mmol) was added, and the resulting solution was stirred at 110° C. for 45 min. The reaction mixture was then cooled to RT and concentrated in vacuo to give crude 8-bromo-3-cyclobutylquinazoline-2,4(1H,3H)-dione (2.59 g, 8.78 mmol) as a light-yellow solid. m/z (ESI, +ve) 295.0/297.0 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]=[O:19])=[CH:13][CH:12]=2)[N:8]=1)=[O:2].[Cl:20]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:20][C:6]1[S:5][C:4]([NH:3][CH:1]=[O:2])=[N:8][C:7]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]=[O:19])=[CH:13][CH:12]=1
Reactant: O=CNc1ccc(SCc2csc(NC=O)n2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=CNc1ccc(SCc2nc(NC=O)sc2Cl)cc1
Temperature: 50 °C
Yield: 61.2 %

Procedure:
To a solution of 2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (2.9 g) in acetic acid (30 ml) was portionwise added N-chlorosuccinimide at 50° C. with stirring. The mixture was heated at 50° C. with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1), washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 5-chloro-2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (2.0 g, yield: 61.2%). mp: 130°-150° C. (dec.) IR (Nujol): 3350, 3200, 1710, 1690-1640, 1590 cm-1
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=O.[CH3:24][NH:25][C:26]([NH2:28])=[S:27].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:23][N:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]1[N:28]=[C:26]([NH:25][CH3:24])[S:27][CH:2]=1)=[CH:13]2)[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: CN(c1cccc2cc(C(=O)CCl)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CNC(N)=S
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CNc1nc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)cs1
Yield: 76.6 %

Procedure:
A mixed solution of N-[2-(2-chloroacetyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (100 mg), N-methylthiourea (30 mg) and N,N-dimethylacetamide (6 ml) was stirred at 60° C. for 5 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3-1:1), and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (84 mg, yield 77%) as pale-yellow prism crystals. melting point 162-163° C. MS:405 (MH+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]4=[N:23][N:24]([CH3:26])[CH:25]=[C:18]34)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]4=[N:23][N:24]([CH3:26])[CH:25]=[C:18]34)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc2c(n1)CCCN2c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc2c(n1)CCCN2c1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 180 μmol) in CH2Cl2 (4 mL) was added TFA (740 mg, 500 μL, 6.49 mmol). After 24 h, the mixture was concentrated in vacuo and the residue was re-dissolved in 5 mL of a mixture of (CH2Cl2/methanol/ammonium hydroxide; 60:10:1) and the mixture stirred at room temperature for 24 h, then evaporated to a yellow solid, which was purified by chromatography (spherical silica 20-45 m, 23 g, Versaflash Supelco, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 30 min) to give a residue that was dissolved in CH2Cl2 then precipitated with cyclohexane. The yellow solid was obtained by decanting the mother liquor and dried under high vacuum to give N-tert-butyl-2-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 36%). 1H NMR (CHLOROFORM-d) δ: 9.46 (br. s., 1H), 8.08-8.21 (m, 2H), 7.97 (br. s., 1H), 7.82 (s, 1H), 3.88 (m, 5H), 2.89 (t, J=6.2 Hz, 2H), 2.14-2.28 (m, 2H), 1.56 (s, 9H). MS (EI/CI) m/z: 354.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=CC=1.C(N(CC)CC)C>C(O)CC>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([C:14]2[S:17][CH:11]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Sc1ccccc1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Nc1cc(-c2cccs2)nc(N)[n+]1[O-]
Yield: 51.7 %

Procedure:
5 g of 2,4-diamino-6-chloropyrimidine 3-oxide, 6.85 g of thiophenol and 11.5 g of triethylamine are placed in 110 ml of n-propanol. The reaction mixture is heated at reflux for 24 hours. It is evaporated to dryness. The residue is taken up in 25 ml of ethyl ether, stirred for 1/2 an hour, filtered on sintered glass and rinsed with 2×25 ml of ethyl ether. The precipitate is taken up in 75 ml of water. The pH is adjusted to 1 with concentrated hydrochloric acid. After stirring for 1/2 an hour, the pH is returned to 8 by addition of concentrated sodium hydroxide solution. The precipitate is filtered, rinsed with 10 ml of water and then recrystallized twice from a 75/25 ethanol/water mixture. 3.35 g of 2,4-diamino-6-thiophenylpyrimidine 3-oxide are obtained.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].[OH:10]O>C(O)(=O)C>[CH3:9][C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][N+:1]=1[O-:10]
Reactant: Cc1cnc(C)c(C)c1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(C)c(C)[n+]([O-])c1
Temperature: 90 °C

