Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2(F)[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9]2)=[N:6][CH:7]=1.[C:15]([O:19][C:20]([N:22]1[C@H:26]([CH2:27][F:28])[C@@H:25]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[O:24][C:23]1([CH3:45])[CH3:44])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[O:12]=[S:10]1(=[O:13])[CH:11]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][C:29]([C@H:25]4[O:24][C:23]([CH3:44])([CH3:45])[N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[C@@H:26]4[CH2:27][F:28])=[CH:34][CH:33]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=S1(=O)CC(F)(c2ccc(Br)cn2)C1
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
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: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C4=CS(=O)(=O)C4)nc3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
The solution of the product of step 3, Example 18 (0.15 g, 0.538 mmol, 1 eq), (4S,5R)-4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (previously described in US2004082553, Example 20, intermediate 19, 0.234 g, 0.538 mmol, 1 eq) and sodium carbonate (0.171 g, 1.613 mmol, 3 eq) in mixture of Toluene/Ethanol/Water (1:1:0.5, 2.5 mL) is degassed with nitrogen for 30 minutes in sealed tube. To the resulting reaction mixture tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.054 mmol, 0.1 eq) is added. Resulting reaction mixture is heated at 80° C. for 6 hours. The reaction mixture is quenched with water (15 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer is dried over sodium sulphate and concentrated in vacuo. The crude compound is purified by column chromatography using (100-200 mesh silica). Desired compound is eluted with 30% ethyl acetate in hexane to afford title compound as yellow solid (0.16 g): 1H-NMR (400 MHz, DMSO) δ: 1.43 (bs, 9H), 1.51 (s, 3H), 1.64 (s, 3H), 3.85-3.90 (m, 1H), 4.47-4.59 (m, 1H), 4.75-4.84 (m, 1H), 5.05 (s, 2H), 5.15 (d, 1H, J=7.16 Hz), 7.62 (d, 2H, J=8.12 Hz), 7.76 (s, 1H), 7.87 (d, 2H, J=8.2 Hz), 7.93 (d, 1H, J=8.12 Hz), 8.31-8.34 (dd, 1H, J1=8.24 Hz, J2=2.16 Hz). 9.07 (d, 1H, J=1.88 Hz). LC-MS (m/z): [M+H] 489.1.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:32])[C:19]([CH3:31])([S:21]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[CH2:33]([Li])CCC.CI>C1COCC1>[CH3:11][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:32])[C:19]([CH3:31])([S:21]([CH:24]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH3:33])(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:1])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C1CCOCC1)S(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 0.4 g (0.85 mmol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide (synthesized according to method B, step 1) in anhydrous THF (5 mL) under nitrogen is cooled to −78° C. A 2.5 M solution of n-butyl lithium in hexanes (1 mL) is added dropwise. The reaction mixture is stirred at −78° C. for 1 h, followed by addition of 0.11 mL (1.69 mmol) of methyl iodide. The reaction is allowed to warm to room temperature and stirred for 18 h. The mixture is quenched by addition of water (5 mL) and the organic solvent is removed under reduced pressure. The aqueous residue is extracted with DCM (2×10 mL). The combined organic extracts are washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by mass-triggered preparative LC (neutral method) to afford 0.1 g of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-[1-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide. Yield: 24%, ES-MS: 403 [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[N:12]1[C:21]2[CH:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:22]([CH:20]2[C:21]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18][CH2:19]2)[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCCN(Cc1cccc2cc[nH]c12)C1CCCc2cccnc21
Yield: 35 %

