Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[C:35](Cl)(=[O:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:35]([O:23][C:6]1[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:10]([CH3:11])[C:5]=1[C:1]([CH3:3])([CH3:4])[CH3:2])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1c(OC2CCCCO2)cc(C(C)(C)C)c(O)c1C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Oc1c(C(C)(C)C)cc(OC2CCCCO2)c(C)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
2,6-Di-tert-butyl-3-methyl-4-tetrahydropyranyloxyphenol (4.4 g) was dissolved in anhydrous tetrahydrofuran (50 ml) and a n-hexane solution (1.1 eq.) of n-butyllithium was added dropwise at 0° C. under a nitrogen atmosphere. After stirring the mixture for 30 min, acetyl chloride (1.08 ml, 1.1 eq.) was added and the mixture was allowed to warm to room temperature. After stirring for 3 h, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the mixture was subjected to extraction with diethyl ether. The extract was washed with water and saturated brine, then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 1-acetoxy-2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxybenzene [4.09 g (yield, 82.2%)] as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[F:20]C1C=C(F)C=CC=1N>[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:20])[C:5]([Cl:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(F)ccc(Cl)c1F
Reactant: Nc1ccc(F)cc1F
Agent: [Pd]
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Yield: 94 %

Procedure:
A solution of 2,6-difluoro-5-chloronitrobenzene (2.0g., 1.03 × 10-2 mole) and triethylamine (2.1g., 2.06 × 10-2 mole) was hydrogenated over 10% palladium carbon catalyst for 18 minutes at room temperature and for an additional 4 hours at 60° C. The catalyst was removed by filtration and washed twice with methanol, using 16 ml. of each wash. The solvent was evaporated and the residue was treated with dichloromethane. The resulting mixture was washed with 15 ml. of water, 70 ml. of ammonium hydroxide solution and then 15 ml. of water, and dried over Na2SO4. Evaporation of the remaining solvent gave 1.25 g. of a yellow oil, a yield of 94%. Gas chromatography established the reaction product to contain 89.5% 2,4-difluoro-aniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Na].Cl[CH2:11][C:12]1[N:16]=[C:15]([CH2:17]Cl)[O:14][N:13]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][C:12]2[N:16]=[C:15]([CH2:17][S:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: ClCc1noc(CCl)n1
Agent: [Na]
Solvent: CCO
Product: Brc1ccc(SCc2noc(CSc3ccc(Br)cc3)n2)cc1

Procedure:
4-Bromobenzenethiol (3.78 g, 0.02 mol) was added to a solution of sodium (0.46 g, 0.02 mol) in ethanol (50 ml.) and 3,5-di-(chloromethyl)-1,2,4-oxadiazole (1.67 g, 0.01 mol) was added dropwise. The solution was then filtered and evaporated to give a solid which was recrystallised from isopropanol to give 3,5-di-(4-bromophenylthiomethyl)-1,2,4-oxadiazole, m.p. 80°.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([N:11]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:8][CH2:9][CH3:10]
Reactant: C=CC(=O)OC
Reactant: CCCCN
Product: CCCCN(CCC(=O)OC)CCC(=O)OC
Reaction time: 20 h
Yield: 99.6 %

Procedure:
At 20 to 30° C., 12.9 g of methyl acrylate was added to 5.00 g of n-butylamine. The resulting mixture was allowed to stand for 20 hours, followed by concentration under reduced pressure, whereby 16.7 g of N-butylbis[2-(methoxycarbonyl)ethyl]amine was obtained (at a quantitative yield).
Reaction SMILES: [K].[S:2]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[S:13])SC)([OH:5])(=[O:4])=[O:3].[N-:14]=[N+:15]=[N-:16].[Na+]>>[S:2]([CH2:6][CH2:7][CH2:8][N:9]1[C:10]([SH:13])=[N:16][N:15]=[N:14]1)([OH:5])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCS(=O)(=O)O
Agent: [K]
Agent: [Na+]
Product: O=S(=O)(O)CCCn1nnnc1S

