Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])([CH3:7])[CH2:3][C:4](=O)[CH3:5].O=[C:17](C=C(C)C)C.[P:23]([O-:30])([O:27]CC)[O:24][CH2:25][CH3:26].[O-]CC.[Na+]>>[O:27]=[P:23]1([O:24][CH2:25][CH3:26])[C:4]([CH3:5])([CH3:17])[CH2:3][C:2]([CH3:7])([P:8]([O:10][CH2:11][CH3:12])([O:13][CH2:14][CH3:15])=[O:9])[O:30]1
Reactant: CCOP([O-])OCC
Reactant: CC(=O)C=C(C)C
Reactant: CCOP(=O)(OCC)C(C)(C)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Product: CCOP1(=O)OC(C)(P(=O)(OCC)OCC)CC1(C)C
Reaction time: 0.08 h

Procedure:
To a mixture of 2.36 grams (10 m moles) of 4-methyl-4-diethylphosphonopentan-2-one (prepared from 1 mole of mesityl oxide and 1 mole of diethyl phosphite by the procedure of A. N. Pudovik, Zhurn Obshch. Khim., 22, 1371 (1952) and 1.64 grams (11.9 m moles) of diethyl phosphite was added 0.30 gram of ethanolic sodium ethoxide solution containing 0.75 m moles of sodium ethoxide. A spontaneous exothermic reaction took place immediately. After 5 minutes the reaction mixture was analyzed by gas phase chromatography and was shown to contain over 70% of the desired 2-oxo-2-ethoxy-3,3,5-trimethyl-5-diethyl-phosphono-1,2-oxaphospholane. The product was then isolated by vacuum distillation as described in Example 3.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[K+].[I:22]I>CN(C=O)C>[I:22][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([C:9]3[CH:8]=[N:7][CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=3)[CH:12]=2)[NH:16][CH:15]=1
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]ccc3c2)n1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(I)c3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.6 %

Procedure:
To a solution of 5-(6-isopropoxy-pyrazin-2-yl)-1H-indole (32 g, 0.126 mol) in DMF (250 mL) was added KOH (17.8 g, 0.316 mol) and then stirred for 15 min at RT. I2 (35.3 g, 0.139 mol) was added to the reaction mixture and stirred at RT for another 1 h. Then reaction mixture was poured into ice water and excess of I2 was quenched with sodium thiosulfite. The resulting solid was collected by filtration, washed with water and dried under vacuum to afford crude 3-iodo-5-(6-isopropoxypyrazin-2-yl)-1H-indole (49 g) as pale brown solid. MS (ESI, m/z): 379.9 (M+1). This material was used to further step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[F:13][CH:14]([F:28])[O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH:14]([F:13])[F:28])=[CH:17][CH:18]=2)(=[O:26])=[O:25])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(OC(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)/C=C/c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
2-Amino-4-chlorobenzenesulfonamide (200 mg, 0.97 mmol) and (E)-2-(4-(difluoromethoxy)phenyl)ethenesulfonyl chloride (260 mg, 0.97 mmol) were dissolved in anhydrous dichloromethane (5 mL) and flushed with argon. Anhydrous pyridine (0.391 mL, 4.84 mmol) was added and the reaction was stirred at room temperature under an inert atmosphere over night. The reaction was quenched using 2 M hydrochloric acid (20 mL) and extracted with dichloromethane. The combined organic phase was washed with water, dried over magnesium sulfate and concentrated under vacuum to give 426 mg (100% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[N:15]=1)[C:5]([O:7]C)=[O:6].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:27][CH2:28][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][CH2:31]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[N:15]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(OC)ccc3n2C)C2CCC(C(C)(C)C)CC2)c(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(N(Cc1ccc(C(=O)O)cc1Br)C1CCC(C(C)(C)C)CC1)n2C
