Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10].[OH-].[K+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C)(C)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccccc1Cl
Yield: 84.3 %

Procedure:
A solution of ethyl 2-(2-chlorophenyl)-2-methylpropanoate (3.48 g, 15.4 mmol) and KOH (8.61 g, 154 mmol) in EtOH/water (1:1, 200 mL) was heated at 150° C. in a sealed vessel for 2 hours. The solution was concentrated in vacuo, suspended in diethyl ether (200 mL), and extracted with 1N NaOH(aq) (3×100 mL). The aqueous solution was made acidic with concentrated HCl and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, concentrated, and dried in vacuo to give to give 2-(2-chlorophenyl)-2-methylpropanoic acid (2.578 g). MS m/e=199 (M+H)+.
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:10](CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:15][S:16]([NH2:10])(=[O:18])=[O:17].[CH3:15][S:16]([NH2:7])(=[O:18])=[O:17].[C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: CS(N)(=O)=O

Procedure:
A mixture of 4-(7-methyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo- 2,3-d!pyrimidin-6-yl)phenylamine (EXAMPLE 188, 206 mg) in 40 ml of dichloromethane is cooled in an ice-water bath and treated with 0.15 ml of triethylamine followed by 0.05 ml of methanesulfonyl chloride. Three additional portions of methanesulfonyl chloride, 0.02 ml, 0.01 ml and 0.01 ml, are added in sequence over the next hour. The mixture is poured onto water, treated with aqueous saturated sodium bicarbonate and extracted with three portions of dichloromethane. The combined organic extracts are dried and concentrated to give a solid which is combined with previously isolated material (from a 50 mg run) and chromatographed over silica eluting with methanol/chloroform (3/97) to give the desired material which is recrystallized from hot acetonitrile to give the title compound, mp 245-248; NMR 7.49-7.47, 7.31-7.28, 6.42, 3.78-3.69, 3.64, 3.58-3.52, 3.36, 1.97-1.85δ.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH2:14])[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25].CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:14][S:24]([C:17]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH3:28])(=[O:26])=[O:25])[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: COC(=O)C(N)CNC(=O)OC(C)(C)C
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 3-tert-Butoxycarbonylamino-2-aminopropionic acid methyl ester (3.5 g, 13.7 mmol), mesitylsulfonyl chloride (3.9 g, 17.8 mmol), DIEA (7.2 mL, 41.1 mmol) in dichloromethane (100 mL) was stirred at 0° C. for one hour and overnight at room temperature. The solvent was removed and the crude reaction product was taken up in ethyl acetate (340 mL). The solution was washed with 5% solution of sodium carbonate (30 mL), 5% solution of hydrochloric acid (30 mL), with saturated sodium chloride solution (30 mL). Solvent was than dried over sodium sulfate and evaporated. Purification of the residue on silica gel (10%MeOH-EtOAc) gave 5.00 g of pure compound O-1 (84% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)COB([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])OC1.Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C@@:42]([CH3:57])([S:53]([CH3:56])(=[O:55])=[O:54])[C:43]([NH:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[O:44])=[CH:36][CH:35]=1.O>O1CCOCC1.[Pd+2]>[C:27]([NH:26][CH2:25][C@H:23]1[O:22][C:21](=[O:30])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][C@@:42]([CH3:57])([S:53]([CH3:56])(=[O:54])=[O:55])[C:43]([NH:45][O:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][O:48]4)=[O:44])=[CH:38][CH:39]=3)=[C:15]([F:31])[CH:16]=2)[CH2:24]1)(=[O:29])[CH3:28]
Reactant: C[C@@](CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OCC(C)(C)CO3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NC[C@@H]1CN(c2ccc(-c3ccc(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Temperature: 90 °C

Procedure:
Palladium (II) EnCat (230 mg, 0.07 mmol) was added to a mixture of potassium carbonate (207 mg, 1.5 mmol), N-({(5S)-3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (234 mg, 0.644 mmol), and 111a (2R)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which was prepared as in Preparation 7 (200 mg, 0.46 mmol) in dioxane:water (6 mL, 5:1) in a 20 mL sealed vial. The vial was heated overnight at 90° C. The reaction was cooled to ambient temperature, filtered through celite and the filtrate was washed with ethyl acetate (30 mL) and methanol (15 mL). The combined organics were concentrated in vacuo and purified by chromatography on silica gel (gradient: 80:20 heptanes:ethyl acetate to 0:100 heptanes:ethyl acetate, followed by ethyl acetate:methanol 90:10) to furnish the title compound as a light brown gum. Yield 50 mg, 18% theoretical yield. LCMS m/z 604.3 (M−1)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[O:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:19]1[CH2:20][O:21][CH2:22][CH:23]=1)(=O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]2[C:19]3[CH2:20][O:21][CH2:22][C:23]=3[C:11]([OH:10])=[C:12]([CH3:14])[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)C1=CCOC1
Reactant: Cc1coc(CCc2ccccc2)n1
Solvent: ClCCl
Product: Cc1nc(CCc2ccccc2)c2c(c1O)COC2