Procedure:
Reaction of methyl 3-sulfopropyldithiocarbamate potassium salt with sodium azide as described in Example 7 gave 1-(3-sulfopropyl)tetrazole-5-thiol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C(COC)OC>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:11][C:2]3[N:3]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=3)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)Oc1cc(N)nc2cc(Cl)ccc12
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(cc(OC(C)C)c3ccc(Cl)cc32)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.9 g of 2-amino-7-chloro-4-isopropoxyquinoline were dissolved in 20 ml of dimethoxyethane and 1.9 g of ethyl bromopyruvate were added thereto followed by 800 mg of triethylamine. The mixture obtained was stirred at room temperature for 4 hours and then the solvent was evaporated under vacuum. The residue was dissolved in 100 ml of chloroform and the solution was dried over MgSO4 and was evaporated to dryness under vacuum. The residue was dissolved in 25 ml of ethanol and the solution was refluxed for 3 hours and then the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel-chloroform/methanol eluant) and then was crystallized from diethyl ether to obtain pale cream needles of ethyl 8-chloro-5-isopropoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 187°-189° C.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16]C)=[C:11]([F:18])[C:10]=2[CH3:19].CO>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([OH:16])=[C:11]([F:18])[C:10]=2[CH3:19]
Reactant: COc1cc2cc(Br)cnc2c(C)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1c(F)c(O)cc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Boron tribromide (80 ml of a 1M solution in CH2Cl2) was slowly added to a solution of 3-bromo-7-fluoro-6-methoxy-8-methyl-quinoline (5.40 g) in CH2Cl2 (300 ml) at 0° C., under an atmosphere of nitrogen. Upon warming to room temperature, the resulting brown mixture was stirred for 24 hrs and then treated with MeOH (100 ml), stirred for 1 hour and then concentrated under reduced pressure. The crude mixture was dissolved in ethyl acetate and washed with water, brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to obtain 3-bromo-7-fluoro-8-methyl-quinolin-6-ol as brown solid (5.01 g) which was used for the next step without any further purification. 1H NMR (DMSO-d6) δ ppm: 10.75 (1H, s); 8.75 (1H, d); 8.52 (1H, d); 7.18 (1H, d); 3.32 (3H, s); 2.56 (3H, d).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[Cl:12][CH:13]([CH2:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:21]([F:35])=[CH:20][C:19]=1[Cl:36])[C:14](Cl)=[O:15]>ClCCl>[Cl:12][CH:13]([CH2:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:21]([F:35])=[CH:20][C:19]=1[Cl:36])[C:14]([O:4][CH:2]([CH3:3])[CH3:1])=[O:15]
Reactant: O=C(Cl)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reactant: CC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reaction time: 1 h
Yield: 68.9 %

