Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][CH:25]([CH3:28])[CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[CH2:17]([O:24][CH:25]([CH3:28])[CH2:26][O:27][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(CO)OCc1ccccc1
Reactant: O=Cc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(COc1cccc(C=O)c1Br)OCc1ccccc1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
A mixture of 2-bromo-4-fluoro-benzaldehyde (30.0 g, 148 mmol), Na2CO3 (78.31 g, 738.8 mmol) and 2-benzyloxy propanol (24.56 g, 147.8 mmol) in anhydrous DMSO (300 mL) was heated with stirring at 130° C. (bath temp) for 72 h under N2. The reaction mixture was cooled to rt and diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexane to 30% EtOAc in hexane) to give the title compound: yield 3.84 g (7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1.[CH:26]1([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][N:15]([C:37]([CH:34]3[CH2:33][CH2:32][N:31]([C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[CH2:36][CH2:35]3)=[O:38])[CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)C2CC2)CC1
Product: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 648, step 1 and 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[CH:15].C(N(CC)CC)C.C(O)C>CC(N(C)C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]#[C:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Reactant: CCOC(=O)c1cc(I)ccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Yield: 77.9 %

Procedure:
Dichlorobis(triphenylphosphine)palladium (0.07 g, 0.1 mmol) and copper(I)iodide (0.04 g, 0.2 mmol) were added to a solution of ethyl 2-hydroxy-5-iodobenzoate (14.9 g, 50 mmol) and 4-ethynyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (14.3 g, 50 mmol) in triethylamine (10 g, 0.1 mol) and dimethylacetamide (60 ml) at 65° C. Hot ethanol was added after 1 h and then hot water (100 ml) with stirring. The solid was filtered off after cooling in the refrigerator and recrystallized from formic acid and water to yield 17.0 g (77% ) product.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>>[C:19]([O:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[C:3]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:2]=3[N:1]=[C:14]2[CH2:3][CH2:2][CH2:17][CH3:16])=[CH:6][CH:7]=1)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1ccc(F)cc1Nc1ccc(CCO)cc1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)OCCc1ccc(-n2c(CCCC)nc3ccc(F)cc32)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-[4-(2-amino-5-fluoroanilino)phenyl]ethanol (step 2) and pentanoyl chloride.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:5])[CH3:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CCOC(C)=O>[Br:1][CH2:2][CH:3]([CH3:4])[O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: C1=COCCC1
Reactant: CC(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(CBr)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromopropan-2-ol (1.25 g, 9.0 mmol) and 3,4-dihydro-2H-pyran (2.04 ml, 22.5 mmol) in dichloromethane (50 ml) at 0° C. was added p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol). The reaction mixture was stirred at 0° C. for 15 min then warmed to room temperature and stirred for 2 h. The reaction was diluted with EtOAc and washed with water, sat NaHCO3, and brine then dried over MgSO4 and concentrated to afford 2-(2-bromo-1-methyl-ethoxy)-tetrahydro-2H-pyran as a light brown oil which was used without further purification.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=O)[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[NH:11][C:10](=[S:39])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=S
Temperature: 110 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
2-Cyclohexyl-8-(2-o-tolyl-ethanesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (24.2 mg, 0.058 mmol), Lawesson's reagent (48.3 mg, 0.116 mmol) and toluene (1.16 ml) were added to a sealed test tube and stirred at 110° C. overnight. The reaction mixture was cooled to ambient temperature, and the solvent was then distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2-MeOH) to give 2-cyclohexyl-8-(2-o-tolyl-ethanesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-4-thione (11.2 mg, 45%).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)([OH:20])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1ccc2ccn3cccc3c(=O)c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2ccn3cccc3c(=O)c2c1

