Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+].[NH:46]1[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48][CH2:47]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:29]([CH2:28][CH2:27][N:46]3[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48][CH2:47]3)(=[O:31])=[O:30])[CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: OC1CCNCC1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCNCC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCN4CCC(O)CC4)CC3)n[nH]c12
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
The title compound was prepared according to the procedure described in Example 33. Thus, 5-(3-fluorophenyl)-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 15) (75 mg, 0.167 mmol) was reacted with 2-chloro-1-ethanesulfonyl chloride (17 uL, 0.167 mmol) in the presence of triethyl amine (93 uL, 0.665 mmol) in DMF (2 mL) at 0° C. After 10 mins., K2CO3 (46 mg, 0.334 mmol) and 4-piperidinol (51 mg, 0.501 mmol) were added to afford the title compound (17.9 mg, 20% for 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>[OH-].[Na+]>[CH2:19]([O:18][C:16]([NH:1][C:2]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(S(N)(=O)=O)ccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1cc(S(N)(=O)=O)ccc1C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 2-amino-4-sulfamoylbenzoic acid (1.32 g) in 2N sodium hydroxide (6 ml) was added dropwise ethyl chloroformate (1.9 ml) and 2N sodium hydroxide on an ice bath. After stirring for 3 hours, the reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate. Combined organic extracts were washed in turn with water and brine, dried over magnesium sulfate and evaporated to give an amorphous of 2-ethoxycarbonylamino-4-sulfamoylbenzoic acid (1.99 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Br:15]N1C(=O)CCC1=O.[C:23]([O:26]C(=O)C)(=O)[CH3:24].CCN(CC)CC>CN(C1C=CN=CC=1)C>[C:7]([C:6]1[CH:5]=[C:4]([Br:15])[S:3][C:2]=1[NH:1][C:23](=[O:26])[CH3:24])(=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1sccc1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1sc(Br)cc1C(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
To a stirred solution of 1.00 g (4.92 mmol) of (2-amino-thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 20) in 20 ml CFCl2 at 0° C. was added 0.92 g (5.18 mmol) NBS (N-bromo succinimide) in one portion. After 10 minutes, 4.65 ml (49.2 mmol) of acetic anhydride, 0.68 ml (4.92 mmol) of Et3N and 0.30 g (2.45 mmol) of DMAP were added. Stirring was continued at RT for 2 hours, the mixture was poured onto water and extracted three times with CH2Cl2. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/CH2Cl2 1:1) afforded 0.85 g (53%) N-(3-benzoyl-5-bromo-thiophen-2-yl)-acetamide as a light brown solid. ES-MS m/e (%): 324, 326 (M+H+, 100).
Reaction SMILES: C([O-])(O)=O.[Na+].[I:6]N1C(=O)CCC1=O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22](C(O)=O)=[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[N:24]3[N:25]=2)=[CH:17][CH:16]=1.O>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([I:6])=[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[N:24]3[N:25]=2)=[CH:17][CH:16]=1
Reactant: CC1CCc2c(C(=O)O)c(-c3ccc(F)cc3)nn21
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCc2c(I)c(-c3ccc(F)cc3)nn21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.1 g (36.9 mmol) of NaHCO3 and 2.8 g (12.3 mmol) of N-iodosuccinimide are added to a solution of 3.2 g (12.3 mmol) of 2-(4-fluorophenyl)-6-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid in 25 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 16 h, water is added and the precipitated solid is filtered off and dried. This gives 3.30 g of the desired product in a purity of 77% which are reacted further without further purification: (log P(HCOOH): 3.82); 1H-NMR (ppm): δ (DMSO-d6)=1.42 (d, 3H), 2.11-2.18 (m, 1H), 2.72-2.82 (m, 3H), 4.49 (m, 1H), 7.28 (dd, 2H), 7.79 (dd, 2H); LC-MS: m/z=343 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14]([NH2:15])=[C:9]3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br.[OH-].[NH4+].C(O)(=O)C>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=4)=[N:13][C:14]([NH2:15])=[C:9]3[C:8]([Br:22])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrBr
