Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[C:20](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[H-].[Na+].IC.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][CH3:20])=[CH:9][C:8]=2[C:14]([F:15])([F:16])[F:17])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CNc1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-(4-Fluorophenoxy)-3-trifluoromethyl-aniline (1.0 g, 3.7 mmol) was dissolved in THF (5 mL), and di-t-butyl dicarbonate (965 mg, 4.43 mmol) was added thereto. The resulting mixture was stirred at 80° C. for 3 hours. The reaction solution was concentrated. The residue was dissolved in THF (5 mL), and sodium hydride (258 mg, 5.6 mmol) was added thereto. The resulting mixture was stirred at room temperature for 30 minutes, and then iodomethane (348 μL, 5.6 mmol) was added thereto. The mixture was further stirred overnight, and a saturated ammonium chloride aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. Then, TFA (2 mL) was added to the residue, followed by stirring for 1 hour at room temperature. The reaction solution was concentrated, and a saturated sodium bicarbonate solution was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure to give a crude product of 4-(4-fluorophenoxy)-3-trifluoromethyl-N-methylaniline.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)=[CH:13][N:12](COCC[Si](C)(C)C)[C:9]3=[N:10][CH:11]=2)[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(OCC4CC4)cc23)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2c[nH]c3ncc(OCC4CC4)cc23)cn1
Yield: 93.2 %

Procedure:
A mixture of 28s (40 mg, 0.10 mmol) and 1.0 M TBAF in THF (3 mL) was heated at reflux for 7 h. The reaction mixture was then cooled, poured onto a mixture of AcOEt and saturated aqueous NaHCO3. The layers were separated, the aqueous phase extracted with more AcOEt (2×) then the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by PTLC using 5% MeOH in CH2Cl2 as eluent) to give 29s as a white solid (25.0 mg, 62%); 1H NMR (400 MHz, CDCl3) δ 0.40 (q, J=4.7 Hz, 2H), 0.69 (m, 2H), 1.33 (m, 1H), 3.91 (d, J=7.0 Hz, 2H), 4.00 (s, 3H), 7.36 (d, J=2.5 Hz, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.60 (s, 1H), 7.75 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 9.14 (bs, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na].[O-]CC>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:28]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium, ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in absolute ethanol (4 mL) was heated to reflux for about 3 d, cooled to room temperature, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotagq Flash 40S™, 10→15% ethyl acetate/hexanes) to give 304 mg (49%) of the title compound of Example 101, Step C as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H), 1.50 (s, 9H); MS (APCI) 312 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[CH:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[CH:18])[N:12]=[CH:11][N:10]=1)[CH2:4][C:5]#[CH:6]
Reactant: C#CCCO
Reactant: C#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCCOc1cc(OCC#C)ncn1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.1 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.13 g of 3-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.6 ml of a tetrahydrofuran solution containing 0.3 g of 4-chloro-6-(2-propynyloxy)pyrimidine was slowly added dropwise. The mixture was further stirred at 0° C. for 4.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(3-butynyloxy)-6-(2-propynyloxy)pyrimidine (the present compound (12)).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCC[C@@H]1C(O)=O.[Cl:25]N1C(=O)CCC1=O>ClCCl>[Cl:25][CH:14]([C:11]1([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH2:12][CH2:13]1)[CH:15]=[O:16]
Reactant: O=CCC1(c2ccc3ncccc3c2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)[C@H]1CCCN1
Solvent: ClCCl
Product: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Temperature: 0 °C

Procedure:
To a mixture of (1-quinolin-6-ylcyclopropyl)acetaldehyde (410 mg, 1.94 mmol), D-proline (45 mg, 0.39 mmol) in dichloromethane (10 mL) cooled (0° C.) was added N-chlorosuccinimide (311 mg, 2.33 mmol) with stirring. The reaction mixture was stirred at 0° C. for 1 h, then gradually warmed to RT. The reaction mixture was quenched with water, extracted with dichloromethane. The combined organic extracts were concentrated and the residue purified by flash chromatography eluting with ethyl acetate in hexanes (0-25% in 18 min) to afford the desired product. (320 mg, 67.1%) LCMS: (M+H)=246.2; (M+H2O+H)=264.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[N:11]#[C:12]Br.C(=O)(O)[O-].[Na+]>O>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[NH:10][C:12]([NH2:11])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