Procedure:
To 9-carbamoyl-11H-pyrrolo[2,1-b] [3]-benzazepin-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 9-carboxy-11H-pyrrolo[2,1-b] [3]benzazepin-11-one.
Reaction SMILES: [OH:1][C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:7][C:4]([CH3:5])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[O:1][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)C(C(O)=NO)C(C)(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)C(C(=NO)OS(C)(=O)=O)C(C)(C)C
Temperature: 35 °C

Procedure:
A solution of 7.5 g (0.04 mol) of 1-hydroxy-3,3-dimethyl-2-methylcarbamyloximinobutane and 5.0 g (0.044 mol) of methanesulfonyl chloride in 50 ml of benzene is treated dropwise with 4.6 g (0.044 mol) of triethylamine with cooling to keep the temperature below 35° C. After the addition, the stirred mixture is heated at 35° C. for 2 hours and then washed with aqueous sodium bicarbonate and with water. The organic layer is dried over magnesium sulfate, filtered, and stripped of volatiles to give 6.7 g (63%) of amber, viscous liquid residue, nD25 1.4810.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-])=O>CO.[Pd]>[NH2:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[NH:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(NC)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
Ethyl 4-methylamino-3-nitrobenzoate (6.80 g, 30.3 mmol) prepared in the Step 1-1-2 was dissolved in methanol (200 ml), and palladium 5% on carbon (1.10 g) was added to the solution. The mixture was stirred under a hydrogen flow at a room temperature overnight. The mixture was filtered, and the filtrate was concentrated to give the title compound (4.85 g, 82%) as a light-brown powder.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(C2C(O)=C[C:19]3[O:20]COC=3C=2)C1=O)CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:38]1[C:39]([OH:47])=[CH:40][C:41]3[O:45][CH2:44][CH2:43][C:42]=3[CH:46]=1)[C:31](=[O:37])[NH:32]2.BrCC(OCC)=O.C=O>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:38]1[C:39]([OH:47])=[CH:40][C:41]3[O:45][CH2:44][CH2:43][C:42]=3[CH:46]=1)([CH2:19][OH:20])[C:31](=[O:37])[NH:32]2
Reactant: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCC2
Agent: C=O
Agent: CCOC(=O)CBr
Product: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 31D, and making non-critical variations to replace 1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, and ethyl bromoacetate with para-formaldehyde, the title compound was obtained that was used directly for further reaction.
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O>[Pd].C(O)C.O>[NH2:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[C@H](N)C(=O)N(CC(=O)O)Cc1ccccc1

Procedure:
A solution of N-carbobenzyloxy-L-alanyl-N-benzyl glycine (6.0 g) and 10% palladium on carbon (2.0 g) in 200 ml ethanol was hydrogenated at 50 psi for 4 hours and filtered. Concentration of the volatiles in vacuo provided a residue which was dissolved in H2O and filtered. The aqueous solution was acidified with 25% aqueous HBr until pH 1 was obtained. The solution was lyophilized. The crystalline product was recrystallized from ether-acetonitrile (m.p. 84°-85° C.).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][OH:11])=[O:7])([CH3:4])[CH3:3].CC(C)(O)[C:18]#[N:19].C(N(CC)CC)C>>[OH:11][CH:10]([C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:12][CH2:13][CH2:14][CH3:15])[C:18]#[N:19]
Reactant: CC(C)(O)C#N
Reactant: CCCC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)C#N
Yield: 79.9 %

