Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:15]=[C:14]([CH2:16]O)[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CS([Cl:31])(=O)=O>C(Cl)Cl>[Cl:31][CH2:16][C:14]1[N:15]=[C:10]([CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][CH:13]=1
Reactant: OCc1cccc(CCCN2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: ClCc1cccc(CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Additionally, to the solution of 495 mg of the resulting [6-(3-morpholin-4-ylpropyl)pyridin-2-yl]methanol and 104 mg of diisopropylethylamine in 20 mL of methylene chloride at ice temperature, 0.18 mL of methanesulfonyl chloride was added dropwise and the mixture was stirred at room temperature overnight. After the solvent was removed, the residue was purified by chromatography on silica gel (methylene chloride-ethanol=40:1) to give 290 mg of 4-[3-(6-chloromethylpyridin-2-yl)propyl]morpholine as a yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH2:27]([O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([O:34][C:35]1[C:40]([C:2]2[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:5]=[C:6]([C:8]([CH3:10])([CH3:11])[CH3:9])[CH:7]=2)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)c1cc(Br)c(C#N)c(C#Cc2ccc(NS(C)(=O)=O)cc2)c1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(C#Cc2ccc(NS(C)(=O)=O)cc2)c(C#N)c(-c2cccnc2OCc2ccccc2)c1
Yield: 64.1 %

Procedure:
step 3—A sealed tube containing 94 (0.290 g, 0.67 mmol), 2-benzyloxy-3-pyridine boronic acid (0.184 g, 0.80 mmol, 141), Pd(PPh3)4 (0.220 g, 0.07 mmol) and Na2CO3 (0.609 g, 2.01 mmol) in MeOH (9 mL) and DCM (3 mL) was irradiated in a microwave reactor at 125° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between DCM and water then the aqueous layer was further extracted with DCM. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 0.230 g (64%) of N-{4-[3-(2-benzyloxy-pyridin-3-yl)-5-tert-butyl-2-cyano-phenylethynyl]phenyl}-methanesulfonamide (96) as a light brown solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:25]3[NH:24][CH:28]=[CH:27][N:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ncc[nH]3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.6 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.10 g, 0.32 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-imidazolecarbaldehyde (0.03 g, 0.31 mmol) was added followed by oxone (0.13 g, 0.21 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.10 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (15 mg, 12.1% yield) as light brown crystals.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1.O>C1COCC1>[F:35][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1
Reactant: Brc1c(COC2CCCCO2)ccc2c1CCCC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1c(COC2CCCCO2)ccc2c1CCCC2
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To stirring solution of bromide 47.5 (1.0 g, 3.1 mmol) in THF at −78° C. is added n-BuLi (1.6 M, 2.11 mL, 3.4 mmol), and stirring is continued for 1 hour. N-Fluorobenzene sulfonimide (3.7 mmol) is added and the mixture is allowed to warm to 23° C. Water is added to quench the reaction. The aqueous layer is extracted with EtOAc (3×100 mL), and the organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford fluoride 47.6.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C([N:38](CC)CC)C.O>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH2:38])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.2 %