Procedure:
18.7 g (100 millimoles) of 2-β-phenylethyl-4-methyloxazole and 29.6 g (200 millimoles) of 3-methylsulfonyl-2,5-dihydrofuran are heated at 160° C. for 20 hours. The mixture is digested in methylene chloride and the residue is filtered off, digested in nitromethane and again filtered off. 10.5 g are obtained. Subsequent recrystallization from dimethylformamide gives pure 4-β-phenylethyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol of melting point 248° C.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: COc1cccc(C(=O)O)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: COc1cccc(C(=O)NC2C3CC4CC2CN(C4)C3)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-methoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 2.30 (d, J=14 Hz, 6H), 2.40 (s, 2H), 3.49 (s, 2H), 3.60 (s, 3H), 3.79-3.89 (m, 4H), 4.38 (s, 1H), 7.13 (d, J=3 Hz, 1H), 7.33-7.44 (m, 3H); MS (APCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29](F)[CH:28]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:48][NH2:49]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:28]=[C:29]3[C:30]([C:33]([NH2:34])=[N:48][NH:49]3)=[CH:31][CH:32]=2)[N:3]=1
Reactant: NN
Reactant: COc1cccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-{[3-(methyloxy)phenyl]methyl}-3-piperidinecarboxamide (186 mg, 0.392 mmol), EtOH (5 mL), Hunig's base (0.068 ml, 0.392 mmol), and hydrazine anhydrous (0.074 mL, 2.35 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (31 mg) as a light yellow solid. LC-MS (ES) m/z=487 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.16 (d, J=6.8 Hz, 3H), 1.58-1.71 (m, 2H), 1.76 (m, 1H), 1.86 (m, 1H), 2.36 (m, 1H), 3.75 (s, 3H), 4.19 (m, 1H), 4.23 (m, 1H), 4.33 (m, 1H), 4.37 (m, 1H), 5.38 (s, 2H), 6.08 (s, 2H), 6.59 (s, 1H), 6.81-6.91 (m, 3H), 7.26 (m, 1H), 7.52-7.63 (m, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 8.48 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: C(O)C.[O-]CC.[Na+].[C:8]([O:15][CH2:16][CH3:17])(=[O:14])[C:9](OCC)=O.[C:18](#[N:20])[CH3:19].[NH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH2:22].S(=O)(=O)(O)O>C(OCC)C.O>[NH2:20][C:18]1[N:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:22]=[C:9]([C:8]([O:15][CH2:16][CH3:17])=[O:14])[CH:19]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NNc1ccccn1
Reactant: CC#N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To diethyl ether (200 mL), was added a 20% sodium ethoxide ethanol solution (280 g, 820 mmol) at 0° C., and subsequently was added dropwise diethyl oxalate (19.8 g, 400 mmol), and the mixture was stirred at the same temperature for 30 minutes. To the solution, was added dropwise a solution of acetonitrile (21 mL, 400 mmol) in diethylether (20 mL), and the mixture was allowed to warm to room temperature and stirred at the same temperature for 24 hours. The resulting crystals were collected by filtration. The crystals were suspended in chloroform (400 mL), to which a solution of 2-hydrazinopyridine (34.3 g, 314 mmol) and conc. sulfuric acid (16.7 mL, 314 mmol) in water (300 mL) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 72 hours. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give the title compound (30.0 g, 45% yield).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:8][I:9]>C(O)C>[IH:9].[CH3:8][N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: C1CNCCNC1
Solvent: CCO
Product: CN1CCCNCC1
Product: I
Temperature: 95 °C
Reaction time: 5 h