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To the title compound of Example 224 Step D (0.07 mmol, 40 mg) in 2 mL of dioxane was added a solution of LiOH (1 mmol, 24 mg) in 1 mL of H2O. The reaction was allowed to stir at 40° C. for 1.5 h. The crude reaction mixture was poured into pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over Na2SO4, then concentrated under reduced pressure to afford the product as a slightly yellow-green foam. HPLC A: 2.32 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11].CCOC(C)=O>C(Cl)(Cl)Cl.CC(C)=O.[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: OC(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanol (0.50 g, 1.24 mmol) in chloroform (7.5 mL) and acetone (4.00 mL) under nitrogen was treated with was treated with manganese dioxide (0.504 g, 6.21 mmol) in one portion. The reaction was heated to 50° C. After 40 minutes, the reaction was filtered through a pad of Celite™. The filtrate was washed (2×) with an aqueous saturated solution of sodium bicarbonate, with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30 to 80% ethyl acetate in hexanes. The pure fractions were reduced under vacuum and the solid obtained was slurried in 1:1 EtOAc:ether, filtered and dried under vacuum to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone as a white solid. MS (ESI, pos. ion) m/z: 400.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O1CCOCC1.CCOC(C)=O.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>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:6]1[O:7][CH:8]=[CH:9][N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncco2)nc1
Yield: 67 %

Procedure:
2-(Tributylstannyl)oxazole (1.00 g, 2.79 mmol), (Ph3P)4Pd (0.1 equiv), and 2-bromopyridine (2 equiv) were dissolved in anhydrous 1,4-dioxane (15 mL) and the mixture was warmed at reflux for 24 h under Ar. The mixture was diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude product that was purified by flash chromatography (SiO2, 10-60% EtOAc-hexanes) to yield the title compound (275 mg, 67%) as a light yellow oil: 1H NMR (CDCl3, 500 MHz) δ 8.63 (m, 1H), 8.04 (d, 1H, J=7.5 Hz), 7.73-7.70 (m, 2H), 7.26-7.22 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 161.0, 150.2, 146.4, 140.1, 137.3, 129.1, 125.0, 122.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:19]=4[S:20][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:25][C:22]1[CH:23]=[CH:24][C:18]2[C:17]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[C:9]4[C:14](=[CH:15][C:16]=3[S:20][C:19]=2[CH:21]=1)[CH:13]=[CH:12][CH:11]=[CH:10]4
Reactant: Oc1ccc(-c2c3ccccc3cc3sc4cc(O)ccc4c23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)sc1cc3ccccc3c(-c3ccc(O)cc3)c12
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
11-(4-Hydroxy-phenyl)-benzo[b]naphtho[2,3-d]thiophen-3-ol (1.36 g, 3.96 mmol), methyl bromoacetate (0.38 mL, 4.01 mmol), potassium carbonate (0.548 g, 3.97 mmol) and N,N-dimethylformamide (21 mL) were combined and stirred at ambient temperatures for 2.5 h. The reaction mixture was added to water and extracted with ethyl acetate and THF. Silica gel was added to the organic phase and the solvent was removed. The adsorbate was flash chromatographed (eluent:gradient dichloromethane to 98:2 dichloromethane:acetonitrile) to provide the title compound as a white solid (0.953 g, 58%): mp: 229-231° C: NMR (DMSO-d6); δ9.78 (s, 1 H), 8.51 (s, 1 H), 8.00 (d, J=8 Hz, 1 H), 7.56-7.39 (m, 4 H), 7.18 (d, J=9 Hz, 2 H), 7.05 (d, J=9 Hz, 2 H), 6.79 (dd, J=9, 2 Hz, 1 H), 6.66 (d, J=9 Hz, 1 H), 4.86 (s, 2 H), 3.68 (s, 3 H); MS (EI): 414 (100%, M+); Anal. Calc. for C25 H18O4S: C, 72.45, H, 4.38, N, 0.00. Found: C, 71.78, H, 4.41, N, 0.13.