Procedure:
In 10 ml of dichloromethane were dissolved 0.18 g of 2-propanol and 0.25 g of triethylamine, and a solution of 1.00 g of 2-chloro-3-(2-chloro-4-fluoro-5-phthalimidophenyl)propionyl chloride prepared by the process described in Example 4 in 15 ml of dichloromethane was slowly added thereto dropwise under stirring. After the dropwise addition, the stirring was continued at room temperature for 1 hour. The reaction mixture was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:8) to give 0.73 g of the title compound (No. 7 of Table 1).
Reaction SMILES: [C:1]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[C:7]=2[CH:6]=[CH:5]1)(=[O:3])[CH3:2].CCN(CC)CC>[Pd].CCO>[NH2:14][CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=12
Reactant: CC(=O)n1ccc2c(C#N)ccnc21
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)n1ccc2c(CN)ccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.872 g, step D), 10% Pd/C (0.882 g), 20 mL of Et3N, and 80 mL of EtOH was stirred at RT under balloon pressure of H2 for overnight. Solid was removed by filtration through a pad of Celite® and the filtrate was concentrated to yield a cream color residue, which was purified by chromatography through silica gel (70 g, 2 to 5% MeOH/CHCl3 with 1% NH4OH) to afford 1-(4-aminomethyl-pyrrolo[2,3-b]pyridin-1-yl)-ethanone as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1.C(N(CC)CC)C.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[S:18]([O:1][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1)(=[O:19])=[O:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OC(=O)C=C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)C=C1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a −78° C. stirred solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (250 mg, 1.95 mmol) in 18 mL of anhydrous CH2Cl2, was added triethylamine (0.40 mL, 2.9 mmol) and Tf2O (0.49 mL, 2.9 mmol). The reaction was stirred at −78° C. for 30 minutes, and quenched with saturated NH4Cl solution (10 mL). The mixture was warmed up to room temperature and separated. The aqueous layer was extracted with CH2Cl2 (2×20 mL). All organic layers were combined, dried over Na2SO4 and evaporated to brown oil, which was purified by plugging through a short pad of silica gel column with EtOAc/hexanes (1/3). Evaporation of solvents gave 2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate as a light brown oil (450 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:4]2[C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[S:8][C:5]2=[N:6][CH:7]=1.CN(C)C1C=CC=CC=1.[F:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>ClCCl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=2[F:30])=[CH:7][N:6]=[C:5]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:4]=12
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 3-amino-4-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (150 mg) and N,N-dimethylaniline (0.065 ml) in dichloromethane (3 ml) was added dropwise 2,4-difluorobenzoyl chloride (0.07 ml) with ice-cooling. The mixture was stirred for 10 minutes with ice-cooling and then stirred at room temperature for 2 hours. Then, the mixture was washed in turn with water, aqueous saturated NaHCO3 solution and water, and dried over MgSO4. The solvent was distilled off to obtain 4-(2-chlorophenyl)-3-(2,4 -difluorobenzoylamino)-6,7-dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (206 mg, 93.6%) as crystals. The crystals were recrystallized from acetone to obtain colorless prisms, mp: 219°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]OC)[CH:9]=1.B(Cl)(Cl)[Cl:15].O>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][Cl:15])[CH:9]=1
Reactant: ClB(Cl)Cl
Reactant: COCc1csc(CC(=O)OC)c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1cc(CCl)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of (4-methoxymethyl-thiophen-2-yl)-acetic acid methyl ester (0.70 g, 3.50 mmol) in dichloromethane (20 mL) is treated with boron trichloride (3.50 mL, 1.0 M, 3.50 mmol) in a dropwise maner. After stirring at room temperature for 30 min the mixture is poured into water and extracted with dichloromethane (3×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is purified by chromatography (silica gel, 5-10% ethyl acetate in heptane) to give (4-chloromethyl-thiophen-2-yl)-acetic acid methyl ester (0.58 g, 81%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.18 (s, 1 H), 6.95 (s, 1 H), 4.52 (s, 2 H), 3.80 (s, 2 H), 3.72 (s, 3 H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[CH:28]=2)=[N:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[N:17][CH:18]=1>CCOCC>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C@:19]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[CH:28]=2)[CH2:2][C:1]#[N:3])=[N:17][CH:18]=1
Reactant: CC#N
Reactant: CC(C)(C)[S@](=O)N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[S@](=O)N[C@](CC#N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
At −78° C. in a 3 neck flask under argon atmosphere, anhydrous acetonitrile (0.150 g, 3.68 mmol) was added to dry ether (2 mL) followed by dropwise addition of LDA (1.84 mL, 3.68 mmol, 2.0M solution in cyclohexanes). The solution was stirred at −78° C. for 20 min. In a separate flask at 0° C. under argon, BF3Et2O (0.260 g, 0.19 mmol) was added to a solution of (S)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (0.750 g, 1.84 mmol) in dry ether (10 mL). The pre-complexed sulfinylimine solution was transferred to the anion solution via syringe dropwise at −78° C. After 30 min the orange solution was quenched by the addition of 1.0M HCl (ca. 10 mL) and the reaction mixture transferred to a separation funnel and extracted with EtOAc (3×20 mL). The combined organic portions were dried over Na2SO4, decanted, concentrated and the diastereomers purified by silica gel ISCO chromatography on 120 g column, 0-90% EtOAc/hexanes. (S)-N-((R)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide eluted next and was isolated as the major product (0.23 mg, 28% yield). Rf0.8 (Hexane:EtOAc 1:1) LCMS: 1.84 min [M+1] 448.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.58 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%; NMR: 400 MHz 1H (CDCl3) 8.62 ppm, d, J=2.6 Hz; 7.73 ppm, dd, J=2.6 and J=8.8 Hz; 7.38, 1H, s; 7.32 ppm, 1H, d, J=7.9 Hz; 7.20 ppm, 2H, d, J=8.8 Hz; 5.87 ppm, 1H, s; 3.76 ppm, 1H, d, J=16.7 Hz; 3.67 ppm, 1H, d, J=16.7 Hz; 1.36 ppm, 3H, s. (S)-N-((S)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide eluted last and was isolated as the a pale yellow oil (0.088 mg, 11% yield). Rf0.7 (Hexane:EtOAc 1:1) LCMS: 1.90 min [M+1] 448.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.65 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])C(OC)=O.[Li+].[Cl-].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCC(CC)(CC)C(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(CC)(CC)CC(=O)OC
Temperature: 170 °C
Yield: 100.3 %