Procedure:
40 g (200 mmol) of (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]hexanol was dissolved in 300 ml of anhydrous methylenechroride, 34 g (400 mmol) of acetone cyanhydrin and 12.1 g (120 mmol) of triethylamine were added to the above-prepared reaction solution, followed by stirring for one night. The reaction solution was concentrated under reduced pressure. The residue thus obtained was washed with 300 ml of ether in addition to distilled water and dried over anhydride sodium sulfate and concentrated under reduced pressure. The residue was separated out by silica gel column chromatography, whereby 38.7 g of (2RS,3S)-2-hydroxy-3-[N-(2-methyl-2-propyloxycarbonyl)amino]heptanenitrile was obtained.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[OH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:4]1
Reactant: O[C@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The pH of a solution of 6.18 g of (S)-3-hydroxy-pyrrolidine hydrochloride in 175 ml of water was adjusted to 10 with 10% sodium hydroxide solution and cooled to 0°-5° C. 7.1 ml of benzyl chloroformate were added dropwise within 30 minutes under argon, with the pH of the solution being held between 9.5 and 11.5 by the dropwise addition of 10% sodium hydroxide solution. After completion of the addition the suspension was stirred at room temperature for 16 hours. The suspension was extracted with ethyl acetate, the organic phase was washed with water, dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the crude product over a silica gel column gave 7.33 g of benzyl (R)-3-hydroxy-pyrrolidine-1-carboxylate as a beige liquid.
Reaction SMILES: [N:1]1([N:7]([CH3:31])[C:8]([C:10]2[C:14](O)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-:32].[F-].[F-].C(N(SN(CC)CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1([N:7]([CH3:31])[C:8]([C:10]2[C:14]([F:32])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1O)N1CCCCC1
Reactant: [F-]
Agent: CCN(CC)SN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1F)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 600 mg of the compound of EXAMPLE 1 in 24 ml of DCM is added dropwise to a solution of 0.19 ml of diethylamino sulfide trifluoride in 24 ml of DCM at -78° C. under nitrogen. The mixture is allowed to warm up slowly to 0° C. and then stirred for one hour at 0° C. The reaction mixture is poured into saturated NaHCO3 solution and then extracted with DCM, washed with saturated NaCl solution and dried over MgSO4. The residue is chromatographed on fine silica using AcOEt/toluene (5/95 to 40/60; v/v) as the eluent to give 250 mg of the expected product, m.p.=184° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH:20][C:21](=[O:25])[C:22](O)=[O:23])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CN(C)C=O>[CH:28]1([NH:31][C:22](=[O:23])[C:21]([NH:20][O:19][CH:16]2[CH2:15][CH2:14][N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:26])([F:27])[F:1])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH2:18][CH2:17]2)=[O:25])[CH2:30][CH2:29]1
Reactant: O=C(O)C(=O)NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (70 mg, 0.37 mmol) was added to a solution of N-[1-(4-trifluoromethoxybenzenesulfonyl)piperidin-4-yloxy]oxalamic acid (102 mg, 0.247 mmol) 1-hydroxybenzotriazole (36 mg, 0.27 mmol) and cyclopropylamine (0.042 ml, 0.61 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for 16 hours and quenched with aqueous 1 N HCl solution (5 ml) and H2O (5 ml). The resulting precipitation was collected and washed with H2O and diethyl ether to give N1-cyclopropyl-N2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)oxalamide (48 mg, 43%) as a white solid: LCMS: 452 [M+1]+. 1H NMR (DMSO-d6) δ: 0.59 (m, 4H), 1.69 (m, 2H), 1.82 (m, 2H), 2.73 (m, 1H), 3.04 (m, 4H), 3.96 (m, 1H), 7.65 (d, 2H), 7.88 (d, 2H), 8.81 (d, 1H), 11.9 (s, 1H).
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Cl:37][C:38]1[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])=[O:41].Cl.CN1C(=O)CCC1>O1CCOCC1>[ClH:37].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Cl)n1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Temperature: 25 °C