Reactant: Nc1nc(-c2ccncc2)nc2c1cnn2C1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-c2ccncc2)nc2c1c(Br)nn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of 1-cyclopentyl-6-(4-pyridyl)-pyrazolo(3,4-d)pyrimidin-4-amine (3.0 g, 0.011 mole) in water 60 ml) at room temperature was added bromine (1.8 g, 0.011 mol). The reaction mixture was stirred at room temperature for 1 hour, then was heated on a steam bath for 2 hours. The solvent was removed in vacuo and the residue was suspended in water. Ammonium hydroxide was added followed by acetic acid until a pH of 4-5 was obtained. A solid was collected by filtration and washed with water. Water (60 ml) and bromine (0.3 ml, 0.006 mol) were added to the solid residue and the mixture was heated on a steam bath for 1 hour. The mixture was poured into ice-water and ammonium hydroxide, then acetic acid was added. A solid was collected by filtration, dissolved in ethyl acetate, dried over MgSO4 and concentrated in vacuo to afford 2.2 g (56%) of 1-cyclopentyl-3-bromo-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 189°-191° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.C(Cl)Cl>[C:27]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Reaction time: 60 h
Yield: 88.1 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (200 mg, 0.54 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added benzoyl chloride (94 μL, 0.81 mmol). Upon complete addition the reaction mixture was stirred for 60 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (35 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with NaHCO3 (35 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a colourless solid (225 mg, 88%): 1H NMR (400 MHz, CDCl3, □ in ppm) 8.05 (dm, J=7.2 Hz, 2H), 7.91 (dm, J=7.2 Hz, 2H), 7.62 (tt, J=1.2, 7.4 Hz, 1H), 7.55-7.41 (m, 5H), 7.39 (d, J=8.6 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.81 (pentet, J=6.3 Hz, 1H), 5.38 (d, J=7.6 Hz, 1H), 5.21 (dd, J=5.9, 7.4 Hz, 1H), 2.31 (s, 3H), 1.50 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H-].[Na+].Cl[CH:22]([C:28](=[O:31])[CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1.O.C(O)(=O)C>[CH2:1]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH:22]([C:28](=[O:31])[CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)C(Cl)C(=O)CC
Reactant: CCCCCCCCCCCc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCc1cccc(OC(C(=O)CC)C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
A mixture of 7.0 grams (0.028 mole) of 3-undecylphenol (prepared in Steps A-C of this Example) and 1.1 grams (0.028 mole) of 60% sodium hydride (in mineral oil) in 100 mL of toluene was stirred for about 20 minutes, and 4.2 grams (0.028 mole) of ethyl 2-chloro-3-oxopentanoate (prepared in Step D of this example) was added dropwise during about a 12 minute period. Upon completion of addition, the reaction mixture was heated to reflux, where it was stirred for about 6.5 hours. After this time, the reaction mixture was allowed to cool to ambient temperature, where it stood for about 16 hours. The reaction mixture was then taken up in 50 mL of water and 5 mL of acetic acid. The mixture was washed with an additional 50 mL of water and then with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 8.9 grams of ethyl 2-(3-undecylphenoxy)-3-oxopentanoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH:17]O.[OH-].[Na+]>CS(C)=O>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:14])=[O:17])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH2:2][CH:3]([CH2:5]1)[CH2:4]2
Reactant: OO
Reactant: CSc1ncc(C#N)c(NC23CC(C2)C3)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSc1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)-pyrimidine-5-carbonitrile (3.45 g, 14.9 mmol) in DMSO (15 mL) was added aqueous hydrogen peroxide solution (8.4 g, 30%, 74.5 mmol) and aqueous sodium hydroxide solution (12.4 mL, 6 mol/L, 74.5 mmol) at 0° C. The mixture was stirred at 50° C. for 15 min and then quenched by the addition of water (30 mL). The solid formed was collected and dried under vacuum to give the desired product (3.5 g, 14.0 mmol, 94% yield). MS (ESI)/m/z=251.2 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH2:6][CH2:5][C:4]1=2.C=O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:7]123[CH2:4][CH2:5][C:6]1=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:3][CH2:2][O:1][CH2:18]3