Procedure:
188 mg (1.16 mmol) of N,N'-carbonyldiimidazole were added to a suspension of 381 mg (0.84 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) in 8 ml of acetonitrile, and the resulting mixture was stirred at room temperature for 40 minutes, after which 282 mg (4.18 mmol) of ammonium chloride and 0.59 ml (4.23 mmol) of triethylamine were added thereto. The reaction mixture was then stirred for 2 hours, after which water was added, and the aqueous mixture was freed from acetonitrile by distillation under reduced pressure. The resulting residue was extracted with ethyl acetate, and the extract was washed with 2 N aqueous hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel, using ethyl acetate as the eluent, to give 352 mg (yield 93%) of the title compound as crystals, melting at 151-152° C. (from a mixture of hexane and ethyl acetate).
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[CH:11](OCC)=[O:12].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH2:24][C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1>O>[CH:11]([CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:27])([F:28])[F:16])[CH:19]=1)[C:25]#[N:26])=[O:12]
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(C=O)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To a slurry of 30.0 g. of sodium methoxide in 1200 ml. of toluene and 43.4 g. of ethyl formate is added dropwise with stirring 98.75 g. of 3-(trifluoromethyl)benzeneacetonitrile in 75 ml. of toluene over a 10 minute period. The temperature of the mixture rises to 35° C. and the mixture thickens. Stirring is continued for 2 hours and then one liter of water is added. The aqueous layer is acidified and a precipitate is formed by scratching to give 85.0 g. of the product of the Example as a white solid, m.p. 103°-106.5° C.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)=[C:2]=[O:3].OC(C(F)(F)F)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:33])[CH2:28]2)[CH2:23][CH2:22]1>CN(C=O)C>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH:1][C:2](=[O:3])[NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=5)=[O:33])[CH2:28]4)[CH2:25][CH2:26]3)=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(NC(=O)Nc3ccc4c(c3)OCO4)CC2)C1
Reaction time: 8 h