Procedure:
To a stirred mixture of 2,3,5-collidine (10 g, 82.5 mmol) and glacial acetic acid (40 mL) was added hydrogen peroxide (30% solution, 20 mL, dropwise) at 65° C. The bath was heated to 90° C. for 1 hour, cooled to 65° C. and additional hydrogen peroxide (30% solution, 10 mL, dropwise) was added. The reaction mixture was heated at 90° C. until completion and cooled to ambient temperature. The solvent was removed under reduced pressure and the crude residue was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:33]1[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)=[O:6]
Reactant: COc1ccc(CN)cc1
Reactant: Nc1ncccc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cccnc2N)cc1
Yield: 100 %

Procedure:
2-Aminonicotinic acid (7.15 g) was suspended in N,N-dimethylformamide (100 ml) and 4-methoxybenzylamine (8.12 ml), diethyl cyanophosphonate (9.92 ml) and triethylamine (8.66 ml) were added sequentially with stirring and cooling on ice. The reaction mixture was stirred at room temperature for 15.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4) and then the solvent was distilled off under reduced pressure to give the title compound (15.9 g, about 100%). Recrystallization from ethyl acetate-ethyl ether yielded a colorless crystal, melting point 165 to 166° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:10](=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:33](CC1C=CC=CC=1)[CH:34]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=1)[CH:35]=[O:36])C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:10](=[O:25])[C@@H:9]1[C@@H:35]([OH:36])[C@@H:34]([NH2:33])[CH2:37][C:38]1[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: O=CC(Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Product: CC(C)CCc1ccccc1N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C1=O

Procedure:
The title is prepared by reacting 4-[2-(3-methyl-butyl)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester with 2-(dibenzylamino)-3-(3,5-difluorophenyl)-propanal essentially as described in Preparation 41.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[N:5][NH:4]1)[CH3:2].[C:18]1([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:25]3[CH:26]=[N:27][O:28][C:24]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:6]=[N:5][NH:4]1)[CH3:2]
Reactant: O=C(O)CCCc1cnoc1-c1ccccc1
Reactant: CCN1NN=CC1CCOc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN1NN=CC1CCOc1ccc(NC(=O)CCCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (0.51 g), 4-(5-phenyl-4-isoxazolyl)butanoic acid (0.51 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.40 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide (0.83 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 125–126° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CN(C)C=O.[H-].[Na+].Cl[CH:14]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:15]1[CH:16]=[CH:17][C:18]2[N:22]=[N:21][N:20]([CH3:23])[C:19]=2[CH:24]=1>O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:14]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[N:21][N:20]([CH3:23])[C:19]=3[CH:24]=2)=[CH:26][CH:27]=1
Reactant: c1nc[nH]n1
Reactant: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc2ccc(C(c3ccc(Cl)cc3)n3cncn3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a stirred solution of 28.4 parts of 1H-1,2,4-triazole in 135 parts of N,N-dimethylformamide were added 11.4 parts of a sodium hydride dispersion 80% under nitrogen atmosphere. After stirring for 1 hour at room temperature, a solution of 40 parts of 6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole in 90 parts of N,N-dimethylformamide was added to the mixture. The whole was stirred for 1 hour at 60° C. The reaction mixture was diluted with 50 parts of water and the whole was evaporated. The residue was extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 13 parts (29.2%) of 6-[(4-chlorophenyl)-(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole; mp. 178.9° C. (compound 64).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])([C:32]#[N:33])[C:30]#[N:31].[OH-].[Na+]>ClCCl>[O:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH2:34][CH2:35][C:36]([F:37])([F:38])[F:39])([C:32]#[N:33])[C:30]#[N:31]
Reactant: N#CC(C#N)(CCCCCO)CCC(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CC(C#N)(CCCCC=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
20 ml of a 15% solution of Dess-Martin periodinane=1,1,1-tris(acetyloxy)-1,1-di-hydro-1,2-benziodoxol-3-(1H)-one in dichloromethane was added dropwise to 1.5 g of 2-(5-hydroxypentyl)-2-(3,3,3-trifluoropropyl)malononitrile, and the mixture was stirred at room temperature for 5 hours. Thereafter, the reaction mixture was added to an aqueous dilute sodium hydroxide solution and then extracted with chloroform. The organic layer was washed successively with water and aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.0 g of 2-(5-oxopentyl)-2-(3,3,3-trifluoropropyl)malononitrile.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:7]=1[NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12]>[Fe].C(OCC)(=O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:6]([F:5])=[C:7]([CH:14]=1)[NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1cc(N)ccc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A mixture of 39.4 g (706 mmol) of iron powder and 75 ml of an aqueous solution of 5% acetic acid was heated to 80° C., and a mixed solution of 16.1 g (70.6 mmol) of ethyl 2-fluoro-5-nitrocarbanilate, 72 ml of acetic acid and 72 ml of ethyl acetate was slowly added dropwise to the mixture. After the reaction was continued for 3 hours, the insolubles were filtered out and washed with ethyl acetate. Thereafter the filtrate was distilled to remove the solvent, and the resultant product was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate, water and saturated saline solution. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 12.8 g of the objective product (yield: 91%) in the form of light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([O:27][CH2:28][CH3:29])[N:18]=1.Cl>C(O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:19]1[N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=1)[CH3:29]
Reactant: CCOc1cc(C(C)(C)O)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(C)(C)O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 10.4 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (102 mg, 0.5 mmol), 2-(2-chloro-6-ethoxy-pyrimidin-4-yl)-propan-2-ol (108 mg, 0.5 mmol) and 1 N aqueous hydrochloric acid (0.025 mL) in ethanol (0.8 mL) was heated in a sealed tube in a microwave oven to 170° C. for 45 min. The mixture was cooled, diluted with ethyl acetate (50 mL), and then washed with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% ethanol as eluent to give the title compound (20 mg, 10%) as yellow foam. MS ISP (m/e): 384.3 [(M+H)+].)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.20, 7.78, 7.75 and 7.63 (4 d, 4×2H), 7.31 (s, 2H), 7.16 (s, 1H), 3.93 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:17])=[O:7])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC
Yield: 311 %

