Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12.CC(C)([O-])C.[K+].[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[N:33]=[C:32]1S(C)(=O)=O.O>CC(N(C)C)=O>[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[N:33]=[C:32]1[O:20][C:17]1[CH:18]=[CH:19][C:14]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]3[CH:11]=[CH:12][N:13]=[C:9]23)=[CH:15][CH:16]=1
Reactant: Cc1ccnc2c1n1ccnc1n2-c1ccc(O)cc1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCn1c(Oc2ccc(-n3c4nccc(C)c4n4ccnc34)cc2)nc2cccnc21
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
To a solution of 4-(5-methyl-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (370 mg) obtained in Example 15, step E) in DMA (3 ml) was added potassium tert-butoxide (168 mg) at room temperature. After stirring for 10 min, a solution of 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (383 mg) in DMA (3 ml) was added, and the obtained mixture was stirred at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/THF) and recrystallized from acetone to give the title compound (531 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([OH:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].BrCBr>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[O:10][CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: COc1cc(Br)cc(O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCBr
Solvent: CN(C)C=O
Product: COc1cc(Br)cc2c1OCO2
Yield: 52 %

Procedure:
To dimethylformamide (400 mL) was added 1-bromo-3,4-dihydroxy-5-methoxybenzene (40 g, 182 mmol), potassium carbonate (75.7 g, 548 mmol), and dibromomethane (95.2 g, 548 mmol), followed by heating to reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was taken up into ethyl ether, filtered, washed with saturated potassium carbonate solution, brine, 1N citric acid solution, and brine. The organic phase was dried over anhydrous magnesium sulfate and filtered through charcoal. The filtrate was concentrated in vacuo giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid. This material was distilled at 2 mm Hg, 125° C., giving a crystalline solid, 21.7 g, 52% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])[CH3:13].C(O)(=O)C.C(OCC)C>C1C=CC=CC=1.N1CCCCC1>[C:12]([C:15](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:16]([CH3:17])=[O:18])(=[O:14])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Yield: 53.5 %

Procedure:
A mixture of 3-nitrobenzaldehyde (20 g), acetylacetone (13.25 g), acetic acid (1.58 g), and piperidine (0.45 g) in benzene (20 ml) was refluxed for 1 hour under azeotropic dehydration. To the reaction mixture was added diethyl ether (100 ml). The mixture was washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) successively, dried over magnesium sulfate, and evaporated in vacuo. The residual substance was recrystallized from ether to afford 1-acetyl-1-(3-nitrobenzyliden)acetone(16.5 g).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]=2[CH3:21])[CH2:6][CH2:5]1.[CH3:22][S-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:21][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][S:23][CH3:22])[CH2:5][CH2:6]1
Reactant: COc1cc(N2CCC(CCI)CC2)c(C)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(CCSC)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To 4-(2-iodoethyl)-1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperidine (40.6 g, 100 mmol) was added sodium thiomethoxide (7.75 g, 111 mmol) and diluted with DMF (201 mL). The reaction was stirred at 50° C. overnight. The solution was diluted with EtOAc and washed with H2O. The organic layer was dried (MgSO4), filtered, and rotovapped down to provide the title compound of step H (33.5 g) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.23 (d, J=12.1 Hz, 2H), 2.60-2.72 (m, 2H), 2.46-2.52 (m, 2H), 2.14 (s, 3H), 2.01 (s, 3H), 1.75 (d, J=12.1 Hz, 2H), 1.50 (t, J=5.7 Hz, 3H), 1.16-1.35 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:30][C:31]1([CH2:36][OH:37])[CH2:35][CH2:34][NH:33][CH2:32]1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[OH:37][CH2:36][C:31]1([CH3:30])[CH2:35][CH2:34][N:33]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:28][CH:27]=2)[CH2:32]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Reactant: CC1(CO)CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(C)(CO)C5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Intermediate 55A (0.165 g, 0.43 mmol), intermediate 84A (3-methylpyrrolidin-3-yl)methanol hydrochloride (0.099 g, 0.65 mmol) and TEA (0.241 mL, 1.74 mmol) were mixed in dichloromethane (4 mL). The mixture was stirred at RT for 30 min and then sodium triacetoxyhydroborate (0.184 g, 0.87 mmol) was added and the mixture was stirred at RT overnight. Aqueous NaHCO3 (sat., 4 mL) and dichloromethane (4 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 than re-purified at pH3 to give 21 mg (10%). 1H NMR (600 MHz, DMSO) δ 1.01 (s, 3H), 1.31-1.39 (m, 1H), 1.57-1.65 (m, 1H), 2.07 (d, 1H), 2.43-2.49 (m, 2H), 3.13-3.25 (m, 3H), 3.46-3.53 (m, 2H), 3.88 (s, 3H), 4.06-4.14 (m, 1H), 4.51-4.67 (m, 2H), 5.05-5.19 (m, 2H), 6.85 (d, 2H), 7.15-7.31 (m, 4H), 8.02 (d, 2H), LC purity: 93%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 94.7 %