The procedure used was similar to that reported in J. Med. Chem. 40:811-818, 1997. A solution of 1,2-diamino-4,5-difluorobenzene (500 mg, 3.47 mmol) in water (5 mL) was cooled to 0° C. and then treated with a solution of cyanogen bromide (0.83 mL, 4.16 mmol, 5 M in acetonitrile) and solid sodium bicarbonate (583 mg, 6.94 mmol). The solution was stirred at rt overnight and was then concentrated in vacuo. The dark residue was suspended in ethanol and heated at reflux for 15 minutes. The hot suspension was filtered, rinsing with hot ethanol, and the filtrate was concentrated in vacuo to afford 5,6-difluoro-1H-benzimidazol-2-amine (580 mg, 59%), which was used in the next step without further purification. LC-MS m/z 170.2 (MH+), ret. time 0.85 min; 1H NMR (300 MHz, DMSO-d6) δ 6.30 (br s, 2H), 7.06 (dd, 2H), 10.79 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[CH2:29]1[C:31]2([CH2:35][NH:34][C:33](=[O:36])[O:32]2)[CH2:30]1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[F:1][C:2]1[CH:7]=[C:6]([N:34]2[CH2:35][C:31]3([CH2:29][CH2:30]3)[O:32][C:33]2=[O:36])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: O=C1NCC2(CC2)O1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cn(-c2ccc(N3CC4(CC4)OC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.24 g, 0.50 mmol), 4-oxa-6-azaspiro[2.4]heptan-5-one (0.068 g, 0.60 mmol), trans-1,2-diaminocyclohexane (0.024 mL, 0.20 mmol), CuI (0.019 g, 0.10 mmol), and K3PO4 (0.21 g, 1.0 mmol) in 1,4-dioxane (3 mL) was stirred at 110° C. under Ar atmosphere for 2 h. The mixture was diluted with AcOEt and filtered through a basic-silica gel pad, and then the silica gel was washed with AcOEt. The filtrate was concentrated under reduced pressure. The residue was chromatographed on basic silica gel (0/100-3/97 MeOH/AcOEt) to give white crystals. The crystals were recrystallized from AcOEt/hexane to give the title compound (0.17 g, 72% yield) as a white solid: mp 200-201° C.; 1H NMR (300 MHz, CDCl3): δ ppm 0.85-0.92 (2H, m), 1.33-1.40 (2H, m), 3.90 (3H, s), 4.08 (2H, s), 6.39 (1H, t, J=8.9 Hz), 6.96 (1H, ddd, J=8.9, 2.5, 1.4 Hz), 7.30 (1H, d, J=1.9 Hz), 7.35-7.45 (5H, m), 7.68 (1H, dd, J=13.7, 2.5 Hz), 7.77-7.79 (2H, m). LC-MS (ESI) m/z 474 [M+H]+. Anal. Calcd. for C25H20FN5O4.H2O: C, 62.94; H, 4.31; N, 14.68. Found: C, 62.83; H, 4.42; N, 14.77.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][C:21]([F:28])=[C:22]([F:27])[CH:23]=2)[N:18]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:26]1[CH:17]=[N:18][C:19]2[C:24](=[CH:23][C:22]([F:27])=[C:21]([F:28])[CH:20]=2)[N:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1cnc2cc(F)c(F)cc2n1
Temperature: 90 °C

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.607 g), and 2-chloro-6,7-difluoroquinoxaline McQuaid et al. J. Med Chem. (1992), 35(18), 3319-24 (0.569 g) were dissolved in dimethylformamide (1 ml) and heated to 90 ° C. for 5 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.460 g), MH+ 379.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].N1C=CC=CC=1.C(NC(C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O)CCCC([NH:28][CH:29]1[C:54](=[O:55])[N:31]2[C:32]([C:38]([O:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])=[C:33]([CH2:36]O)[CH2:34][S:35][C@H:30]12)=O)(=O)C1C=CC=CC=1.C(OC(C)C)(C)C>C(Cl)Cl.O.CO>[NH2:28][CH:29]1[C:54](=[O:55])[N:31]2[C:32]([C:38]([O:40][CH:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:39])=[C:33]([CH2:36][Cl:2])[CH2:34][S:35][C@H:30]12
Reactant: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