Procedure:
A heavy-walled Pyrex tube was charged with a solution of indole-7-carboxaldehyde (0.50 g, 3.44 mmol) in 1,2-dichloroethane (5 mL). This solution was treated with tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (1.21 g, 3.78 mmol), sodium triacetoxyborohydride (1.46 g, 6.88 mmol) and a catalytic amount of acetic acid (2 drops). The reaction mixture was exposed to microwave irradiation for 10 min at a temperature of 100° C. After the irradiation, the reaction tube was cooled with high-pressure air until the temperature had fallen below 40° C. The crude reaction mixture was poured onto a saturated aqueous solution of sodium bicarbonate. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.54 g (35% yield) of the desired product 6: 1H NMR (400 MHz, CDCl3) δ 12.87 (bs, 1H), 8.56 (d, J=3.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.41-7.37 (m, 2H), 7.10 (dd, J=5.2, 7.6 Hz, 1H), 6.97-6.88 (m, 2H), 6.51-6.49 (m, 1H), 4.26-4.20 (m, 2H), 3.96 (d, J=13.2 Hz, 1H), 3.60 (d, J=13.2 Hz, 1H), 2.92-2.72 (m, 3H), 2.65-2.55 (m, 2H), 2.50-2.40 (m, 1H), 2.29-2.20 (m, 1H), 2.14-2.04 (m, 1H), 1.95-1.68 (m, 2H), 1.47-1.15 (m, 2H), 1.39 (s, 9H); ESI+ MS: m/z (rel intensity) 449.2 (100, [M+H]+) Step b: Preparation of N1-((1H-indol-7-yl)methyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (B). A solution of tert-butyl 4-(((1H-indol-7-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)butylcarbamate, 6, (0.27 g, 0.60 mmol) in methanol (5 mL) was treated with thionyl chloride (1 mL) at room temperature. The resulting mixture was stirred for 30 min. The reaction mixture was then concentrated and dried under reduced pressure to afford 0.26 g (87% yield) of the desired product, B: 1H NMR (400 MHz, d6-DMSO) δ 11.97 (bs, 1H), 8.44 (d, J=4.8 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.48-7.40 (m, 1H), 7.35-7.20 (m, 2H), 6.98 (t, J=6.8 Hz, 1H), 6.44 (bs, 1H), 4.90-4.78 (m, 2H), 3.60-3.53 (m, 2H), 3.10-3.00 (m, 2H), 2.80-2.60 (m, 4H), 2.50-2.39 (m, 1H), 2.30-1.40 (m, 7H); ESI+ MS: m/z (rel intensity) 349.2 (100, [M+H]+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1(Br)[CH:18]([CH3:20])[CH3:19].N12CCCC1=NCCC2.O>CS(C)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]=[C:3]1[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C1(Br)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: C1CN=C2CCCN2C1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C1=Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 69.2 %

Procedure:
(1-Oxo-2-bromo-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (17.3 g., 0.044 mole) is dissolved in dimethyl sulfoxide (DMSO, 100 ml.) stirred under nitrogen and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (13 g.) is added dropwise. When the exothermic reaction ceases, the mixture is stored at 20°-25°C. for 1 1/2 hours and then poured into water (1.5 l.). The precipitate is recrystallized from acetic acid-water (1:1) to afford (1-oxo-2-isopropyl-6,7-dichloroinden-5-yloxy)acetic acid (9.6 g.), m.p. 175.5°-176°C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17](=[O:19])(=[O:18])[NH:16][C:15](=[O:20])[CH:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CS(C)=O>[C:21]([NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:17](=[O:19])(=[O:18])[NH:16][C:15](=[O:20])[CH:14]=2)=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.2 %

Procedure:
(2S)-2-amino-3-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]propanoic acid (45 mg, 0.15 mmol) was dissolved in N-methylpyrrolidinone (1.0 mL) with 20 drops of DMSO added to fully dissolve. To the solution was added acetic anhydride (14 μL, 0.15 mmol) and N,N-diisopropylethylamine (79 μL, 0.46 mmol). The solution was stirred at room temperature for 2 h. The product was purified by preparative LCMS to afford the desired product (61 mg, 96%). LCMS found for C14H15N2O6S (M+H)+: m/z=339.1
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:11][C@H:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]3[C:14]=2[C:15]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[NH:16][C:17](=[O:24])[NH:18]3)[CH2:9]1)=[O:7])(C)(C)C.Br.O>C(O)(=O)C>[C:6]([OH:7])(=[O:5])[CH3:8].[Cl:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][C@H:10]2[CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:11]2)=[C:14]2[C:19]=1[NH:18][C:17](=[O:24])[NH:16][C:15]12[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H](Oc2ccc(Cl)c3c2C2(CCCCC2)NC(=O)N3)C1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2c(Cl)ccc(O[C@H]3C[C@H](C(=O)O)C3)c2C2(CCCCC2)N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product of step (a) (207 g, 0.492 mol) was slurried in acetic acid (3100 ml) and heated to 60° C. 48% Hydrobromic acid (4.93 mol) was added dropwise keeping the temperature at 60° C. The solution was stirred at 60° C. for 30 minutes. Water (700 ml) was added dropwise keeping the temperature above 55° C. The slurry was cooled to 20° C. and stirred for a further 30 minutes after which it was filtered, washed with acetic acid:water (2000 ml) and water (1000 ml) before being dried in a vacuum oven overnight at 60° C. to yield a white solid of the title compound as an acetic acid solvate (153.6 g, 73.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[O:8]C.C[S-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(C2OCCO2)cc1F
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Oc1ccc(C2OCCO2)cc1F
Yield: 51.7 %