Reactant: OCC1CCCCCCCCC2=C1CC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C1CCCCOCC23CCC2=C3CCCC1

Procedure:
A mixture of the alcohol obtained as indicated above (1 g), 0.2 g of paraformaldehyde, 0.1 g of p-toluenesulphonic acid and 10 ml of acetic acid in the presence of a few drops of acetic anhydride was heated for 41/2 hour at 95° while stirring. The usual treatments of extraction, separation, drying, and evaporation gave 0.7 g of a product which was distilled on a bulb apparatus. The purity of the thus obtained compound was of about 95 % as shown by gas chromatographic analysis. This compound was in all respects identical to that prepared in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH2:17]([NH2:27])[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:27][CH2:17][C:18]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Yield: 82.4 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of piperonylamine (0.23 g, 1.52 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.47 g, 81%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 3.96 (2H, d, J=6.4 Hz); 5.94 (2H, s); 6.66–6.85 (3H, m); 6.71 (1H, d, J=16.4 Hz); 7.49–8.07 (5H, m); 8.14 (1H, br t, J=6.4 Hz).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])(O)=O.[Na+]>O.ClCCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C(C)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Yield: 12.3 %

Procedure:
To a mixture of methyl 2-(3,4-methylenedioxyphenyl)propionate (1.0 g, 4.8 mmol), 4-nitrobenzoic acid (1.6 g, 9.6 mmol) and 1,2-dichloroethane (35 mL) was added P2O5 (4 g) and the mixture obtained was heated to reflux for 12 h. Water was added to the reaction mixture and it was neutralized to pH=7-8 by NaHCO3 solution. It was extracted with EtOAc and washed with brine. The product (211 mg, 12.3%) was obtained by a chromatographic purification (EtOAc:Hex=1:4). 1H NMR (CDCl3) 8.31 (d, J=8.7, 2H), 7.94 (d, J=8.7, 2H), 7.00 (s, 1H), 6.73 (s, 1H), 6.06 (s, 2H) 4.15 (q, J=7.1, 1H), 3.59 (s, 3H), 1.51 (d, J=7.1, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[CH2:24](Br)[C:25]#[CH:26]>>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([N:8]([CH2:26][C:25]#[CH:24])[CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:23])(=[O:11])=[O:10])=[CH:17][CH:16]=1)[C:20]#[C:21][CH3:22]
Reactant: C#CCBr
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Product: C#CCN(C(C(=O)OC)C(C)C)S(=O)(=O)c1ccc(OCC#CC)cc1
Yield: 99.9 %

Procedure:
According to the procedure of Example 5, 0.800 g (2.36 mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.53 g (4.72 mmol) of 80% propargyl bromide gave 0.89 g of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-3-methylbutanoate as a colorless oil. Electrospray Mass Spec 378.2 (M+H)+.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=1)[C:17]([OH:19])=O.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>C1COCC1>[Br:13][C:14]1[CH:22]=[C:21]([CH:20]=[C:16]([C:17]([N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])=[O:19])[CH:15]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCCNCCC
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reaction time: 0.5 h

Procedure:
Carbonyl diimidazole (3–0 g, 18 mmol) is added to a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (XIX, PREPARATION 2, 3.9 g, 15 mmol) in THF (30 mL). The mixture is stirred for 0.5 hours. Dipropylamine (AMINE, 4.2 mL, 30 mmol) is added to the mixture, which is then stirred for 24 hours. The solvent is then removed under reduced pressure and the mixture is partitioned between ethyl acetate and water. The organic phase is then washed with saline, dried over anhydrous magnesium sulfate, filtered, and concentrated. Column chromatography (silica gel; ethyl acetate/hexanes, 15/85) gives the title compound, IR (diffuse reflectance) 2968, 2958, 1714, 1637, 1479, 1440, 1422, 1321, 1310, 1288, 1273, 1252, 889, 772 and 718 cm−1; NMR (300 MHz, CDCl3) δ 8.21, 7.96, 7.70, 3.95, 3.46, 3.15, 1.69, 1.57, 1.00 and 0.78; MS (ESI+) for C15H20BrNO3 m/z (M+H)+=344.1.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.[N:26]1([C:31](=N)[NH2:32])C=CC=N1>C(#N)C>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:31]([NH2:32])=[NH:26])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: FCCOc1ccc(N2CCNCC2)cc1