Procedure:
Prepared from (2-amino-4-thiazol-2-ylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G11) (89 mg, 0.28 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978, 25) (74 mg, 0.34 mmol) according to the general procedure K. Obtained as a light yellow solid (129 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:30][C@H:31]([CH2:39][OH:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)CCl>[C:33]1([CH2:32][CH:31]([NH:30][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[N:22][C:14]=2[N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:39][OH:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CCCCOC(=O)N1CCN(c2ncccc2C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(c2ncccc2C(=O)NC(CO)Cc2ccccc2)CC1

Procedure:
13 g of 2-(4-butoxycarbonylpiperazin-1-yl)nicotinic acid were dissolved in 150 ml of methylene chloride and 14.7 ml of triethylamine analogously to Example 1c and treated successively with 6.4 g of phenylalaninol, 1.9 g of HOBT and 8.11 g of EDC, 16.7 g (90%) of the product being obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][C:15]3=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][CH2:15]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2CCC3=O)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2cccc3c2C=CC3)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
9.0 g (34 mmol) of 4-(4′-tert-butylphenyl)indanone and 1.3 g (34 mmol) of sodium borohydride together with 32 ml of toluene are placed in a reaction vessel. The reaction mixture is heated to 50° C., after which 6.2 ml (148 mmol) of methanol are added over a period of 10 minutes. After the addition is complete, the mixture is stirred at 50° C. for 2 hours. After addition of 30 ml of a saturated ammonium chloride solution, the mixture is stirred for another 30 minutes. After separating off the aqueous phase, the organic phase is washed once with a saturated ammonium chloride solution and once with a saturated sodium chloride solution. After drying over magnesium sulfate, the solvent mixture is removed on a rotary evaporator, the residue is made up to a total volume of 150 ml with toluene and is admixed with 0.2 g of p-toluenesulfonic acid. After 30 minutes, no more elimination of water is observed. The reaction mixture is subsequently washed once with a saturated sodium hydrogen carbonate solution, then dried over magnesium sulfate and the solvent is removed in an oil pump vacuum. 7.3 g (86%) of the desired product are isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:48][O:49][C:50]1[CH:82]=[CH:81][C:53]([CH2:54][N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([N:64]([CH2:73][CH2:74][N:75]4[CH2:80][CH2:79][O:78][CH2:77][CH2:76]4)[C:65]4[CH:70]=[CH:69][C:68]([NH2:71])=[CH:67][C:66]=4[F:72])=[C:58]3[CH:57]=[N:56]2)=[CH:52][CH:51]=1>CN(C=O)C>[CH3:48][O:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([N:64]([CH2:73][CH2:74][N:75]4[CH2:80][CH2:79][O:78][CH2:77][CH2:76]4)[C:65]4[CH:70]=[CH:69][C:68]([NH:71][C:15]([C:12]5[C:13](=[O:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]=[CH:10][CH:11]=5)=[O:17])=[CH:67][C:66]=4[F:72])=[C:58]3[CH:57]=[N:56]2)=[CH:81][CH:82]=1
Reactant: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.0310 g, 0.132 mmol) (prepared according to the procedure of Example 19, Step C) was taken up in DMF (1 mL). EDCI (0.0422 g, 0.220 mmol), HOBt (0.0298 g, 0.220 mmol), and DIEA (0.0384 ml, 0.220 mmol) were then added. After stirring under N2 for 15 minutes, N1-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-fluoro-N1-(2-morpholinoethyl)benzene-1,4-diamine (0.021 g, 0.0441 mmol) was added in DMF (1 mL). After stirring for 5.5 hours, DCM was removed. The product was taken up into EtOAc and washed with diluted NaHCO3 and brine. The product was dried over Na2SO4, filtered and concentrated. Purification via Flash Si 5 g eluting with 1-5% MeOH/DCM with NH4OH to obtain 15.7 mg (51%) of product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 8.41 (d, 1H), 8.24 (m, 2H), 7.93 (dd, 1H), 7.63 (m, 2H), 7.43 (m, 1H), 7.35 (m, 1H), 7.27 (m, 4H), 6.80 (m, 2H), 6.61 (br s, 1H), 6.31 (d, 1H), 5.48 (s, 2H), 3.94 (t, 2H), 3.75 (s, 3H), 3.65 (t, 3H), 2.88 (s, 1H), 2.75 (t, 2H), 2.47 (t, 4H); 19F NMR (376 MHz, CDCl3) −111.41 (s, 1F), −117.59 (s, 1F); LRMS (apci pos): 693.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:27](=[O:29])[CH3:28])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 60 °C
Yield: 91 %

