Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:14][O:15][C:16](=[O:21])[C@@H:17]([CH3:20])[CH2:18][OH:19].O>CN(C)C=O>[CH3:14][O:15][C:16](=[O:21])[C@@H:17]([CH3:20])[CH2:18][O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Imidazole (13.3 g, 196 mmol) and tert-butyldimethylsilyl chloride (14.2 g, 94.1 mmol) were added to a solution of (S)-3-hydroxy-2-methylpropionic acid methyl ester (11.0 g, 93.1 mmol) in dimethylformamide (100 mL), and the mixture was stirred at room temperature for four hours. Water was added to the reaction mixture, followed by extraction with hexane twice. The extract was then dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 24 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(Cl)Cl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)[N:3]=1
Reactant: Clc1n[nH]c2ccccc12
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Clc1cc(-n2nc(Cl)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-chloroindazole (1 g, 6.6 mmol) in methylene chloride (25 mL) and methanol (25 mL) were added 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (3.6 g, 15 mmol) and copper(II) acetate (1.4 g, 7.5 mmol), followed by triethylamine (2 mL, 15 mmol). The resulting mixture was vigorously stirred at room temperature for 20 h. The reaction was filtered and the gray solid was discarded. The blue filtrate was concentrated in vacuo and the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate and brine and dried over MgSO4. Flash chromatography of the crude product mixture with 25:10:65 and 35:10:55 EtOAc-CH2Cl2-Hexane gave the title compound as a white solid. MS (ES+): 264.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH2:28])=[CH:23][CH:22]=2>CCO>[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:23][CH:22]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Solvent: CCO
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCCC5)sc34)ccc2[nH]1
Temperature: 25 °C
Yield: 112.4 %

