Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][N:18]2[C:21](OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.C(O)=O.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1.O>CCOC(C)=O>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:12])[C:13]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][N:18]2[CH3:21])/[N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCN1C(=O)OC(C)(C)C
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: O
Product: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of the product of Example 12B (0.45 g, 0.79 mmol) in formaldehyde (2 mL, 72.6 mmol) and formic acid (4 mL, 104 mmol) was warmed to 100° C. and was allowed to stir for 2 h then was cooled to ambient temperature and was concentrated under reduced pressure. The mixture was purified via column chromatography (SiO2, 100% CH2Cl2 to 9:1:0.1 CH2Cl2:CH3OH:NH4OH). The free amine was dissolved in EtOAc (1 mL) and p-toluenesulfonic acid-H2O (1 eq) in EtOAc (1 mL) was added. The p-toluenesulfonic acid salt of the title compound (0.25 g, 0.38 mmol, 48% yield) was isolated via filtration. 1H NMR (300 MHz, CD3OD) δ ppm 0.98 (dd, J=6.6, 2.2 Hz, 6H), 1.39 (s, 9H), 2.27-2.34 (m, 1H), 2.36 (s, 3H), 2.55-2.76 (m, 2H), 3.06 (s, 3H), 3.98-4.18 (m, 3H), 4.26-4.37 (m, 1H), 4.50 (d, J=3.4 Hz, 2H), 4.73-4.80 (m, 1H), 7.19-7.26 (m, 3H), 7.34 (d, J=8.8 Hz, 1H), 7.67-7.73 (m, 2H), 7.79 (dd, J=8.8, 2.0 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 484 (M+H)+. Anal. calculated for C24H32F3N3O2S.C7H8O3S.0.2H2O: Calc: C, 56.47; H, 6.18; N, 6.37. Found: C, 56.19; H, 6.28; N, 6.38.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](Cl)=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1.ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42](=[O:43])[C:39]4[CH:40]=[CH:41][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:37][CH:38]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.450 g, 1.03 mmol) in pyridine (8 mL) at −5° C. was treated with a solution of 4-(trifluoromethoxy)-1-benzenecarbonyl chloride (0.231 g, 1.03 mmol) in dichloromethane (2.5 mL) drop-wise. The reaction mixture was stirred at −5° C. for 30 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. 1 N sodium hydroxide solution (10 mL) was added, and stirred for 1 h. The organic solvent was removed under reduced pressure. Dichloromethane (10 mL) was added and the layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure and the crude compound was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent to give 0.430 g (67%) N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (0.430 g, 0.688 mmol) in ethyl acetate (15 mL) was treated with a hot solution of maleic acid (0.240 g, 2.07 mmol) in ethyl acetate. A precipitate was formed, filtered under nitrogen, and dried under high vacuum to give N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide tris-maleate salt.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:36]([O:38][C:39]([C:41]1([NH2:50])[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])[CH3:37].C(N(CC)C(C)C)(C)C>CC(O)C.C(Cl)Cl.C(Cl)Cl>[CH2:36]([O:38][C:39]([C:41]1([NH:50][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
A 100 mL round bottom flask is charged with 2-iodo-3-methylbenzoic acid (1.92 g, 7.31 mmol) and dry DCM (25 mL). A stirring bar is added and stirring is initiated. After 5 min, the HBTU (2.37 g, 7.31 mmol) is added. After 5 min, the 2-amino-indane-2-carboxylic acid ethyl ester (1.5 g, 7.31 mmol) is added followed by N,N-diisopropylethyl-amine (3.2 mL, 18.37 mmol). The reaction is allowed to stir for 118 h. Analysis by tlc of the reaction mixture (silica, 15% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (70 mL). This is washed dilute aqueous HCl (3%, 2×30 mL), saturated aqueous NaHCO3 (2×30 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 2.04 g of a white solid. This material is dissolved in 15 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 4 column volumes followed by a linear gradient to 50% EtOAc over 10 column volumes. 27 mL fractions of UV active eluent are collected. Fractions 10 through 15 are combined and evaporated in vacuo. Pumping to constant weight gives 1.04 g a white solid material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[C:3]([Br:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: [Br-]
Reactant: COC(=O)c1ccc2cc(N)ccc2c1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(Br)c(N)ccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 6-amino-2-naphthoate (0.5 g) in THF (10 ml) was added pyridinium tribromide (0.87 g). The reaction mixture was stirred at 0° C. for 1 h after which it was then filtered through a pad of SiO2 and washed with hexane. The organic washings were evaporated to dryness and the residue was purified by flash chromatography eluting with hexane to afford the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([O:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][C:20]2[N:19]=[CH:18][C:17]3[N:25]([CH3:36])[N:26]=[C:27]([C:28]4[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=4)[C:16]=3[C:15]=2[CH:14]=1)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:27]2[C:16]3[C:15]4[CH:14]=[C:13]([O:12][CH:4]([C:5]5[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=5)[C:3]([OH:37])=[O:2])[C:22]([O:23][CH3:24])=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:25]([CH3:36])[N:26]=2)=[CH:29][CH:30]=1)#[N:35]
Reactant: COC(=O)C(Oc1cc2c(cc1OC)ncc1c2c(-c2ccc(C#N)cc2)nn1C)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
Methyl[1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-(4-fluorophenyl)acetate (260 mg, 524 μmol) is dissolved in tetrahydrofuran and methanol (66 ml each). Sodium hydroxide solution (1.0 M, 1.58 ml, 1.58 mmol) is subsequently added dropwise. The reaction mixture is stirred at room temperature for 18 h. When the reaction is complete, the mixture is evaporated to dryness in vacuo, and the residue obtained is taken up in water (100 ml). The mixture is carefully acidified to pH 5 by addition of hydrochloric acid (1.0 M) and stirred for a further 30 min. The precipitate formed is filtered off with suction and rinsed with water. The filter cake is subsequently suspended in 2-propanol (5 ml), filtered off with suction again, and the residue is dried overnight in a high vacuum, giving [1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl-oxy]-(4-fluorophenyl)acetic acid (235 mg, 488 μmol) as a solid having a melting point of 211.6° C. MS: 483.1 (M+H+), TLC (HPTLC): Rf=0.11 (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nccc2c1

