Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2Cl)[CH2:7]3)=[CH:4][C:3]=1[F:15].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20]>CCCCO.O>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[NH:20][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])[CH2:7]3)=[CH:4][C:3]=1[F:15]
Reactant: Fc1cc2c(cc1Br)C(Cl)=NC1CC2C1
Reactant: COC(CN)OC
Solvent: CCCCO
Solvent: O
Product: COC(CNC1=NC2CC(C2)c2cc(F)c(Br)cc21)OC
Temperature: 100 °C
Yield: 107.7 %

Procedure:
Into a 100-mL 3-necked round-bottom flask was placed a solution of 5-bromo-8-chloro-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene (3.75 g, 13.00 mmol, 1.00 equiv) in n-BuOH (50 mL) and 2,2-dimethoxyethan-1-amine (1.5 g, 14.27 mmol, 1.10 equiv). The resulting solution was stirred at 100° C. for 1.5, diluted with 50 mL of water and extracted with 1×50 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum to afford 5.0 g (crude) of 5-bromo-N-(2,2-dimethoxyethyl)-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraen-8-amine as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:31]=[C:32]([Cl:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:31]=[C:32]([Cl:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(Cl)cc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-chloro-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[H-].[Na+].[CH:34]([S:37](Cl)(=[O:39])=[O:38])([CH3:36])[CH3:35]>C1COCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[NH:1][S:37]([CH:34]([CH3:36])[CH3:35])(=[O:39])=[O:38])=[CH:17][CH:16]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N)n2Cc1ccc(Cl)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 8-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (95 mg, 0.21 mmol, intermediate 53) in THF (5 mL) was added sodium hydride (10 mg, 0.23 mmol) at 0° C. The reaction was stirred at room temperature for 1 h; then Isopropylsulphonyl chloride (29 mg, 0.21 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature 1 h. The reaction was quenched with aqueous ammonium chloride (2 mL) at 0° C. and then was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the product as a yellow syrup (60 mg) which was used without purification. LCMS retention time 1.519 min; LCMS MH+-THP 470.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([O:16][CH3:17])[CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[N:3]=1.C(O)(=[O:20])C>O>[CH2:12]([C:11]1[C:2](=[O:20])[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:14][CH3:15])[CH:7]=[CH:6][C:5]=2[O:16][CH3:17])[CH3:13]
Reactant: CCc1cc2c(OC)ccc(OC)c2nc1Cl
Reactant: CC(=O)O
Solvent: O
Product: CCc1cc2c(OC)ccc(OC)c2[nH]c1=O
Yield: 100 %

Procedure:
A solution of 200 mg (0.92 mmol) of 2-chloro-3-ethyl-5,8-dimethoxyquinoline in acetic acid (3 ml) and water (1 ml) was refluxed for 5 h. After evaporation of the solvent, the residue was dissolved in water, basified with 25% aqueous ammonium hydroxide and extracted with chloroform (3×25 ml). The combined chloroform layers were dried over sodium sulphate and evaporated, yielding 185 mg (100%) of 3-ethyl-5,8-dimethoxy-1H-quinolin-2-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=3)[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 1-(bromomethyl)-4-nitrobenzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 8.25 (d, 2H), 7.99 (d, 1H), 7.80 (d, 2H), 7.25 (d, 1H), 5.20 (s, 2H), 4.66 (s, 1H), 3.93 (s, 3H); MS (ESI): 487.8.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([CH2:16][CH3:17])[C:12]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:22]#[N:23])C1C=CC=CC=1>ClCCl.[Fe](Cl)(Cl)Cl>[CH2:16]([C:13]1[C:12]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])=[C:11]([CH2:10][CH2:9][OH:8])[NH:15][N:14]=1)[CH3:17]
Reactant: CCc1n[nH]c(CCOCc2ccccc2)c1Oc1cc(F)cc(C#N)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: CCc1n[nH]c(CCO)c1Oc1cc(F)cc(C#N)c1
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
Iron(III)chloride (9.30 g, 57.5 mmol) was added to a solution of the pyrazole from Example 147 (2.10 g, 5.75 mmol) in dichloromethane (90 ml) under nitrogen at room temperature. After stirring for 20 minutes the mixture was diluted with dichloromethane (50 ml), washed with water (100 ml) then saturated aqueous sodium ethylenediaminetetraacetate solution (70 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2 changing to 95:5, by volume) to provide the title compound (1.2 g) as a brown oil which solidified on standing.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]4[O:21][CH:19]4[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1>C(OCC)(=O)C.[I-].[Zn+2].[I-]>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][C:19](=[O:21])[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CC2CC3OC3c3cccc1c32
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1