Procedure:
A solution of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone (0.359 g, 1.34 mmol) and 2-methyl-1H-indol-5-ylamine (0.19 g, 1.3 mmol) in EtOH (10 mL) was heated to reflux for 48 h. The reaction mixture was cooled to room temperature and concentrated onto silica gel (5 mL). Purification by flash chromatography on silica gel eluting with CH2Cl2/NEt3 (99.5/0.5) afforded the title compound as a yellow solid (550 mg) MS: 377.2 (MH+); HPLC Rf: 4.45 min; HPLC purity: 97%.
Reaction SMILES: F[C:2]1[C:19](F)=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:22])[C:4]=2[CH:3]=1.[C:23]([O-:26])([O-])=O.[K+].[K+].[CH3:29][OH:30].Cl>CS(C)=O>[CH3:29][O:30][C:2]1[C:19]([O:26][CH3:23])=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:22])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: CO
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
1 g (3.4 mmol) of 2,3-difluoro-naphthacene-5,12-dione, 0.94 g (6.8 mmol) of K2CO3, 2.18 g of methanol and 20 ml of DMSO are stirred at 110° C. for 22 hours. The mixture is poured onto dilute hydrochloric acid. The product is filtered off, washed four times with water, dried and recrystallized from CH2Cl2 /pentane; yield 0.72 g (67%); melting point >250° C.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[CH3:12][N:13]([CH3:16])[CH:14]=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[CH3:12][N:13]([CH:16]=[N:3][C:2]1[NH:1][C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=1)[CH3:14]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 30 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was added to 175.4 g (2.4 mol) of N,N-dimethylformamide, and then 23.0 g (0.15 mol) of phosphorus oxychloride was added drop by drop, followed by stirring at 30° C. for 1 hour. The reaction mixture was added to 500 ml of ice water, and then neutralized with 75.6 g (0.9 mol) of sodium hydrogen carbonate. The precipitating crystal was collected by filtration and washed with 50 ml of water to yield 14.6 g (0.07 mol) of a white crystal of N-dimethylaminomethyleneguanine (yield 71%). Its properties are as follows:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: OC1CC[C@@H](c2ccc(F)cc2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
(5S)-2-Hydroxy-5-(4-fluorophenyl) tetrahydrofuran (211, 620 mg, 3.5 mmol), t-butyldimethylsilyl chloride (700 mg, 5.25 mmol) and imidazole (595 mg, 8.75 mmol) were dissolved in 2 mL of dry DMF. The resulting solution was stirred under dry argon overnight, poured into 200 mL of water, and extracted with a 2:1-mixture of ethyl acetate and hexane (3×100 mL). The combined organic extracts were washed with water (4×200 mL) and brine (100 mL), dried over sodium sulfate and the solvent was removed in vacuo to yield 1 g (96%) of (5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, mixture of cis and trains isomers) as a colorless oil, which did not need further purification. 1H-NMR (CDCl3) δ 7.40-7.50(2H, m, minor isomer), 7.25-7.35 (2H, m, major isomer), 7.00-7.10 (2H, m, both major and minor isomers), 5.71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90-4.98 (1H, m, minor isomer), 2.40-2.55 (1H, m, both major and minor isomers), 2.05-2.17 (1H, m, both major and minor isomers), 1.87-2.00 (1H, m, both major and minor isomers), 1.67-1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, both major and minor isomers), 0.16 (s, 6H, both major and minor isomers).
Reaction SMILES: [I-:1].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[C:38](=[O:39])[N:13]2[C:14]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20]Cl)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([O:7][C:8]([NH:10][CH:11]1[C:38](=[O:39])[N:13]2[C:14]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][I:1])[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice cooled solution of sodium iodide (900 mg, 6 mmol) in acetone was added a solution of diphenylmethyl 7-t-butoxycarbonylamino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (VIa) (1.08 g, 2 mmol) in acetone (2.5 ml). The mixture was stirred while being cooled in an ice bath for 3.5 hours, and was concentrated under reduced pressure. The residue was diluted with ethyl acetate and aqueous sodium thiosulfate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated. 923mg of the title product was obtained as a yellow powder after crystallization from a small volume of ethanol (73% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[C:5]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][C:3]=1[OH:25].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[Br:1][C:2]1[C:3]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:4][C:5]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[C:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])[C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)c(Br)c(Cl)c1O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1Br
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a mixture of 0.042 g (0.090 mmol) of 17, 0.016 g (0.11 mmol) of t-butyldimethylsilyl chloride, and 0.003 g (0.010 mmol) of DMAP in 2 mL of dichloromethane under argon at 25° C. was added 0.05 mL (0.260 mmol) of triethylamine. The reaction mixture was stirred for 3 h, diluted with 30 mL of water, and extracted three times with diethyl ether (30 mL each). The combined ether extracts were with 30 mL of brine, dried (MgSO4), and concentrated to give 0.051 g (99% yield) of 4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:17])[NH:5][CH:6]([CH3:16])[N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].O1CCOC[CH2:26]1>>[C:18]([NH:1][CH:2]([C:3]1[C:4](=[O:17])[NH:5][CH:6]([CH3:16])[N:7]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]=1)[CH3:26])(=[O:20])[CH3:19]
Reactant: CC1NC(=O)C(CN)=NN1Cc1ccccc1
Reactant: C1COCCO1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(C)C1=NN(Cc2ccccc2)C(C)NC1=O
Temperature: 25 °C

Procedure:
Dry dioxan (80 ml) was added to 6-(1-aminomethyl)-2-benzyl-3-methyl-1,2,4-triazin-5(4H)-one (4.34 g) and the cloudy suspension stirred at room temperature was treated with acetic anhydride (1.9 ml). The mixture was stirred for 2 hours then concentrated to a brown solid. Recrystallisation from ethanol-ether afforded the acetamide, 3.1 g, m.p. 196°-203°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO.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>[C:9]1([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cc(Br)co1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1cc(-c2ccccc2)co1
Yield: 97 %

Procedure:
In a screw cap pressure tube, 4-bromofuran-2-carbaldehyde (504 mg, 2.88 mmol) and phenyl boronic acid (491.7, 4.03 mmol) were suspended in a mixture of toluene:EtOH (4:1). Na2CO3 (sat) (6.0 ml) was added. N2 was bubbled through the mixture for 5 minutes. Pd(PPh3)4 (166.4 mg, 0.05 mmol) was added. The tube was sealed and the mixture heated to reflux for 4.0 h. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (Pet. Ether/EtOAc 90/10→85/15) to afford the title substance in 97% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](C#N)[N:8]([C@@H:26]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:38].[Na+].[CH2:40]([OH:43])CO.O>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)=[C:9]([C:40]([OH:43])=[O:38])[N:8]([C@@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)c(C(=O)O)n2[C@@H]1CCNC1
Temperature: 150 °C
Yield: 4 %