Procedure:
Step C To a solution of 2-(1,1-diethyl-propyl)-malonic acid dimethyl ester (2.5 g, 11 mmol) in DMSO (30 mL) was added LiCl (0.91 g, 21.6 mmol) and H2O (0.19 mL, 11 mmol). The reaction mixture was heated at 170° C. for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentanoic acid methyl ester as a yellow oil (1.9 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1>ClCCl.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]2=3)=[O:16])=[CH:12][C:11]=1[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)ccc1/C=C/C(=O)OC(C)(C)C
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)OC(C)(C)C
Yield: 82 %

Procedure:
4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid from Example E45.1 (1.1 g, 4.2 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (720 mg, 3.6 mmol) were dissolved in dichloromethane (50 ml) and triethylamine (0.75 ml). DMAP (4.45 g, 3.6 mmol) and WSCD (1.36 g, 7.1 mmol) were added and the mixture was heated at re-flux for 2 days. The solution was diluted with di-chloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.35 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:11]=[N:27][O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: COC(=O)C1(C=O)CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCCCC1
Yield: 87.9 %

Procedure:
A mixture of 1-formyl-cyclohexanecarboxylic acid methyl ester (1.23 g, 7.23 mmol), sodium acetate (1.0 g, 14.5 mmol) and O-benzylhydroxylamine hydrochloride (2.3 g, 14.5 mmol) were stirred in methanol (40 mL) for 18 h. The methanol was removed in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to provide the title compound as a clear colorless liquid (1.75 g, 88%). MH+276.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]4[CH:28]=[C:27]([NH2:29])[C:26]([F:30])=[CH:25][C:24]=4[CH3:31])[C:15](=[O:22])[N:16]3[CH:19]([CH3:21])[CH3:20])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:27]1[C:26]([F:30])=[CH:25][C:24]([CH3:31])=[C:23]([C:14]2[C:15](=[O:22])[N:16]([CH:19]([CH3:20])[CH3:21])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:28]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1C)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.8 %

Procedure:
To a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (1.0 g, 2.2 mmol) in DCM (10 mL) was added TFA (3 mL) at RT. The resulting mixture was stirred at RT for 6 h, then washed with H2O (6×). The combined aqueous layers were neutralized with NH3H2O, extracted with DCM (3×) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.5 g, 66.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.60 (s, 1H), 6.95 (m, 1H), 6.90 (d, J=12.4 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 6.50 (s, 1H), 5.21 (br s, 1H), 4.95 (s, 2H), 2.92 (d, J=4.8 Hz, 3H), 2.02 (s, 3H), 1.58 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 341.2[M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1([S:13][CH2:12]1)[CH3:11]>CCOCC>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11]
Reactant: CC1(C)CS1
Reactant: Nc1ccccc1N
Solvent: CCOCC
Product: CC(C)(S)CNc1ccccc1N
Temperature: 80 °C
Yield: 26.4 %

Procedure:
o-Phenylenediamine (15.31 g, 1.42×10-1 mol, 100 M%) and 12.46 g (1.42×10-1 mol, 100 M%) isobutylene sulfide (Synder et al, J. Am. Chem. Soc. 69: 2672-2674, 1947) were mixed in a Parr bomb and heated in an oven at 80° C. for 18 hr. The bomb was cooled to room temperature and then opened. The crude brown oil contained some solid. The mixture was dissolved in 150 ml ether (some white solid did not dissolve), washed with saturated aqueous NaCl solution, and the solvent was removed on the rotary evaporator. The oily residue was placed on flash silic in a 600 ml sintered glass funnel and eluted with 500 ml portion of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether. Evaporation of the first 50:50 hexane/ether fraction gave 7.36 g (26.5%) of 2-amino-1-(2-mercapto-2-methylpropylamino)benzene as a waxy crystalline product, mp 38°-40° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:30]=[CH:29][C:21]2[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:20]=2[CH:19]=1.O>CN(C=O)C>[CH:19]1[C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=2[CH:29]=[CH:30][C:18]=1[O:17][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc2oc3ccccc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3oc4ccccc4c3c2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-hydroxydibenzofuran (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(dibenzofuran-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[C:26]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:26]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: O=C1CCCC1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1 step (g)) and cyclopentanone. Mass spectrum (ESI, m/z): Calcd. for C24H28N4O2, 405.2 (M+H), found 405.1.