Procedure:
6-Methoxy-2H-isoquinolin-1-one in POCl3 was heated to gentle reflux for 3 h then evaporated in vacuo. The residue was poured into ice-water (20 mL) and neutralized to pH 10 with 10 M NaOH. Extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated. The residue was purified by flash chromatography (hexane-EtOAc) to afford a white solid.
Reaction SMILES: [F-:1].[F-].[F-].C(N(S([O-])([O-])=O)CC)C.[Cl:13][C:14]1[C:15]2[CH2:22][CH2:21][CH:20](O)[C:16]=2[N:17]=[CH:18][N:19]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[C:15]2[CH2:22][CH2:21][CH:20]([F:1])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: OC1CCc2c(Cl)ncnc21
Reactant: [F-]
Agent: CCN(CC)[SH](=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Product: FC1CCc2c(Cl)ncnc21
Reaction time: 0.17 h

Procedure:
Under ice cooling, 3.9 ml of diethylaminosulfite trifluoride (DAST) was added dropwise to 5.00 g of 4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine obtained above dissolved in 40 ml of chloroform, and the mixture was stirred at the same temperature for 10 minutes. After the solvent was removed under reduced pressure, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and condensed. The obtained residue was applied to silica gel column chromatography to obtain 3.09 g of the title compound as a yellow oily product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH:10]=[O:11])[CH2:4][CH2:3]1.CC1C=CC(C=O)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: CC1CCC(CCC=O)CC1
Agent: Cc1ccc(C=O)cc1
Product: Cc1ccc(CCC=O)cc1

Procedure:
4-Methyl cyclohexanepropanal was similarly prepared as described in Examples I and II. First, 4-methyl benzaldehyde (140 g, commercially available from Mitsubishi Gas Chemical America, Inc.) was used to obtain 3-(4-methyl-phenyl)-propionaldehyde (130 g) with a boiling point of 120° C. at a pressure of 21 mmHg 3-(4-Methyl-phenyl)-propionaldehyde (180 g) was consequently used to provide 4-methyl cyclohexanepropanal (104 g) with a boiling point of 112° C. at a pressure of 24 mmHg
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:14]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:14]=1[O:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]1
Reactant: Oc1cnc2ccccc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(OC2C=Nc3ccccc3C2)c(Cl)c1
Temperature: 0 °C