Procedure:
To a mixture of (R)-tert-butyl 3-(4-amino-6-cyano-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (101) (2.0 g, 4.0 mmol) in ethylene glycol/H2O (20 mL/5 mL) was added and NaOH (1.0 g, 25 mmol). The reaction mixture was purged with N2 (2×) before heated at 150° C. overnight. After cooling to r.t., the reaction was diluted with ice-water, neutralized to pH 7 by slow addition of con. HCl. The aqueous layer was washed with DCM, concentrated under vacuum. Part of the residue was purified by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% HCOOH)) to give (R)-4-amino-5-(4-phenoxyphenyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (127) (60 mg, 4%) as a white solid. LC-MS (ESI): m/z (M+1) 416.0.
Reaction SMILES: [Mg:1].II.C([Cl:8])CCC.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCC>>[O:15]([Mg:1][Cl:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [Mg]
Reactant: CCCCCl
Reactant: Oc1ccccc1
Agent: II
Solvent: CCCC
Product: Cl[Mg]Oc1ccccc1
Temperature: 121 °C
Reaction time: 0.33 h

Procedure:
A reactor equipped witha reflux condenser was charged under an argon atmospher with 6.55 gm of magnesium metal powder (0.269 moles), 250ml. of Isopar "E" isoparaffinic hydrocarbon solvent and a few crystals (0.2 gm) of iodine. This mixture was heated to reflux temperature (121° C.) for about 60 minutes to activate the metal. Then, 28.0 ml (0.27 moles) of n-butyl chloride was added in 30 minutes to this metal slurry at reflux temperature; the resulting reaction mixture was allowed to reflux for 90 minutes. Anhydrous crystalline phenol (C6H5OH) 28 gm (0.298 moles) was then added slowly in melted form along with Isopar E solvent (50° C.) under good agitation. The phenol addition was completed in 20 minutes. During addition of phenol, heating was cut off and maintained at the reflux of released butane from the reaction. The reaction slurry turned from a grayish to a whitish color. The reaction slurry was then heated up to 90° C. with distillation of the refluxing butane. The slurry color turned from gray to white with no visible metal particles. Reaction was continued at 90° C. for another two hours with the addition of another 12 gms (0.128 moles) of phenol. The second addition of phenol was to see if any magnesium solubilized. The hot reaction slurry was then filtered to collect solid product. The solid product was washed with pentane to remove leftover solvents. The filtrate was tested for magnesium and found to be nil. The solid was dried under argon pressure until it was found to be a free flowing powder. Analysis of the solid white product showed 14.82% total magnesium, 56.78% C6H5O, 21.27% Cl, and remaining is free solvent: The filtrate was found to have all the excess phenol in it. This solid white product had an RO/Mg/X (i.e., C6H5O/Mg/Cl) molar ratio almost equal to 1:1:1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[N:18][C:13]3[O:14][CH2:15][CH2:16][NH:17][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Br:34])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(N(CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]([C:26]([N:17]2[CH2:16][CH2:15][O:14][C:13]3[N:18]=[CH:19][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)=[CH:11][C:12]2=3)=[O:27])[CH:29]=[C:30]([Br:34])[C:31]=1[O:32][CH3:33]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: FC(F)(F)Oc1ccc(-c2cnc3c(c2)NCCO3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(OC(F)(F)F)cc4)cc32)cc1Br
Yield: 69.8 %