Procedure:
A solution of 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane (250 mg, 1.26 mmol) and Sodium thiomethoxide (106 mg, 1.51 mmol) in dry N,N-dimethylformamide (3.5 mL) was heated at 100° C. under nitrogen for 4 hours. Then a saturated solution of ammonium chloride (15 mL) was added and the aqueous layer extracted with methylene chloride (4×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 7:3) to produce 4-[1,3]dioxolan-2-yl-2-fluoro-phenol as a pale brown oil (120 mg, 52%). 1H-NMR (CDCl3, 200.15 MHz): δ 7.24–7.01 (m, 2H), 6.88 (t, 1H, J=8.4), 6.07 (sa, 1H), 5.71 (s, 1H), 4.13–3.95 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]\[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[O:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][C:22]1[C:30]2[NH:29][C:28]([CH2:31][CH2:32][CH3:33])=[N:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:21][C:22]1[C:30]2[N:29]=[C:28]([CH2:31][CH2:32][CH3:33])[N:27]([CH2:2][C:3]3[CH:20]=[CH:19][C:6]4/[C:7](=[CH:16]\[C:17]#[N:18])/[C:8]5[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=5[O:10][CH2:11][C:5]=4[CH:4]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: N#C/C=C1\c2ccc(CBr)cc2COc2ccccc21
Reactant: CCCc1nc2cccc(C)c2[nH]1
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/C#N
Yield: 76.2 %

Procedure:
[step 1] Using (E)-2-(8-bromomethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonitrile (1.5 g, 4.6 mmol) obtained in Reference Example B13 and 4-methyl-2-propylbenzimidazole (EP400835; 842 mg, 4.83 mmol) and in the same manner as in Example 92, step 1, (E)-2-{8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile (1.47 g, 76%) was obtained. [step 2] (E)-2-{8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile (150 mg, 0.34 mmol) obtained in step 1 was dissolved in ethanol (1.8 mL), hydroxylamine (50% aqueous solution, 1.1 mL, 17.9 mmol) was added, and the mixture was stirred under reflux for 18 hr. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (1.8 mL), triethylamine (75 μL, 0.54 mmol) and ethyl chlorocarbonate (51 μL, 0.54 mmol) were added at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene (0.9 mL) and THF (0.9 mL), potassium tert-butoxide (80 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 20 min. 5% Aqueous citric acid solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 10/90) to give the title compound (compound 104) (119 mg, 70%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7](O)=[C:6]([OH:11])[C:5]=1[OH:12]>O.[Rh]>[C:4]1([CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=1[OH:12])[OH:3]
Reactant: Oc1ccc(O)c(O)c1O
Agent: [Rh]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(O)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.4 %

Procedure:
A solution consisting of 0.4 g of NaOH (10 mmol) dissolved in 10 mL H2O was freeze-thaw degassed three times under Ar. This solution was then added via cannula under Ar to a 250 mL Parr bottle containing 1,2,3,4-tetrahydroxybenzene (1.42 g, 10 mmol) and 5% Rh/Al2O3 (0.25 g), which had been flushed with Ar and then sealed with a septum. The resulting red/brown solution was hydrogenated under 50 psi. H2 using a Parr Hydrogenator. After 12 h, the solution was filtered through Celite® and the catalyst rinsed with 10 mL H2O. The resulting dark brown solution was adjusted to pH=6.0 with 10% HCl and then concentrated to a brown oil. The oil was dissolved in 50 mL 0.5 M H2SO4 that had been degassed by aeration with Ar for 20 minutes. The solution was heated to reflux under Ar for 12 h, cooled to room temperature, and then extracted with Et2O (4×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to a brown oil. Kugel-Rohr distillation of the oil under vacuum (1 mm Hg) at 90° C. afforded 0.56 g pyrogallol (4.44 mmol, 44% yield) as a white, crystalline solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:7]([OH:9])=O.[NH2:20][C:21](=[N:37]O)[C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:37]=[C:21]([C:22]3[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=3)[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Reactant: CCOC(=O)CCCOc1cccc(C(N)=NO)c1
Product: CCOC(=O)CCCOc1cccc(-c2noc(-c3ccc(N4CCCCC4C)c(COC)c3)n2)c1