Procedure:
0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) was added to a mixture of 0.47 ml of acetic anhydride and 0.39 g of pyridine, and the resulting mixture was heated at 60° C. for 2 hours. At the end of this time, the reaction mixture was poured into ice-water, after which a saturated aqueous solution of sodium hydrogencarbonate was added. The aqueous mixture was then extracted with chloroform. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give 0.51 g (yield 91%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]([O:9][CH3:10])=[CH:6][CH2:7][CH:8]=1.[Li]CCCC.[CH:16]1(Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1.CCCCCC>[CH:16]1([CH:4]2[C:3]([O:2][CH3:1])=[CH:8][CH2:7][CH:6]=[C:5]2[O:9][CH3:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC1=CCC=C(OC)C1
Reactant: BrC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=CCC=C(OC)C1C1CCCC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a solution of 2,5-dihydro-1,3-dimethoxybenzene (9.88 g, 70 mmol) in dry THF (150 mL) was added dropwise nBuLi solution (2.5 M, 42.4 mL) in hexane at −20° C. The orange colored reaction mixture was stirred for 0.5 hour at −20° C., then cyclopentyl bromide (20.9 g, 140 mmol) was added dropwise. The reaction mixture was stirred for 1 hour at −20° C. to 0° C. Excess nBuLi was destroyed cautiously with methanol. To the reaction mixture, 140 mL of cold water was added. The product was extracted with ethyl acetate (3×80 mL). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as light yellow liquid (14.12 g, 96.8%). 1H NMR: δ 1.0–2.4 (Complex, 9H), 2.7–2.94 (m, 3H), 3.52 (s, 6H, 2×OCH3), 4.70 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][C@@H:24]([CH3:28])[NH:23]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:25][C@H:24]([CH3:28])[NH:23][C@H:22]([CH3:21])[CH2:27]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H](C)N1
Yield: 66.8 %

Procedure:
A mixture of 280 mg of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 542 mg of cis-2,6-dimethylpiperazine and 10 ml of pyridine was heated under reflux for 2.5 hours. The solvent was evaporated under reduced pressure. To the residue was added a 1N aqueous solution of sodium hydroxide, and the insoluble matter was removed by filtration. A 10% aqueous solution of acetic acid was added to the filtrate to adjust its pH to 8. The solution was then extracted with chloroform. The chloroform layer was dried with sodium sulfate, and concentrated under reduced pressure. Acetonitrile was added to the residue, and the mixture was cooled with ice. The crystals were collected by filtration, and recrystallized from aqueous ammonia to give 250 mg of 5-amino-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 253°-254° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([NH2:20])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18](=[S:30])[NH2:20])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-c2c(C(N)=O)cnn2C(C)(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(N)=S)cnn2C(C)(C)C)cc1
Yield: 52.8 %

Procedure:
A solution of the compound (1.45 g, 5.30 mmol) obtained in step 10 and Lawesson's reagent (2.146 g, 5.30 mmol) in THF (25 mL) was stirred at 60° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 2→60% ethyl acetate/hexane) to give 1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazole-4-carbothioamide (0.81 g, 2.80 mmol, 53%) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH2:23]Br)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH2:23][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:9][C:3]=2[CH:4]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2ccc(C)cc2O1
Yield: 47.3 %