Procedure:
By the same method as in the step c) of Example 45, 7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (83 mg, 0.28 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (138 mg, 0.42 mmol) and triethylamine (78 μl, 0.56 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (115 mg, 69.8%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[O:11][C:8]2=[N:9][CH:10]=1)(=[NH:4])[NH2:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[OH-].[Na+].Cl>O1CCCC1>[CH2:23]([O:22][C:20]([NH:3][C:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[O:11][C:8]2=[N:9][CH:10]=1)=[NH:4])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc2cc(C(=N)N)cnc2o1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(NC(=O)OCc1ccccc1)c1cnc2oc(C(=O)O)cc2c1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
Tetrahydrofuran (32 ml) was added to ethyl 5-amidinofuro[2,3-b]pyridine-2-carboxylate hydrochloride (2.05 g, 5.10 mmol), and benzyl chloroformate (1.09 ml, 7.65 mmol) was dropwise added under ice-cooling while maintaining the mixture at pH 10-12 with a 1N aqueous sodium hydroxide solution. Thereafter, the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1.5 hours. Tetrahydrofuran (20 ml) and a 1N aqueous sodium hydroxide solution (20 ml) were added to this reaction mixture and the mixture was stirred at room temperature for 1.5 hours. The mixture was adjusted to pH 4-5 with 1N hydrochloric acid and low boiling matters were distilled away under reduced pressure. The residue was purified by reversed-phase column (Chromatorex-ODS DM1020T, Fuji Silysia Chemical) chromatography. (water-acetonitrile) to give 695 mg of 5-(benzyloxycarbonylamidino)furo[2,3-b]pyridine-2-carboxylic acid as a yellow solid (35%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH2:15](C([Sn])=C(CCCC)CCCC)[CH2:16]CC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:15]=[CH2:16])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(=O)OC)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
To a solution of 4-bromo-2-nitro-benzoic acid methyl ester (1 g, 3.85 mmol) in dioxane (5 mL) were added tributylvinyltin (1.7 mL, 5.76 mmol) and Pd(Ph3P)2Cl2 (275.4 mg, 0.385 mmol). The reaction mixture was stirred at 80° C. for 18 h, was cooled to r.t. and was diluted with EtOAc. After removal of the precipitate by filtration, the solution was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes 1:1 hexanes:EtOAc) to provide the title compound (820 mg, 100%, 97% purity by HPLC) as a yellow oil. ESI-MS: m/z 208.2 [M+H]+, rt 5.14 min.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][C:20](OC)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[CH:4]([C:3]1[N:7]=[C:20]([CH2:19][CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Reactant: CC(C)C(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
2.20 g (21.54 mmol) N-hydroxy-isobutyramidine are placed in 10 ml dimethylformamide and molecular sieve. 0.948 g (23.69 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 6.20 g (30.51 mmol) methyl 3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added and the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phases are evaporated down. The residue is purified by chromatography.
Reaction SMILES: CO[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].Br[CH2:10][C:11]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])=O.[NH2:21][CH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>>[OH:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[CH2:22][NH:21][C:3]([C:4]1[CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]=1[CH3:6])=[O:8]
Reactant: O=C(CBr)c1cc(F)ccc1F
Reactant: NC[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)CC(C)=O
Product: Cc1c(C(=O)NCC2CCCCC2O)cc(-c2cc(F)ccc2F)n1CC1CCCCC1

Procedure:
The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-(2,5-difluorophenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3—(CH2)m—NH2 and trans-2-aminomethyl-1-cyclohexanol as R1R2NH, MS (ISP) 445.5 (M+H)+.
Reaction SMILES: COC1C=C(C=CC=1OC)C(C1C=CC(OC)=C(OC)C=1)=O.[C:23]1([O:31][CH3:32])[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:25][CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[C:40]=1[C:41](Cl)=[O:42]>>[CH3:49][O:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH3:37])[C:40]=1[C:41](=[O:42])[C:29]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:23]([O:31][CH3:32])[CH:30]=1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COc1ccccc1OC
Agent: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2c(OC)cccc2OC)cc1OC

Procedure:
2′,6′,3,4-Tetramethoxybenzophenone was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone except using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.47 g, 11 mmol) and 2,6-dimethoxybenzoyl chloride (2.0 mL, 10 mmol) with a reaction time of 24 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 2.11 g (70%) of the product as a white solid: mp 128–129° C.; 1H NMR (CDCl3) δ 7.66–7.60 (m, 1H), 7.40–7.20 (m, 2H), 6.88–6.79 (m, 1H), 6.67–6.65 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.71 (s, 6H); 13C NMR (CDCl3) δ 193.8, 157.4, 153.4, 148.9, 130.9, 130.5, 125.3, 118.0, 110.2, 109.9, 104.0, 55.9, 55.8; Anal. Calcd for C17H18O5. Theoretical: C, 67.54; H, 6.00. Found: C, 66.51; H, 5.91.