Procedure:
3-Hydroxyquinoline (I) (prepared according to the procedure of Naumann et. al., Synthesis 4:279–281 (1990)) (3 g) and 1,2,3-trichloro-5-nitrobenzene (4.7 g) were dissolved in DMF (80 mL) and heated with cesium carbonate (7.4 g) for 2 h at 60° C. The reaction was poured into ice/water (500 mL). The resulting off-white precipitate was collected by filtration and rinsed with hexane to afford compound II as a solid (6.9 g) suitable for use in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][C:11]2[N:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[NH2:26])([O-])=O.CN(C)C=O>CO.O1CCCC1.[Pd]>[C:20]1([C:17]2[CH:18]=[CH:19][C:14]3[N:15]([C:11]([CH2:10][C:8]4[CH:9]=[C:4]([NH2:1])[C:5]([NH2:26])=[CH:6][CH:7]=4)=[N:12][N:13]=3)[N:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cc2nnc3ccc(-c4ccccc4)nn23)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Cc2nnc3ccc(-c4ccccc4)nn23)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
A mixture of 2-nitro-4-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-phenylamine (89 mg, 0.257 mmol) and 10% wt Pd/C (27 mg, 0.026 mmol) in methanol (4 mL), tetrahydrofuran (2 mL), and dimethylformamide (2 mL) was stirred at room temperature under hydrogen atmosphere for 4 h. Catalyst was filtered through celite and the filtrate was concentrated and dried in vacuo to provide 81 mg of the product as a beige solid. 1HNMR (DMSO) δ 4.30 (s, 2H), 4.32 (s, 2H), 4.43 (s, 2H), 6.43 (m, 2H), 6.50 (s, 1H), 7.60 (m, 3H), 7.93 (d, 1H), 8.11 (m, 2H), 8.39 (d, 1H); MS (m/z) 317 [M+H+]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]2COS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH:13]1[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH2:16][CH2:17][C:10]21[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:11]2)=[N+:32]=[N-:33]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1N=[N+]=[N-]
Temperature: 60 °C

Procedure:
10 mmol of tert-butyl 2-benzyl-6-methanesulphonyloxymethyl-2,7-diazaspiro[4.5]decane-7-carboxylate are dissolved in 20 ml of N,N-dimethylformamide and the solution is admixed with 15 mmol of sodium azide. The reaction mixture is heated at 60° C. for 6 hours, then poured into water and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:31][C:32]([C:34]1[C:35](=[CH:37][CH:38]=[C:39]([CH:44]=1)S(O)(=O)=O)[OH:36])=[O:33]>CO>[S:8]([O:36][C:35]1[C:34](=[CH:44][CH:39]=[CH:38][CH:37]=1)[C:32]([O-:31])=[O:33])([OH:11])(=[O:10])=[O:9].[C:6]1([CH3:12])[C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)O)ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1ccccc1S(=O)(=O)[O-]
Product: O=C([O-])c1ccccc1OS(=O)(=O)O
Temperature: 0 °C

Procedure:
In a preferred embodiment, a mixture containing an 11a-halo-6-deoxy-6-demethyl-6-methylenetetracycline, preferably the p-toluene sulfonate of 11a-chloro methacycline; bis(triphenylphosphine)(hydroxylamine hydrochloride) dichloro rhodium (II) or its O-alkyl derivative complex, preferably hydroxylamine hydrochloride complex; and a tertiary phosphine, preferably triphenylphosphine, in methanol is subjected to agitation in a stainless steel autoclave, and hydrogenated at about 50° to 90° C. under a pressure between about 3 and 12 kg/cm2, prior to the termination of the reaction. Sulfosalicylic acid is added and the reaction mixture is cooled to about 0° C. for 2-4 hours. The alpha-6-deoxy-5-oxytetracyline sulfosalicylate, preferably doxycyline sulfosalicylate (or toluene sulfonate) thus obtained is filtered and washed with methanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:28]([C:27]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=1[Cl:25])=[O:29]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 64.5 %