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (40 mg, 164 μmol, Compound C of Example 1) and 2-chloro-N-(2,4-difluorophenyl)-6-methylnicotinamide (51 mg, 181 μmol) were suspended in 1,4-dioxane (1 mL). 4M HCl in 1,4-dioxane (0.16 mL, 0.333 mmol) was added and the reaction was irradiated (CEM personal microwave, 300 W) to a temperature of 160° C. for 60 min. The reaction was cooled to ambient temperature and NMP (1 mL) was added. The reaction mixture was re-heated to 160° C. (microwave irradiation, 300 W) for an additional two hours. The 1,4-dioxane was removed by rotary evaporation and the residue was partitioned between 10% aq. NaHCO3 solution (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted EtOAc (2×10 mL). The combined organic layers were washed with 10% LiCl (20 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative (RP) HPLC Chromatography (YMC S5 ODS, 20×100 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA). The fractions containing the desired product were combined and concentrated. The purified material was dissolved in MeOH (1 mL), acidified with 4 N HCl in 1,4-dioxane (0.10 mL) and concentrated. The resulting salt was triturated with hot EtOAc and collected by filtration to afford a brown solid (4.4 mg, >97% HPLC purity). 1H NMR (DMSO-d6) δ 3.15 (s, 3H), 6.48 (s, 1H), 6.69 (d, 1H, J=6.10 Hz), 6.91 (d, 1H, J=7.63 Hz), 7.06-7.21 (m, 1H), 7.31-7.44 (m, 2H), 7.46-7.64 (m, 3H), 8.12-8.42 (m, 3H), 10.41 (s, 1H), 10.96 (s, 1H), 12.58 (s, 1H); MS(ESI+) m/z 490.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC(C#N)(CC(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
In 20 ml of acetone, 2.8 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 4.5 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate were dissolved, 2.2 g of potassium carbonate was added and the mixture was stirred at room temperature for 8 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.10 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(2,2,3,3,3-pentafluoropropyl)malononitrile (hereinafter, referred to as the present compound (91)).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2=[CH:12][N:13]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:18](=[O:19])[C:17]4[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:16]=4[Cl:15])=[CH:27][CH:26]=3)[N:14]=[C:8]2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc2[nH]ncc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc2nn(Cc3ccc(C(=O)c4ccc(Cl)cc4Cl)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (5 ml) was dissolved 5-t-butyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (288 mg) followed by addition of 4-(2,4-dichlorobenzoyl)benzyl bromide (791 mg) and potassium carbonate (318 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexaneethyl acetate=1:1). Then, 5-t-butyl-2-[4-(2,4-dichlorobenzoyl)benzyl]-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one was washed with n-hexane-diethyl ether and dried.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O=S(Cl)[Cl:19]>>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCc1ccccc1C(=O)O
Product: CCCCCCCc1ccccc1C(=O)Cl
Yield: 80 %

Procedure:
Heptylbenzoyl chloride (530 mg., 0.0022 M), obtained by reaction of heptylbenzoic acid with SOCl2, and 380 mg. of ##STR15## (0.002 M) in 5 ml. of pyridine are allowed to react at ambient temperature for 48 hours. Then the reaction mixture is poured into a solution of 5 ml. of concentrated H2SO4 and 50 g. of ice. The organic fraction is extracted with ether (3 times, 100 ml. total). The organic fraction is washed with water (3 times) and dried over anhydrous Na2SO4. The solvent is evaporated and the solid residue is treated by chromatography on silica with a benzene (50%) hexane (50%) mixture. The product is finally recrystallized twice from ethanol. The yield is above 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=C(C)C=C(C)C=1S(O[NH2:42])(=O)=O>CN(C=O)C>[NH2:42][N:12]1[C:13]2[C:18](=[CH:17][C:16]([I:21])=[CH:15][CH:14]=2)[C:19](=[O:20])[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=2)=[O:9])=[CH:11]1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reaction time: 24 h
Yield: 65.3 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (2.0 g) of Preparation No. 4 and of potassium carbonate (2.0 g) in DMF (40 mL) is stirred at room temperature for 5 hrs and then treated with of O-(mesitylsulfonyl)hydroxylamine (1.5 g). After 24 hrs, the solvent is evaporated under reduced pressure and the residue is diluted with water(150 mL). The resulting solid is filtered and washed with water (3×) and ether (2×). Recrystallization from hot acetic acid/water affords 1.35 g of the title compound as a tan solid.