Procedure:
Twenty grams of 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole were dissolved in 500 ml. of benzene. 7.7 g. of zinc iodide were added and the resulting mixture refluxed under nitrogen for about 1.5 hours. Thin layer chromatrography indicated one major spot slightly slower than the spot corresponding to starting material. The reaction mixture was cooled and then diluted with ethyl acetate. The resulting organic layer was washed with water, and with saturated aqueous sodium chloride and was then dried. Evaporation of the solvent yielded a residue comprising 1-benzoyl-4-keto-1,2,2a,3,4,5-hexahydrobenz[cd]indole formed in the above reaction. The residue was crystallized by trituration with ether containing a small amount of benzene, yielding crystals melting at 146°-149° C. (yield equals 16.9 g.)
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:20])[CH:8]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=O)C.C(=O)([O-])[O-].O>CO>[CH3:20][CH:7]([CH:8]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][OH:4]
Reactant: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: CCOC(C)OC(CC=C(C)C)C(C)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene (0.5 mmole), saturated potassim carbonate solution (9 ml), water (6 ml) and methanol (100 ml) is stirred for 3 hours at room temperature. Most of the methanol is removed in vacuo and the residue is treated with ethyl acetate (500 ml) and water (200 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give the crude product. This material is further purified by column chromatography on silica gel (25 g, 15% ethyl acetate in hexane) to give 3,7-dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol as a colorless oil.
Reaction SMILES: [C:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C([Cl:40])=O>O1CCCC1>[C:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([Cl:40])=[O:36])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
16-Hexadecanoyloxyhexadecanoic acid (7.73 g, 15.13 mmol) prepared as in (f) above was dissolved in tetrahydrofuran (140 ml) and oxalyl chloride (4.80 g, 37.83 mmol) was added dropwise. The mixture was stirred at room temperature for 3 days and then the solvent and unreacted oxalyl chloride were evaporated under reduced pressure to give 8.0 g (100%) of the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][Br:13])=[CH:7][C:6]=1[CH2:15][O:16]C(=O)C)(=O)C.Br.O>CO>[Br:13][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([CH2:15][OH:16])[CH:7]=1)=[O:14]
Reactant: CC(=O)OCc1cc(C(=O)CBr)ccc1OC(C)=O
Agent: Br
Solvent: O
Solvent: CO
Product: O=C(CBr)c1ccc(O)c(CO)c1
Yield: 68.9 %

Procedure:
2-Acetoxymethyl-4-bromoacetylphenyl acetate (18.6 g) was dissolved in 90 ml of methanol, 100 ml of 47% hydrobromic acid was added with stirring under ice-cooling, and the mixture was subjected to 16 hours of reaction at room temperature. Water was added to the reaction solution with stirring under ice-cooling, and the resulting precipitates were collected by filtration and washed with water and hexane to give 9.54 g of 2-bromo-4'-hydroxy-3'-hydroxymethylacetophenone having a melting point of 117 to 119° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:29][NH2:30].C(O)C>>[CH3:29][NH:30][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Solvent: CCO
Product: CNc1cc(Oc2ccc(NC(=O)Nc3ccc(C(C)(C)C)cc3)cc2)ncn1

Procedure:
Under N2-atmosphere, a solution of N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea (319 mg, 0.80 mmol) in methylamine/ethanol (8.03 M; 5 ml) is stirred for 50 min at 40° C. Then the reaction mixture is concentrated in vacuo, the residue re-dissolved in water and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated in vacuo after adding 2 g of SiO2. The resulting powder is put on top of a SiO2-column and eluted with AcOEt/hexane 9:1, yielding the title compound: m.p.: 245-246° C.; 1H-NMR (DMSO-d6): 8.7 (s, HN), 8.6 (s, HN), 8.13 (s, 1H), 7.45 (d, 2H), 7.35 (d, 2H), 7.31 (d, 2H), 7.05 (d, 2H), 6.78 (s, HN), 5.79 (s, 1H), 2.83 (MeN), 1.30 (Me3C).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([B:7]([OH:9])[OH:8])=[CH:4][CH:3]=1.O[C:11]([C:14](O)([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[S:6][C:5]([B:7]2[O:9][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2ccc(Cl)s2)OC1(C)C
Yield: 50 %