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 58 (158 mg; 0.60 mmol) and Intermediate 67 (151.79 mg; 0.57 mmol), the crude mixture was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.32 (d, J=2.1 Hz, 1H), 8.09 (dd, J=8.2, 2.1 Hz, 1H), 7.77 (dd, J=7.7, 1.2 Hz, 1H), 7.69 (dd, J=2.5, 1.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.04 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 4.68-4.57 (m, 2H), 4.20-4.09 (m, 4H), 3.49 (s, 3H), 3.16 (br s, 1H), 3.06-3.02 (m, 1H), 2.65-2.62 (m, 1H), 2.56 (t, J=7.3 Hz, 2H), 2.20-2.11 (m, 2H), 1.86-1.69 (m, 4H), 1.49-1.45 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H). LC/MS (Method B): 494.5 (M+H)+. HPLC (Method A) Rt 4.59 min (Purity: 98.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[I:11]I>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[I:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH:7]=[O:8]
Reactant: COc1ccc(C=O)cc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C=O)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate (0.92 g, 4.19 mmol) were mixed in dichloromethane (25 mL). Iodine (1.19 g, 4.7 mmol) was added in small portions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an aqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3×20 mL) followed by drying with MgSO4 and evaporation in vacuo afforded 0.94 g of 3-iodo-4-methoxybenzaldehyde.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([C:34](O)=[O:35])[CH:25]=1>>[OH:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:34]([C:26]3[CH:25]=[N:24][C:33]4[C:28]([CH:27]=3)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:35])[CH2:3][CH2:2]1)[CH2:11]2
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Reactant: O=C(O)c1cnc2ccccc2c1
Product: CCCN(CCN1CCN(C(=O)c2cnc3ccccc3c2)CC1)C1CCc2c(O)cccc2C1
Yield: 99.9 %

Procedure:
Compound 40j was prepared following Procedure G using 39b (172 mg, 0.542 mmol) and quinoline-3-carboxylic acid (112 mg, 0.650 mmol) to give 40j (256 mg, 85%) after column chromatography. 1H NMR (400 MHz, CD3OD) 0.93-0.96 (t, 3H, J=7.2 Hz), 1.57-1.59 (m, 3H), 2.18 (m, 2H), 2.55-3.00 (m, 14H), 3.55 (bs, 2H), 3.85 (bs, 2H), 6.53-6.58 (t, 2H, J=8 Hz), 6.88-6.91 (t, 1H, J=11.2 Hz), 7.81-7.72 (t, 1H, J=7.6 Hz), 7.85-7.88 (t, 1H, J=7.6 Hz), 8.03-8.1 (m, 2H), 8.45 (bs, 1H), 8.89 (bs, 1H). The free base of 40j was converted into its HCl salt. m.p. 142-146° C. Anal. [C29H36N4O2.3HCl.2H2O] C, H, N.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[N:25]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[N:12]3[N:11]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH3:42]>O1CCOCC1>[CH:19]1([NH:18][C:17]2[N:12]3[N:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:26]=[CH:27][C:3]([CH2:2][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH3:42])=[CH:4][CH:5]=4)[N:25]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(CCl)cc1
Reactant: CNCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3cccc(NC4CCCCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a reaction vessel containing 4-chloromethyl-N-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B8), 90 mg, 0.23 mmol, 1 eq.) and N,N-diisopropylethylamine (0.35 mmol, 61 μL, 1.5 eq.) in dioxane (3 mL) was added N-(2-methoxyethyl)methylamine (0.28 mmol, 25 μL, 1.2 eq.) dropwise. The vessel was capped and the reaction stirred at room temperature for 1 hour and heated to 80° C. for a further 15 hours. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a light yellow solid (3.9 mg, 4%). HPLC, Rt: 3.46 min (purity: 93%). LC/MS M+(ESI): 437.2, M−(ESI) 435.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[C:22]=1[CH3:31].CN(C=O)C>CC#N>[CH3:31][C:22]1[C:23]([CH3:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C
Reactant: Nc1cc(O)ccn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccnc(N)c2)ccc([N+](=O)[O-])c1C
Temperature: 25 °C

Procedure:
To a suspension of 2-aminopyridin-4-ol (339 mg, 3.07 mmol) in MeCN (4.0 mL) at RT was added DBU (570 μL, 3.78 mmol) and after 30 min a solution of 1-fluoro-2,3-dimethyl-4-nitrobenzene (400 mg, 2.36 mmol) in MeCN (2.0 mL) was added dropwise. The reaction mixture was maintained at RT for 16 hr; DMF (2.0 mL) was added and the mixture heated to 80° C. for 72 hr and then cooled to RT for 64 hr. The resulting mixture was evaporated in vacuo and the residue was partitioned between DCM (50 mL) and brine (30 mL). The organic layer was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 20-100%, gradient elution and then SiO2, 12 g, 50% EtOAc in isohexane, isocratic elution) to afford 4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-amine, as a yellow solid (117 mg, 19%); Rt 1.47 min (Method 2); m/z 260 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([S:14]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7].CN(C=O)C.I[CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:36]([N:17]([S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])=[O:7])[CH:9]=1)(=[O:15])=[O:16])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1)[CH2:37][CH3:38]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)nc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a mixture of 500 mg of methyl 6-{[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate and 10 mL of DMF were added 0.300 mL of 1-iodopropane and 400 mg of potassium carbonate, followed by stirring at 80° C. for 5 hours. The reaction mixture was left to stand to cool and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain 200 mg of a methyl 6-{propyl[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate as a colorless oily substance. ESI+: 479