Procedure:
To a solution of 2-amino-5-methylphenol (10 g, 81.3 mmol) in acetone (150 mL) was added K2CO3 (24.5 g, 243.9 mmol) and ethyl 2,3-dibromopropanoate (23.3 g, 89.4 mmol). The mixture was heated at reflux for 16 h. The filtrate was concentrated in vacuo to give an oil. Purification by silica gel chromatography (hexane/ethyl acetate gradient) provided ethyl 7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (8.5 g, 47.3% yield). 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J=0.8 Hz, 1H), 6.60 (dd, J=1.2, 8.0 Hz, 1H), 6.19 (d, J=8.0 Hz, 1H), 4.78 (t, J=3.6 Hz, 1H), 4.29-4.21 (m, 2H), 3.59-3.52 (m, 2H), 2.23 (s, 3H), 1.28 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:47][OH:48]>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH:47][OH:48])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 47.6 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide was prepared by the procedure of example 8 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.2 g, 1.3 mmol) and hydroxylamine hydrocloride (0.1 g, 1.4 mmol) in THF (10 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide as white solid (0.25 g, 50% yield): mp 148-150° C.; 1HNMR (CDCl3): δ1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.19 (s, 3H, CH3CO), 3.19 (dd, J=5, 15 Hz, 1H, CH2), 3.47 (dd, J=10, 15 Hz, 1H, CH2), 4.02 (q, J=7.0 Hz, 2H, OCH2CH3), 5.75-5.82 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, CF2H), 7.02-7.07 (m, 3H, Ar), 7.36 (d, J=7.5 Hz, 1H, Ar), 7.54 (t, J=7.5 Hz, 1H, Ar), 8.64 (d, J=8.8 Hz, 1H, Ar), 9.40 (s, 1H, NHCO). 13CNMR (CDCl3): δ 14.5, 24.8, 34.6, 51.1, 64.7, 111.8, 113.5, 115.1, 115.9, 120.1, 122.6, 124.9, 131.0, 136.0, 136.7, 137.4, 140.0, 150.5, 167.1, 167.7, 169.3, 169.6 Anal Calcd for C22H21F2N3O7+0.3H2O: C, 54.73; H, 4.51; N, 8.70. Found: C, 54.36; H, 4.25; N, 8.54, 0.1% H2O.
Reaction SMILES: [Mg].II.Br[CH2:5][CH3:6].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>C(Cl)Cl.O1CCCC1>[F:7][C:8]([F:17])([F:18])[C:9]1[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH2:5][CH3:6])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
Dry tetrahydrofuran (700 mL), magnesium turnings (16.75 g, 0.69 mol, 1.2 eq), and a iodine crystal were placed in a flask and the mixture was stirred intensively at 0° C. Bromoethane (68 g, 46.7 mL, 0.69 mol, 1.1 eq) was added dropwise and the resulting mixture was allowed to stir for 30 min. Then the reaction mixture was treated with 4-trifluoromethylbenzaldehyde (100 g, 0.57 mol, 1 eq). After stirring at room temperature for 2 h, the reaction mixture was cooled to 0° C. and poured carefully to a mixture of 1N HCl (750 mL) and ice cooled to 0° C. and poured carefully to a mixture of 1N HCl (750 mL) and ice with CH2Cl2. The organic layer was washed with 5% aqueous NaHCO3 and with CH2Cl2. The organic layer was washed with 5% aqueous NaHCO3 and brine, then dried over anhydrous Na2SO4, the drying agent was filtered and
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Li+].C[Si]([N-:55][Si](C)(C)C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:55])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)ccn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Nc1cc(OCc2ccccc2)ccn1
Temperature: 65 °C
Yield: 96 %

Procedure:
To a mixture of 4-(benzyloxy)-2-chloropyridine (1.10 g, 5.01 mmol), Pd2 dba3 (46 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (57 mg, 0.120 mmol) in THF (10 mL) was added LHMDS (6 mL of 1.0 M solution). After heating to 65° C. for 30 minutes, the mixture was cooled to room temperature and concentrated onto silica gel. The product was eluted with 20:1 ethyl acetate/methanol to isolate a pale gold solid (0.97 g, 96%).