Procedure:
The title compound (50%, oil) was prepared from 5-chlorothiophen-2-boronic acid and pinacol.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14]OC(N[C@H](C(O)=O)CC3C=CC=CC=3C)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:14]=[C:12]1[C:13]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1ccccc1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=C1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes andthen the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying therewere obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[C:2]1([NH:1][C:17](=[O:18])[CH2:16][Cl:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
A mixture of aniline (9.3 g) and triethylamine (10.1 g) in dichloromethane (40 ml) was added dropwise during 1 hour to an ice-cooled solution of chloroacetyl chloride (11.3 g) in dichloromethane (40 ml). The mixture was further stirred for 18 hours. The organic phase was separated by filtration, washed with water (3×50 ml), dried (MgSO4) and the solvent removed by evaporation to give N-phenyl-2-chloroacetamide (6.1 g) as a white solid, mp 128°-129° C., which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([F:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Reactant: OB(O)c1cc(F)cc(F)c1
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: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2ncccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,8-naphthyridine (0.4 g, 1.877 mmol), 3,5-difluorophenylboronic acid (0.445 g, 2.82 mmol), Pd(PPh3)4 (0.217 g, 0.188 mmol), potassium carbonate (0.519 g, 3.75 mmol) in toluene (6 mL) at 95° C. for 18 h. Purification by column chromatography (silica gel; 0-25% EtOAc in hexanes) gave 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,8-naphthyridine as a yellow amorphous solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>COCCOC>[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 28.2 g (0.2 mol) of 1-fluoro-4-nitrobenzene, 31.3 g (0.25 mol) of 3-imidazol-1-ylpropylamine and 34.8 ml of triethylamine in 30 ml of 1,2-dimethoxyethane was heated for half an hour with stirring. The mixture was poured into 1.5 liters of ice-cold water and the crystalline precipitate was filtered off, reimpasted in water and then in isopropyl alcohol and dried under vacuum at 40° C. over phosphorus pentoxide. Yellow crystals (36.6 g) which, after purification by recrystallization from refluxing 96° ethanol, melted at 124° C., were obtained, the elemental analysis of which, calculated for C12H14N4O2, was:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CC#N>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:7][C:8]1[CH:9]=[C:10]([C:11]([NH2:13])=[O:12])[CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)c1cccc(O)c1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCCCCCCBr)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
K2CO3 (1.38 g, 10 mmol, 1 equiv.) was added to a suspension of 3-hydroxybenzamide (1.37 g, 10 mmol, 1 equiv.) in CH3CN (100 ml). The mixture stirred for 10 min at room temperature, before 1,6-dibromo-hexane (9.76 g, 40 mmol, 4 equiv.) was added. The resulting mixture was stirred at 60° C. for 16 h. After this time, the reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate evaporated under reduced pressure to dryness. The residue was taken-up in EtOAc and water. The organic phase was separated and washed consecutively with K2CO3 solution, water and brine. Dried with MgSO4 and evaporated under reduced pressure to a small volume. The precipitant solid was filtered and washed with EtOAc/pentane, to give the desired compound as a white solid (2.0 g, 67%), mp 115-117° C. HPLC-MS (method 1): m/z 300 [M]+, 302 [M+2H]+, Rt=4.08 min.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18](=[O:43])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]([OH:42])[CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[N:37]=3)[N:32]=[CH:31][C:30]=2O)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[C:13]([O:17][C:18](=[O:43])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]2[CH2:28][C:29]3=[C:38]4[C:33](=[N:32][CH:31]=[C:30]3[O:42]2)[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[N:37]4)[CH2:22][CH2:21]1)([CH3:14])([CH3:16])[CH3:15]
Reactant: COc1ccc2ncc(O)c(CC(O)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)O3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl azodicarboxylate (650 μL, 4.13 mmol, 2.0 eq) is added at 0° C. to a stirred solution of {trans-4-[2-hydroxy-3-(3-hydroxy-6-methoxy-[1,5]naphthyridin-4-yl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester (890 mg, 2.06 mmol, 1.0 eq) in tetrahydrofuran (100 mL), followed by triphenylphosphine (1.08 g, 4.13 mmol, 2.0 eq). After 1 hour stirring at room temperature, solvent is removed and the crude is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford [trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid (420 mg, 49% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[N:29][C:30]#[N:31])[C:8]=2[CH:32]=1)([O-:3])=[O:2].[C:33]([O-])([O-])=O.[K+].[K+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]([CH3:33])[C:21]3=[N:29][C:30]#[N:31])[C:8]=2[CH:32]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=NC#N)n(C)c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
400 mg (0.91 mmol) of the compound obtained in example 1 was dissolved in 5 ml of DMF, then 250 mg (1.82 mmol) of K2CO3 and 170 mg (1.18 mmol) of CH3I were added thereto. The reaction was stirred at room temperature for 12 hours, 30 ml of saturated NaHCO3 solution was added, and aqueous layer was extracted with 50 ml of ethyl acetate. Organic layer was washed with brine and dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 390 mg (yield: 95%) of the target compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>ClCCl>[CH3:24][C:23]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]([F:21])([F:22])[F:5])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a mixture of 4.367 kilograms (32.75 moles) of aluminum chloride and 8.8 liters of dichloromethane at 0° C. is added gradually a solution of 3,267 kilograms of 1,4-bis(2,2,2-trifluoroethoxy)benzene and 1.899 kilograms (13.7 moles) of acetic anhydride in 1.3 liters of dichloromethane. The reaction temperature is maintained to 5° to 10° C. while stirring the mixture for about 16 hours. The reaction mixture is then heated to its reflux temperature and maintained under reflux for 4 hours. The reaction mixture is then acidified with 8.76 kilograms of 10 percent hydrochloric acid. Ice is added to the mixture to maintain the temperature below 20° C. The organic layer is separated and the aqueous layers are extracted several times with dichloromethane. The organic layers are dried, then evaporated to provide a residue which is triturated with hexane to provide a yellow solid product. Two crops of product are obtained providing a total yield of 3.088 kilograms of 2,5 -bis(2,2,2trifluoroethoxy)acetophenone, m.p. 84° to 88° C., yield 82 percent.