Procedure:
5-Isocyanato-benzo[1,3]dioxole (Aldrich, 50 mg, 0.302 mmol) was added into a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide TFA salt (150 mg, 0.302 mmol) and TEA (127 μL, 0.906 mmol) in DMF (3 mL) at room temperature. The reaction was stirred overnight and quenched with saturated sodium bicarbonate. The reaction was then partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:21]1[CH2:25][CH2:24][CH:23]([CH2:26]O)[CH2:22]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:26][CH:23]2[CH2:24][CH2:25][O:21][CH2:22]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCC2CCOC2)C1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), tetrahydro-furan-3-yl-methanol (0.5 mmol), and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL) was heated at 120° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (120 mg). To this compound was added CH2Cl2 (20 mL) and TFA (3 mL). After 4 h at rt the mixture was concentrated to give the title compound (161 mg). MS (ESI): mass calcd. for C14H18ClNO3, 283.1; m/z found, 284.0 [M+H]+. 1H NMR (MeOD): 7.05-6.96 (m, 2H), 6.88 (d, J=1.9 Hz, 1H), 5.15-5.05 (m, 1H), 4.57-4.48 (m, 2H), 4.28-4.19 (m, 2H), 4.04-3.88 (m 4H), 3.82-3.70 (m 2H), 2.82-2.70 (m, 1H), 2.20-2.09 (m, 1H), 1.84-1.73 (m, 1H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].S(=O)(O)[O-].[Na+]>C(OCC)C>[Br:1][CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:4]=1[Cl:3])[C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10]
Reactant: COC(C)(C)C(=O)COc1ccc(Cl)cc1Cl
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Bromine (10.73 g, 0.067 mole) was slowly added to a stirred solution of 18.6 g (0.067 mole) of 1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone in 350 ml diethyl ether containing 0.2 g aluminum chloride at about 3° C. After the addition, the mixture was stirred an additional 30 minutes, then poured into aqueous sodium bisulfite. The organic layer was separated, extracted with sodium bicarbonate solution, dried using MgSO4, and the solvent evaporated. There was thus obtained 23.6 g (99% yield) of 1-bromo-1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11](=O)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O=P(Cl)(Cl)[Cl:21].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:21][C:11]1[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1nc2ccsc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2sccc2n1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
A solution of 2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.80 g, 3.1 mmol), POCl3 (0.28 mL, 3.1 mmol), and N,N-dimethylaniline (1.6 mL, 4.7 mmol) in benzene (3.5 mL) was heated at 80° C. for 2 h. An additional portion of POCl3 (0.28 mL, 3.1 mmol) was added, and the reaction was heated at 80° C. for 16 h. The reaction was cooled, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.61 g, 71% yield). LC/MS: m/z 277.1 (M+H)+ at 2.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].O.Cl.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH:18]=1)#[N:4]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 8.8 gm (157 mMol) potassium hydroxide in 85 mL methanol were added 8.15 gm (57.33 mMol) 5-cyano-1H-indole and 7.86 gm (51.17 mMol) 4-piperidone hydrochloride monohydrate. The resulting mixture was heated to reflux for 48 hours and was then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure to about half volume and was then treated with 1M HCl until the pH of the solution was between 1 and 2. The resulting solution was extracted twice with 100 mL of diethyl ether and the remaining aqueous phase was treated with 5N sodium hydroxide until the pH of the solution was between 12 and 14. This aqueous phase was extracted 5 times with 10% methanol in dichloromethane. These organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to a residue. This residue was subjected to flash silica gel chromatography, eluting with dichloromethane which contained 20% methanol and 2% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 6.86 gm (60%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([N+:12]([O-])=O)=[CH:6][CH:5]=1)[CH3:2]>Cl.CO.[Fe]>[NH2:12][C:7]1[C:8]([C:10]#[N:11])=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCOc1ccc([N+](=O)[O-])c(C#N)n1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CCOc1ccc(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a suspension of the compound prepared in Example 280 (0.672 g) in hydrochloric acid (2.3 mL) and methanol (7 mL) was added portionwise iron (0.680 g) slowly. After addition was complete, the mixture was stirred at room temperature for 1 hour. The mixture was evaporated in vacuo, diluted with dichloromethane, filtered, and purified by column chromatography on silica gel (5-70% ethyl acetate in hexane) to obtain the title compound (0.460 g) having the following physical data.
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH3:21])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:22].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:22].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH3:21])[CH2:15]1)[CH2:5][OH:6]
Reactant: CC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of 23.5 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-ethyldihydrofuran-2-one obtained in Example (106e) (81.3 mmol), 40.0 ml of a solution of 4 N hydrochloric acid in dioxane (160 mmol) and 5.21 g of 10% palladium-carbon (50% wet) in ethanol (400 ml) was stirred under a hydrogen atmosphere at room temperature for 12 hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 300 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-ethyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:28]2[C:19](=[CH:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH:27]=2)[CH:18]=[C:17]2[C:12]=1[C:13]1[CH:44]=[CH:43][C:42]3[C:29](=[CH:30][C:31]4[C:40]([CH:41]=3)=[CH:39][C:38]3[C:33](=[CH:34][C:35](Br)=[CH:36][CH:37]=3)[CH:32]=4)[C:14]=1[CH:15]=[CH:16]2>C1(C)C(C)=CC=CC=1>[C:1]1([C:11]2[C:28]3[C:19](=[CH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH:18]=[C:17]3[C:12]=2[C:13]2[CH:44]=[CH:43][C:42]4[C:29](=[CH:30][C:31]5[C:40]([CH:41]=4)=[CH:39][C:38]4[C:33](=[CH:34][C:35]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:36][CH:37]=4)[CH:32]=5)[C:14]=2[CH:15]=[CH:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc2cc3cc4ccc5c(ccc6cc7cc8ccccc8cc7c(Br)c65)c4cc3cc2c1
Reactant: OB(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccc3cc4cc5ccc6c(ccc7cc8cc9ccccc9cc8c(-c8ccccc8)c76)c5cc4cc3c2)cc1

Procedure:
Naphthacenonaphthacene (Chemical Abstract Service (CAS) Registry Number 180-50-1) is dissolved in carbon tetrachloride. While the resultant mixture is cooled, 1 mol equivalent of bromine is added thereto. The mixture is reacted for 4 hours and brominated. Thereafter, the mixture is purified in accordance with a usual method, and 6,13-dibromonaphthacenonaphthacene is obtained. 2 mol equivalent of phenylboronic acid [Ph—B(OH)2] (where “Ph” represents a phenyl group) is refluxed and reacted for 12 hours with the 6,13-dibromonaphthacenonaphthacene obtained in this way, in a xylene/2M sodium carbonate aqueous solution, by using 0.01 mol equivalent of tetraquis(triphenylphosphine)palladium (0) [Pd(PPh3)4] (where “Ph” represents a phenyl group) as a catalyst. Thereafter, the resultant mixture is purified in accordance with a usual method, and the 6,13-diphenyl-naphthacenonaphthacene expressed by the following formula is synthesized. (Note that, in the formula, “Ph” represents a phenyl group.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]>C(O)C.CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(Cl)cc1)n2-c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1ncc2c(cc(-c3ccccc3)n2-c2ccccc2)c1O
Reaction time: 30 h
Yield: 27.9 %