To a suspension of phosphorus pentachloride (27.0 g) in methylene chloride (200 ml) was added dropwise pyridine (10.3 g) at 0° C., followed by stirring at 5° C. for 20 minutes. Thereto was added at a time benzhydryl 7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate (21.0 g) at -40° C., followed by stirring at -30° C. for an hour and at -10° C. for additional an hour. To the reaction mixture was added at a time at -40° C methanol (100 ml), which was pre-cooled to -40° C., followed by stirring at -10° C. for an hour. Removal of the solvent gave a residue, to which methylene chloride (100 ml), water (30 ml) and diisopropyl ether (100 ml) were added in turn, and the mixture was stirred under ice-cooling for a while. The precipitated crystals were collected by filtration and suspended in ethyl acetate (300 ml), followed by adjusting to pH 8.0 with an aqueous sodium bicarbonate. The separated organic solution was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (2.8 g), mp 135°-140° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH:22]1[C:26]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1>>[NH:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:15](=[O:17])[CH:14]([N:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:20]#[N:21])=[CH:9][C:10]3=[O:19])[CH3:18])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2nc[nH]c2c1
Product: CC(C(=O)Nc1ccc2nc[nH]c2c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (purity 83%, 0.18 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 26 mg (0.20 mmol) of 1H-benzimidazole-6-amine were reacted according to General Method 1. Yield: 11 mg (15% of theory)
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:23])[C@H:4]([NH:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1)=[O:10])[C:5]([OH:7])=O.[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:5]([C@@H:4]([NH:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[CH:13]=2)=[O:10])[CH:3]([CH3:2])[CH3:23])=[O:7])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(NC(=O)N[C@H](C(=O)O)C(C)C)c2ccccc2n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)N[C@H](C(=O)N2CCC(Cc3ccccc3)CC2)C(C)C)c2ccccc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-3-methyl-2-[3-(2-methyl-quinolin-4-yl)-ureido]-butyric acid hydrochloride (337.8 mg, 1 mmol), 4-benzylpiperidine (175.3 mg, 1 mmol), HOBt (183 mg, 1.2 mmol) and TEA (0.35 mL, 2.5 mmol) in DMF (10 mL) is added EDC (230.0 mg, 1.2 mmol). The mixture is stirred for 15 h at room temperature and then quenched with sat. aqueous Na2CO3 (30 mL). The aqueous phase is extracted with CH2Cl2 (3×20 mL). The combined extracts are dried (Na2SO4), filtered and evaporated. The residue is purified by flash chromatography (SiO2, CH2Cl2/MeOH, 5/1) to provide the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[C:14]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:11]([C:43](OC)=[O:44])[C:10]=2[C:47]([O:49]C)=[O:48])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O.CO.C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[C:10]3[C:47](=[O:48])[O:49][C:43](=[O:44])[C:11]=3[C:12]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:13]3[C:18]=2[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=[C:14]3[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(C(=O)OC)c(OCc2ccccc2)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C1OC(=O)c2c1c(OCc1ccccc1)c1c(OCc3ccccc3)ccc(OCc3ccccc3)c1c2OCc1ccccc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
12.50 g of dimethyl 1,4,5,8-tetrakis(phenylmethoxy)-2,3-napthalene dicarboxylate prepared in Step 2A-c above was refluxed with 12.0 g of KOH in 24 mL of water, 300 mL of methanol and 100 mL of THF for 1 hour. The solvent was removed, and the residue acidified with 1N HCl. The solid was then collected by filtration and was refluxed in 55 mL of acetic anhydride for 30 minutes. After cooling to room temperature, a mixed solvent of 1:1 v/v diethyl ether and petroleum ether was added. The yellow crystalline solid was collected by filtration to yield 8.94 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([Si](C)(C)C)[N:15]=[N:14]1.[I:22]I>O1CCCC1.FC(F)(F)C([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([I:22])[N:15]=[N:14]1
Reactant: II
Reactant: C[Si](C)(C)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(-n2cc(I)nn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilyl-1,2,3-triazole (EP-400842-A1; 1.00 g) in tetrahydrofuran (20 ml) was added silver trifluoroacetate (623 mg) and iodine (716 mg) at −78° C. under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature over 1 hour and then left to stir for a further 16 hours. The reaction was filtered and the filtrate diluted with water (100 ml) and extracted with ether (100 ml), the organic fraction was separarted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography (silica, 100 g) eluted with dichloromethane:hexane (2:1) to give the title compound as a pale yellow crystalline material, m.p. 194-195° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:24]([O:26][CH2:27][CH3:28])=[CH2:25])CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].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:26][C:24]([C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1)=[CH2:25])[CH3:28]