Procedure:
To a solution of homopiperazine (5 g, 50 mmol) in 10 mL of ethanol added a solution of methyl iodide (0.62 mL, 10 mmol) in 5 mL of ethanol in a sealed tube. It was gently stirred at 95° C. for 5 hours. The resulting white precipitate was filtered, washed with a small mount of cold ethanol, and the filtrate was concentrated in vacuo to yield 1-methyl homopiperazine hydroiodide. MS m/z M+H=115. The obtained 1-methylhomopiperazine hydroiodide is convened into free base according to the procedure describing in Example 25. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-methyl homopiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-methylhomopiperazine (700 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The reaction is carried out at 45° C. for 15 hours. Semi-pure compound is isolated from silica gel column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][NH:55][CH3:56]>CS(C)=O.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([N:55]([CH3:56])[CH3:54])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:44])([F:43])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=3)[C:28]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CNC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(N(C)C)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 40 °C
Reaction time: 72 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) is dissolved in dimethylsulfoxide (2 ml), and thereto is added a 2M solution (300 μl) of dimethylamine in tetrahydrofuran under ice-cooling. The mixture is stirred at 40° C. for 72 hours in a closed vessel, and partitioned by adding water and ethyl acetate to the reaction solution. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-dimethylamino-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (78 mg). MS (m/z): 682 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32](=[O:34])[CH3:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:10]=12.N1C=CC=CC=1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl.C(OCC)(=O)C>[CH3:51][C:41]1[CH:46]=[CH:45][C:44]([S:47]([O:20][CH2:19][CH2:18][C:17]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:31][C:32](=[O:34])[CH3:33])=[CH:3][C:2]=3[F:1])[N:15]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:16]=2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCO)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCOS(=O)(=O)c2ccc(C)cc2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.10 mmol) of N-[3-fluoro-4-({3-(2-hydroxyethyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo-[2,3-b]pyridin-4-yl}oxy)phenyl]acetamide are initially charged in 2.0 ml of dichloromethane. 25 μl (0.31 mmol) of pyridine and 19.7 mg (0.10 mmol) of p-toluenesulfonyl chloride are added, and the mixture is stirred at RT overnight. Two more times, the same amounts of pyridine and p-toluenesulfonyl chloride are added, at intervals of 2 hours. After the reaction has come to completion, the reaction solution is diluted with ethyl acetate and extracted twice with saturated ammonium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[N:23]=[C:22]([Cl:29])[N:21]=1>CN(C)C=O>[ClH:29].[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[N:23]=[C:22]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:21]=1
Reactant: CCCc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2)n1
Product: Cl
Yield: 43.8 %

Procedure:
After 4-fluoroaniline(0.27 ml, 2.85 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-6-propyl-2-chloropyrimidine(0.5 g, 1.66 mmol) and dimethylformamide(5 ml), 0.3 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:31])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccc(F)cc1
Reactant: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2CN(CC)C(=O)OCc2ccc(F)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C:8]([OH:10])=O)=[N:2]1.[N+]([O-])(O)=O.[O:15]([CH2:19][CH2:20][NH2:21])[N+:16]([O-:18])=[O:17].C(OC(C)C)(C)C>>[O:15]([CH2:19][CH2:20][NH:21][C:8](=[O:10])[CH2:7][O:6][C:3]1[CH:4]=[CH:5][O:1][N:2]=1)[N+:16]([O-:18])=[O:17]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1ccon1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1ccon1)NCCO[N+](=O)[O-]
Yield: 54.1 %

Procedure:
Following a similar treatment to that in Example 2 and using 286 mg of 3-isoxazolyloxyacetic acid and 338 mg of nitroxyethylamine nitrate, 250 mg of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][NH2:24]>>[ClH:1].[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Reactant: NCC(O)CN
Product: COc1ccc2c(NCC(O)CN)cc(-c3ccccc3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 184-186° C. (and MS: m/e=323 (M+), was prepared from 4-chloro-7-methoxy-2-phenyl-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:16])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=1)[CH3:2].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:7]2[N:6]([CH3:16])[N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:9]=1)=[O:15])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1cnn(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCc1cnn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (106 mg, 0.45 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (164 mg, 0.43 mmol) [prepared according to Preparation 6] and PyBrop (254 mg, 0.54 mmol) in Chloroform (6 mL). DIEA (400 μL, 2.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (182 mg, 0.32 mmol, 71%): LC-MS (ES) m/z=567 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)[C:5]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: NS(=O)(=O)c1ccc(CNc2nc(Cl)ncc2-c2cccs2)cc1

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodopyrimidine, 4-aminomethyl-benzenesulphonamide and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.