Procedure:
To a mixture of 3-bromo-2-(4-chloro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (200 mg, 0.42 mmol)(from Example 36(d)) in ethanol (12 mL) and DMF (3 mL) was added Pd/C (10% wet, containing 50% water)(120 mg) was stirred under hydrogen atmosphere (balloon pressure) for 30 h. Reaction mixture was filtered through a pad of celite and rinsed with EtOAc. Filtrate was concentrated and purified by silica gel chromatography (eluting with 25%-50% EtOAc/hexanes) to give the title compound 42 mg. MS-(+)-ion: M+1=359.04.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH2:12][CH3:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:18]2[NH:19][C:20](=[O:22])[S:21][C:17]=2[CH:16]=1.Cl>C(OCC)C.C(O)C>[CH2:12]([C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:14][C:15]3[CH:24]=[CH:23][C:18]4[NH:19][C:20](=[O:22])[S:21][C:17]=4[CH:16]=3)[C:3]=2[C:10]=1[CH3:11])[CH3:13]
Reactant: CCc1[nH]c2ncnc(Cl)c2c1C
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCc1[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c2c1C
Yield: 85.4 %

Procedure:
A mixture comprising 60.0 mg (307 μmol) 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate example 1a), 51 mg 6-amino-1,3-benzothiazol-2(3H)-one (CAS-No: 56354-98-4), 1.75 mL ethanol and 16.9 μL hydrochloric acid (4M in dioxane) was reacted at 110° C. for 10 hours. The residue was digested in a mixture of diethyl ether and ethanol and dried to give 85.3 mg (85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][OH:12])=[NH:9])=[CH:4][N:3]=1
Reactant: NO
Reactant: N#Cc1cnc(N)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1cnc(N)nc1
Yield: 72.1 %

Procedure:
A stirred mixture of commercially available 2-amino-5-cyano-pyrimidine [CAS-No. 1753-48-6] (1.39 g, 11.6 mmol), hydroxylamine hydrochloride (1.61 g, 23.2 mol) and potassium carbonate (4.8 g, 34.7 mol) in ethanol (57 mL) was heated under reflux conditions for 3 h. The reaction mixture was evaporated and purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) to yield the title compound (1.28 g, 72%) as an off-white solid. MS (EI) 153.1 [(M)+]; mp 218° C.
Reaction SMILES: [I-].[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][N+:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[C:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH:15]=1
Reactant: CCC[n+]1ccc(-c2cc(OC)c([N+](=O)[O-])cc2C)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CC=C(c2cc(OC)c([N+](=O)[O-])cc2C)CC1
Reaction time: 2 h
Yield: 96 %

Procedure:
To 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]-1-propylpyridinium iodide (1.04 g, 2.51 mmol) in 25 mL of MeOH at 0° C. was added, NaBH4 (0.284 g, 7.53 mmol) over 1 h. The mixture was allowed to come to rt over 2 h. The solvent was reduced to approximately 5 mL and then diluted with EtOAc, washed with conc. NaHCO3, dried (Na2SO4), filtered, rotovaped down, and purified by flash chromatography to give the title compound of step C (0.7 g, 2.41 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (s, 1H), 7.00 (s, 1H), 5.61-5.67 (m, 1H), 3.87 (s, 3H), 2.98-3.07 (m, 2H), 2.60 (t, J=5.50 Hz, 2H), 2.28-2.37 (m, 4H), 2.20 (s, 3H), 1.43-1.53 (m, 2H), 0.87 (t, J=7.52 Hz, 3H).