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cnc(NC(=O)CCC(=O)OC)cn1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
Methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 1.00 g, 3.47 mmol) was dissolved in toluene in a microwave vial and lithium chloride, (0.178 g, 4.17 mmol), palladium triphenylphosphone tetrakis (0.405 g, 0.347 mmol) and tributyl(1-ethoxyvinyl)stannane (1.88 g, 5.21 mmol) were added. The reaction mixture was heated in a sealed vial overnight at 100° C. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, and the solvent were evaporated. The product was purified by flash chromatography (AcOEt/cyclohexane: 1/99→99/1) to give methyl 4-[[5-(1-ethoxyvinyl)pyrazin-2-yl]amino]-4-oxo-butanoate (0.36 g, 1.3 mmol, 37% Yield). This product (0.34 g, 1.2 mmol) was dissolved in tetrahydrofuran (2.20 g, 2.4 mL) and hydrochloric acid (1.2 mL, 2.4 mmol. 2M) was added. After 1 h, brine was added to the mixture and it was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The product was purified by flash chromatography (AcOEt/cyclohexane: 1/99→99/1) to give methyl 4-[(5-acetylpyrazin-2-yl)amino]-4-oxo-butanoate A34 (0.14 g, 0.56 mmol, 46% Yield). 1H NMR (400 MHz, CDCl3) 9.52 (1H, s), 9.19 (1H, s), 8.88 (1H, s), 3.70 (3H, s), 2.88-2.75 (2H, m), 2.58 (3H, s).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:32])=[C:27]([CH:29]([OH:31])[CH3:30])[CH:28]=1>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:32])=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=1
Reactant: CC(O)c1cc(Br)ccc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1Cl
Reaction time: 15 h
Yield: 85.7 %

Procedure:
Pyridinium dichromate (2.6 g, 6.94 mmol) was added to a solution of 1-(5-bromo-2-chloro-phenyl)-ethanol (1.09 g, 4.6 mmol) in CH2Cl2 (20 mL). The reaction was stirred for 15 hours and then more pyridinium dichromate (2.6 g, 6.94 mmol) was added. After another 24 hours celite was added and the mixture was stirred for 20 mins. The reaction mixture was filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (0.92 g, 85%). 1H NMR (400 MHz, CDCl3): δ 2.64 (s, 3H), 7.29 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:22]([NH2:23])=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[C:6]=2[CH:5]=1)([O-:3])=[O:2].C(C1C(N)=C[C:29]2[O:30]C(C)(C)[C@@H](O)[C@H](N3CCCC3=O)[C:28]=2C=1)#N>>[N+:1]([C:4]1[C:22]([NH:23][C:29](=[O:30])[CH3:28])=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2cc(N)c([N+](=O)[O-])cc2[C@@H](N2CCCC2=O)[C@@H]1O
Reactant: CC1(C)Oc2cc(N)c(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2

Procedure:
6-nitro-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically salt thereof; or 6-cyano-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically acceptable salt thereof.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6].[N:14]([O-])=O.[Na+].[Sn](Cl)Cl>O1CCOCC1.O.Cl>[NH:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6])[NH2:14]
Reactant: O=N[O-]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CONC(=O)c1ccc(C)c(NN)c1
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
To a stirred solution of 3-amino-4-methylbenzoic acid 1 (5.64 g, 31.2 mmol, 1.0 eq) in 100 mL of dioxane and 100 mL of water at 0° C. was added 100 mL of conc. HCl followed by the portionwise addition of sodium nitrite (2.82 g, 40.9 mmol, 1.1 eq) as a solid at a rate to control gas evolution and foaming over 45 minutes. A clear brown solution resulted. Anhydrous tin(II)chloride (15.62 g, 83.7 mmol, 2.25 eq) was dissolved in conc. HCl (25 mL) and added dropwise over 25 mL at 0° C. After 1 hour, the precipitate was filtered and washed with dioxanes then dried under vacuum to provide 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 as a tan solid (4.98 g, 66%): HPLC (4 minute gradient) tR 0.97 min; MS m/z 167 [M+H]+; 1H (300 MHz, DMSO-d6) δ 10.03 (s, 1 H, COOH), 7.89 (s, 1 H), 7.51 (s, 1 H), 7.27 (d, J=8.0, 1 H), 3.38 (s, 3 H, NHNH2), 2.23 (s, 3 H) ppm.