Procedure:
To a suspension 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.5 mmol, 0.180 g), 2-chloro-6-methylbenzoic acid (0.55 mmol, 0.084 g) and HBTU (0.6 mmol, 0.227 g) in DMF (4 mL) was added diisopropylethylamine (3.0 mmol, 0.52 mL) at room temperature. After 1 min, everything went into solution and the yellow clear solution was stirred 15 h at room temperature. By this time, it turned to a brown solution was diluted with ethyl acetate (25 mL). The ethyl acetate layer was washed successively with water (2×20 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel column chromatography to afford 151.5 mg (72% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as a white solid: mp 155-157° C. EI-HRMS m/e calcd for C24H24N3O5Cl (M+) 470.1483, found 470.1484.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4C=C[N:24]=[CH:23][C:22]=4F)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[N:41]([CH:44]([CH3:46])[CH3:45])=[C:42]=[O:43].[C:47](O)([C:49]([F:52])(F)F)=O>C(Cl)Cl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:47][C:49]=4[F:52])=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][C:42](=[O:43])[NH:41][CH:44]([CH3:46])[CH3:45])[CH2:3][CH2:4]3)[CH:10]=2)[CH2:39][CH2:40]1
Reactant: CC(C)N=C=O
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Solvent: ClCCl
Product: CC(C)NC(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (40.0 mg, 0.073 mmol) in CH2Cl2 (1 mL) was added 2-isocyanatopropane (0.0072 mL, 0.073 mmol). The reaction solution was stirred at room temperature for 30 min. The reaction mixture was concentrated and treated with TFA (1.132 mL, 14.69 mmol) at 70° C. for 1 hr. The reaction mixture was purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to obtain the title compound, 8-(cyclopropylamino)-N-(3-fluoro-4-pyridinyl)-6-((trans-4-((isopropylcarbamoyl)amino)cyclohexyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide, as a white solid (16.9 mg, 45.2%). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.73 (M+H=510.32). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.38 (1H, s), 8.68 (1H, d, J=2.75 Hz), 8.51 (1H, t, J=6.05 Hz), 8.44 (1H, d, J=5.50 Hz), 8.01 (1H, s), 7.59 (1H, s), 6.92 (1H, br. s.), 5.99 (1H, s), 5.61 (2H, br. s.), 3.79 (2H, br. s.), 3.52-3.74 (2H, m), 2.00 (2H, d, J=9.90 Hz), 1.83 (2H, d, J=10.45 Hz), 1.12-1.41 (4H, m), 1.02 (6H, d, J=6.60 Hz), 0.71-0.83 (2H, m), 0.54-0.69 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([NH2:29])[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([NH:29][CH2:23][C:24]1[O:28][CH:27]=[CH:26][CH:25]=1)=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)O)ccn1
Reactant: NCc1ccco1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)NCc2ccco2)ccn1
Yield: 25.3 %

Procedure:
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (16 mg, 0.047 mmol), furfuryl amine (9.1 mg, 0.094 mmol) and DMAP (8.6 mg, 0.07 mmol) in DMF 4 ml was added PyBOP (36 mg, 0.07 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-furan-2-ylmethyl-isonicotinamide as a colorless solid (5 mg, 25.3% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]([F:17])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:24]1[N:23]=[C:22]2[CH:26]=[N:27][CH:28]=[CH:29][C:21]2=[N:20][C:19]=1[N:14]1[CH2:15][CH2:16][CH:11]([CH:10]([C:4]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=2[F:2])[F:17])[CH2:12][CH2:13]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: Fc1ccc(C(F)C2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)C2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 102 %

Procedure:
A mixture of 4-((2,4-difluorophenyl)fluoromethyl)piperidine hydrochloride (247 mg, 0.929 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (169 mg, 0.845 mmol) and DIPEA (441 μL, 2.53 mmol) in DCM (1.69 mL) was stirred at 0° C. for 5 min then at rt for 30 min. The mixture was then partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was dissolved in EtOAc and filtered through a pad of silica. The filtrate was concentrated to afford 3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (338.4 mg) as a yellow foam. ESI-MS m/z [M+H]+ 393.2.