Reaction SMILES: C([N-][CH:5]([CH3:7])C)(C)C.[Li+].[Si:9]([N:16]1[CH:19]([CH2:20][CH2:21][O:22]C(=O)C)[CH2:18][C:17]1=[O:26])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[OH2:27].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Si:9]([N:16]1[CH:19]([CH2:20][CH2:21][OH:22])[CH:18]([C:5](=[O:27])[CH3:7])[C:17]1=[O:26])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: O
Reactant: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1CCO

Procedure:
To a solution of 1.1 equivalents of freshly prepared lithium diisopropylamide in 3 ml anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° is added a solution of 1-(t-butyldimethylsilyl)-4-(2'-acetoxyethyl)-2-azetidinone (61 mg, 0.225 mmole) in 1 ml anhydrous tetrahydrofuran which has been cooled to -78°. After 12 minutes the reaction mixture is poured into 5 ml water. The solution is saturated with sodium chloride and extracted with methylene chloride. The combined methylene chloride solutions are washed with brine, dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives 50 mg of crude product. Purfication by preparative thick-layer chromatography on silica gel developing with ethyl acetate gives 1-(t-butyldimethylsilyl)-3-acetyl-4-(2'-hydroxyethyl)-2-azetidinone (19 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH2:22][OH:23].ClCCl.[C:27](Cl)(=[O:29])[CH3:28]>C(N(CC)CC)C>[C:27]([O:23][CH2:22][C:3]1[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:29])[CH3:28]
Reactant: O=c1c2sc3c(c2cnn1-c1nccc(Cl)c1CO)CCCC3
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A round-bottomed flask was charged with 230g (597 mg, 1.72 mmol), dichloromethane (50 mL), and triethylamine (5 mL). The solution was stirred at 0° C. for 0.5 h and acetyl chloride (135 mg, 1.72 mmol) was added slowly. The mixture was stirred at 0° C. for another 2.5 h. It was then concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 9:1 petroleum ether/ethyl acetate to afford 230h (602 mg, 90%) as a yellow solid. MS-ESI: [M+H]+ 390.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:26])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2)cc1C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(Sc2ccc(CCl)cc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
An oven-dried 1 L round-bottomed flask was charged with compound 7.2 (30.0 g, 90.2 mmol) and chloroform (300 mL) and the mixture was cooled to 0° C. Thionyl chloride (7.90 mL, 107 mmol) was added dropwise at 0° C., and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give 7.3 as a slightly yellow oil (33.5 g), which was used in the next step without further purification. 1H NMR (400 MHz) (CDCl3) δ 7.30-7.20 (4H, m); 7.12 (2H, d, J=8.3 Hz); 6.68 (1H, d, J=8.4 Hz); 4.65 (2H, s); 4.53 (2H, s); 4.27 (2H, q, J=7.1 Hz); 2.27 (3H, s); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][O:9][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cncc(Br)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of ethyl 5-bromonicotinate (10.0 g, 43.46 mmol) in anhydrous THF (20 mL) was added dropwise to a slurry of LiAlH4 (1.91 g, 47.81 mmol) in anhydrous THF (200 mL) under argon at −78° C. and the mixture was stirred for 1.5 h at the same temperature, then warmed to r.t. The reaction mixture was added 15 ml of aqueous HCl (1 M) slowly at −78° C., the mixture was then warmed to rt and added anhydrous Na2SO4, stirred for overnight. The resulting mixture was filtered through celite and the solvent was removed under reduced pressure to give crude (5-bromopyridin-3-yl)methanol, which was used in the next step without purification. To a solution of (5-bromopyridin-3-yl)methanol (10.6 g, 56.40 mmol) in DMF (30 mL) was added, under argon, imidazole (9.98 g, 146.5 mmol) followed by triisopropylsilyl chloride (TIPS—Cl) (15.53 mL, 73.29 mmol). After stirring for 24 h at room temperature the reaction mixture was evaporated to dryness. Purification by flash chromatography (silica gel, hexanes/EtOAc, 9:1) gave 3-bromo-5-((triisopropylsilyloxy)methyl)pyridine as a colourless oil (11.8 g, 81% overall). 1H NMR (CDCl3): d: 1.00-1.237 (m, 21H), 4.837 (s, 2H), 7.849 (s, 1H), 8.480 (s, 1H), 8.556 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[O:19])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 53.8 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and isopropyl isocyanate (80 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (111 mg, 54%). LC-MS (m/z) 308.