Reactant: N=C(N)n1cccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCN(c2ccc(OCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1-(4-(2-fluoroethoxy)phenyl)piperazine (50 mg, 0.15 mmol) and diisopropylethylamine (59 μL, 0.34 mmol) in ACN (1 mL) was added 1H-pyrazole-1-carboximidamide (25 mg, 0.17 mmol). The reaction stirred at room temperature for 1 h, monitored by LC-MS. The precipitate was then filtered and washed with ACN to obtain the desired product as a white solid (33.8 mg, 58% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.55 (br s, 3H), 6.95-6.86 (m, 4H), 4.78 (m, 1H), 4.62 (m, 1H), 4.21 (m, 1H), 4.11 (m, 1H), 3.57 (dd, 4H, J=5.2, 4.9 Hz), 3.09 (dd, 4H, J=5.1, 5.0 Hz); 19F NMR (DMSO-d6): δ−222.037 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 156.0, 152.2, 144.9, 119.2, 115.1, 82.2 (81.1), 67.4 (67.2), 48.9, 44.9; HRMS calcd. for C12H17FN2O: 267.16157 found 267.16146.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[CH:24][N:23]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([CH2:28][O:29][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:25]=[CH:24][N:23]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Yield: 96 %

Procedure:
Imidazole (2.1 g, 31 mmol) and tert-butyldimethylsilyl chloride (4.4 g, 29 mmol) were added to a solution of (2-tert-butoxycarbonylaminopyridin-4-yl)methanol (Reference compound No. 4-1, 6.2 g, 28 mmol) in N,N-dimethylformamide (120 mL) at room temperature, and the mixture was stirred for 2 hours. Ethyl acetate (300 mL) was added to the reaction mixture, then the mixture was washed with water (750 mL) and brine (200 mL), and then the mixture was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure to give 9.0 g of the title reference compound as a colorless solid. (Yield 96%)
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][S:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[S:23])[CH:20]=1)=[O:12])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:38](Cl)(Cl)=[O:39]>ClCCl.C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][S:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([N:21]=[C:22]2[N:24]3[N:25]([CH2:26][CH2:27][CH2:28][CH2:29]3)[C:38](=[O:39])[S:23]2)[CH:20]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1COCC1OC(=O)CSc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1COCC1OC(=O)CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl

Procedure:
In 15 ml of dichloromethane was dissolved 1.48 g of 1-(5-(4-acetoxytetrahydrofuran-3-yloxycarbonylmethylthio)-4-chloro-2-fluorophenylaminothiocarbonyl)hexahydropyridazine, followed by addition of 0.59 g of pyridine, which was then cooled in an ice-cold bath. Under stirring, 3.3 g of a 26.8% solution of phosgene in toluene was added dropwise, and after addition was completed, the resulting product was stirred at room temperature for 3 hours. The reaction mixture was washed with water, subsequently with aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=1/1), to obtain 1.20 g of a compound (No. 26) described in Table 1 (77%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>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.CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#C[Si](C)(C)C)cc2c1=O
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Compound D (450 mg, 1.15 mmol), trimethylsilylacetylene (179 μL, 1.27 mmol), PdCl2(PPh3)2 (40.5 mg, 0.058 mmol), CuI (22 mg, 0.12 mmol), triethylamine (321 μL, 2.31 mmol) and DMF (5.8 mL) were added to a microwave vial. The vial was capped and place in a microwave reactor at 150° C. for one hour. The reaction was washed with water and brine and extracted with EtOAc (2×). The organics were combined, dried (MgSO4), and concentrated to dryness. Purification by flash chromatography on silica gel afforded 205 mg (44%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.24 (d, J=1.84 Hz, 1H), 7.76-7.73 (m, 2H), 7.68 (dd, J=8.8 Hz, 1H), 7.52 (t, J=8.64, 8.72 Hz, 2H), 6.93 (d, J=8.8 Hz, 1H), 4.22 (q, J=7.08 Hz, 2H), 1.25 (t, J=7.12, 7.04 Hz, 3H), 0.24 (s, 9H); ES-MS [M+1]+: 408.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2F)CC1
Reaction time: 2 h
Yield: 121.4 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 2-fluorobenzoyl chloride (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (50 mg). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.