Procedure:
A solution of 2-ethoxy-4-nitrobenzoic acid (2.035 g, 9.45 mmol, Aldrich) in methanol (40 ml) was treated with p-toluenesulfonic acid monohydrate (583.3 mg, 3.07 mmol) and heated at reflux under argon for 17 hrs. The solvent was removed and the residue was dissolved in ethyl acetate, washed with saturated Na2CO3, water and saturated NaCl and dried over Na2SO4, filtered and concentrated to give methyl 2-ethoxy-4-nitrobenzoate (2.15 g, 101%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:18]=[C:19]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[N:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[C:21]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:49]=2)C=CC=1OC)C1C=CC=CC=1>O=P(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:18]=[C:19]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:49])[C:21]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(C3CCC3)n3ccnc(Cl)c23)cc1OCc1ccccc1
Reactant: COc1ccc(C(NC(=O)C2CCC2)c2nccnc2Cl)cc1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc(C3CCC3)n3ccnc(N)c23)cc1OCc1ccccc1
Temperature: 55 °C
Yield: 87 %

Procedure:
1-(3-Benzyloxy-4-methoxyphenyl)-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine: Cyclobutanecarboxylic acid [(3-benzyloxy-4-methoxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-amide (308 mg, 0.703 mmol) was dissolved in POCl3 (5 ml) and heated at 55° C. for 17 h. After that time, the excess POCl3 was removed in vacuo and the remaining mixture was basified with NH3 (2 N in iPrOH). The precipitate formed was filtered off and washed with CH2Cl2, and the filtrate was purified by chromatography on silica gel to obtain a yellow-brown solid of the title compound (87% purity by LC-MS); 1H NMR (DMSO-d6, 400 MHz) δ 2.03-2.20 (m, 2H), 2.47-2.67 (m, 4H), 3.95 (s, 3H), 5.22 (s, 2H), 7.00 (d, 1H, J=8.0 Hz), 7.25-7.47 (m, 8H); MS (ES): 420.0/422.1 (M/M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([OH:20])[C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:10])=[CH:5][CH:4]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:38]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[O:20][C@H:11]([C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C@@H:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[CH3:10])([CH3:40])[CH3:39]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: C=C[C@H](CCC(C)C)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=C[C@H](CCC(C)C)[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To an ice-cooled solution of (2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol (3.70 g, 12.07 mmol) in anhydrous CH2Cl2 (60.4 ml) were added 2,6-dimethylpyridine (1.97 ml, 16.9 mmol) and triisopropylsilyl trifluoromethanesulfonate (3.89 ml, 14.5 mmol), and the mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate (NaHCO3) solution and mixed thoroughly. The phases were separated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (gradient, hexanes/ethyl acetate) to furnish the title product as a colorless oil (4.76 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.19 (m, 2H), 6.88-6.81 (m, 2H), 5.63-5.50 (m, 1H), 5.05-4.89 (m, 2H), 4.51-4.29 (m, 2H), 3.84 (dd, J=6.6, 3.0 Hz, 1H), 3.79 (s, 3H), 3.55-3.46 (m, 1H), 2.11-1.98 (m, 1H), 1.75-1.61 (m, 1H), 1.56-1.41 (m, 1H), 1.24-1.17 (m, 1H), 1.15 (d, J=6.2 Hz, 3H), 1.13-0.97 (m, 20H), 0.85 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.88, 139.86, 131.19, 129.19, 115.64, 113.50, 78.34, 76.39, 70.08, 55.24, 49.46, 36.94, 28.35, 28.23, 22.83, 22.51, 18.43, 18.41, 13.71, 13.18; ESIMS m/z 485.4 ([M+Na]+).