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1>O1CCCC1.C(N(C(C)C)CC)(C)C>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=4)=[O:42])=[CH:3][C:4]=3[F:29])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (84.3 mg) in tetrahydrofuran (2.5 ml) were added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 5.02 ml) and diisopropylethylamine (0.218 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (34.0 mg, 28%) as white powder.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[CH3:24].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=3)[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)c(C)c3)CC2)nn1C(C)(C)C

Procedure:
95 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(3,4-dimethylphenyl)piperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=O>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][C:31]([F:32])([F:33])[F:34])=[C:22]([F:21])[CH:23]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: O=Cc1ccc(OC(F)(F)F)c(F)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-fluoro-4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 429.97 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C:8]2[CH:17]=[C:16](B(O)O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.C1(S([N:31]2[C:35]3=[CH:36][N:37]=[CH:38][CH:39]=[C:34]3[C:33](I)=[CH:32]2)(=O)=O)C=CC=CC=1.[C:41](=O)([OH:43])[O-:42].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:41]([OH:43])=[O:42].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C:8]2[CH:17]=[C:16]([C:33]3[C:34]4[C:35](=[CH:36][N:37]=[CH:38][CH:39]=4)[NH:31][CH:32]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: OB(O)c1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccncc21
Reactant: O=C([O-])O
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cl)cc1-c1cc(-c2c[nH]c3cnccc23)c2cccnc2n1
Product: O=CO
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A slurry of 363 mg (1.20 mmol) 2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 384 mg (1.00 mmol) 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-c]pyridine (synthesis described in WO2006/052568) and 111 mg (1.32 mmol) sodium bicarbonate in 2 ml DMF and 1 ml water was heated to 80° C. under nitrogen. Then 41 mg (0.05 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 2 days at 90° C. Water was then added to the reaction mixture and the resulting precipitate was filtered off. The residue was purified by preparative HPLC yielding 2-(5-chloro-2-fluoro-phenyl)-4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-[1,8]naphthyridine formate as colourless solid; HPLC-MS: 1.57 min, [M+H] 375.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:9].[C:10]1([CH3:18])[CH:15]=[C:14](C)[CH:13]=[C:12](C)[CH:11]=1>[Ru]>[CH2:1]([NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:1](=[N:9][CH2:18][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: OCc1ccccc1
Reactant: Cc1cc(C)cc(C)c1
Agent: [Ru]
Product: C(=NCc1ccccc1)c1ccccc1
Product: NCc1ccccc1
Reaction time: 1 h
Yield: 28 %
Yield: 69 %

Procedure:
Benzyl alcohol was reacted with ammonia in the presence of ruthenium catalyst 1 (0.1 mol %) in refluxing mesitylene (b.p. 163° C.). As shown in Table 1 entries 1-3, 98% conversion of the alcohol was observed after 1 hr, yielding 69% of benzylamine and 28% of N-benzylidenebenzylamine. Slightly higher yields of benzylamine were observed at longer reaction times. Similar results were obtained at lower temperature in refluxing p-xylene (b.p. 138° C.) after 3 hrs (Table 1, entry 4). When the reaction was performed for the same period in toluene (b.p. 110.5° C.) the conversion of benzyl alcohol was less efficient (Table 1, entry 5), but after 13 h 99% conversion of benzyl alcohol occurred (Table 1, entry 6) to provide benzylamine in 87% yield along with N-benzylidenebenzylamine (12%). A further drop in reaction temperature using dioxane (b.p. 100° C.) as a solvent resulted in a lower conversion (Table 1, entry 7).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[CH3:29][S:30]([CH2:33][CH2:34][NH2:35])(=[O:32])=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:35][CH2:34][CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1
Reactant: CS(=O)(=O)CCN
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-(methylsulfonyl)ethanamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light brown semisolid, MS (ESI−): m/z=479.1 [M−H]−.