Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[Cl-].[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:40]COC)=[C:18]([CH:39]=1)[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.S([O-])(O)=O.[Na+]>C(#N)C.C1C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[F:13][C:14]1[CH:15]=[CH:16][C:17]([OH:40])=[C:18]([CH2:19][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=2)[CH:39]=1
Reactant: COCOc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1F
Agent: [Rh]
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cc(CCc2cc(F)ccc2O)ccc1F
Temperature: 60 °C
Reaction time: 14 h
Yield: 83.7 %

Procedure:
547 mg of 4-fluoro-3-methoxybenzaldehyde, 1990 mg of 5-fluoro-2-methoxymethoxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 8) and 0.58 ml of DBU were allowed to react together in 30 ml of acetonitrile, subsequently treated, and purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, in the same manner as described in Preparation 2, to give 948 mg of an oily substance. 936 mg of this oily substance were dissolved in 9 ml of a 1:2 by volume mixture of benzene and ethanol, and then 155 mg of tris-(triphenylphosphine)rhodium(I)chloride were added to the resulting solution. The resulting mixture was then stirred under a hydrogen atmosphere at atmospheric pressure and at 60° C. for 14 hours. A saturated aqueous solution of sodium hydrogen sulfite was then added to the reaction mixture and the mixture was then stirred for about 10 minutes. The resulting insoluble substances were then removed by filtration using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 785 mg (yield 73%) of the title compound as an oily substance.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)[NH2:2].O=[C:17]1[CH2:21][S:20][CH2:19][CH:18]1[C:22](OC)=[O:23]>>[O:23]=[C:22]1[N:1]([C:3]2[N:8]=[CH:7][C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)[NH:2][C:17]2[CH2:21][S:20][CH2:19][C:18]1=2
Reactant: CC(C)(C)OC(=O)c1ccc(NN)nc1
Reactant: COC(=O)C1CSCC1=O
Product: CC(C)(C)OC(=O)c1ccc(-n2[nH]c3c(c2=O)CSC3)nc1
Yield: 61.1 %

Procedure:
According to the process described in Example 1, starting with 0.75 g of tert-butyl 6-hydrazinopyridine-3-carboxylate and 0.58 g of methyl 4-oxotetrahydrothiophene-3-carboxylate, 0.7 g of tert-butyl 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-carboxylate is obtained in the form of a white solid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of cyanuric chloride (2 g, 10.84 mmol) in DCM (40 ml) at 0-5° C. was added dropwise a solution of N-methyl aniline (1.16 ml, 10.84 mmol) and DIPEA (2.08 ml, 12.26 mmol) in DCM (30 ml). The resulting mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was diluted with DCM (40 ml) the solution was then extracted with 2M aq. HCl (2×40 mL) and saturated brine (30 mL) and dried further over anhydrous sodium sulfate. The organic phase was evaporated to dryness to furnish the title compound as an off white solid (2.726 g, 99%). Method C HPLC-MS: MH+ requires m/z=255. Found: m/z=255, Rt=1.48 min (100%). 1H NMR (500 MHz, CDCl3) δ ppm 7.35-7.42 (2H, m), 7.29 (1H, d), 7.15-7.21 (3H, m), 3.48 (3H, s).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C=O)C>[CH:13]1([O:12][C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cnc(OC2CCCC2)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2ccccn2)c1
Yield: 42.1 %

Procedure:
A solution of methyl 5-bromo-6-(cyclopentyloxy)nicotinate (4.53 g, 15.1 mmol) and 2-(tributylstannyl)pyridine (5.00 g, 13.6 mmol) was stirred in 100 mL of DMF at 120° C. for 6 h. The resulting solution was cooled and concentrated in vacuo. The crude reaction mixture was then partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted 1×EtOAc. The organic phases were combined, washed 3× brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and loaded on to a 40 g pre-packed silica gel column. Elution with 0-30% EtOAc:hexanes provided the title compound as an off-white powder (1.71 g, 38%). MS m/z: 299 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])[N:10]([CH2:31][CH3:32])[C:6]2=[N:7][C:8]=1[CH3:9].[C:33](Cl)(=[O:35])[CH3:34].Cl>N1C=CC=CC=1>[C:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:18])([F:19])[F:20])=[O:14])[N:10]([CH2:31][CH3:32])[C:6]2=[N:7][C:8]=1[CH3:9])(=[O:35])[CH3:34]
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CN)c(C)nc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CNC(C)=O)c(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
5-(Aminomethyl)-1-ethyl-6-methyl-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (70.0 mg, 0.15 mmol) was initially charged in pyridine (1.7 ml), acetyl chloride (14.4 mg, 0.18 mmol) was added and the mixture was stirred at room temperature for 2 hours. Ice-water was added, the reaction mixture was acidified with 2N HCl and the precipitated product was filtered off. After drying, the product was chromatographed using cyclohexane/ethyl acetate (1/1), which gave 5.00 mg (6.5% of theory) of 5-(acetamidomethyl)-1-ethyl-6-methyl-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide. HPLC-MS: log P=3.16; mass (m/z): 501.1 (M+H)+; 1HNMR (D6-DMSO): δ 1.23 (t, 2H), 2.57 (s, 3H), 3.32 (s, 3H), 4.34 (m, 2H), 4.58 (q, 2H), 6.28-6.30 (m, 1H), 7.30 (s, 1H), 7.70-7.87 (m, 2H), 8.05 (d, 1H), 8.20 (s, 1H), 8.25 (m, 1H), 9.68 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([CH3:3])[CH3:2].ClC1C=C(C2N=C(CCC(O)=O)OC=2)C=C(C(F)(F)F)C=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1nc(-c2cc(C(C)C)cc(C(F)(F)F)c2)co1
Agent: O=C(O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Product: CC(C)c1cc(-c2coc(CCC(=O)O)n2)cc(C(F)(F)F)c1
Yield: 76 %

Procedure:
The title compound was prepared from methyl 3-(4-(3-isopropyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 50) by a procedure similar to the one described for 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (Reference example 52) to provide 3-(4-(3-isopropyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.132 g, 76%) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(C)=O.[O:16]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]12>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:20]3[CH2:21][CH:17]([OH:16])[CH:18]=[CH:19]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: C1=CC2OC2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(I)nn2C1C=CC(O)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 61.4 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.30 g, 1.14 mmol) and dimethyl sulfoxide (3 mL) was stirred at ambient temperature in the dark for 2 minutes and cooled to 0° C. A solution of 2,4a-dihydro-1aH-cyclopenta[b]oxirene (0.14 g, 1.72 mmol) in tetrahydrofuran (3 mL) was added into the mixture at 0° C. and stirred at 0° C. for 3 hours. The mixture was stirred at ambient temperature overnight and purified by preparative HPLC to yield 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-cyclopenten-1-ol (0.24 g, 0.70 mmol) as a white solid: RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 4.23 min. MS: MH+ 344.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:44]=[CH:43][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=2)[O:30][CH2:31][CH:32]2[CH2:34][CH:33]2[C:35]([O:37]CC)=[O:36])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCCC1>O>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=2)[O:30][CH2:31][CH:32]2[CH2:34][CH:33]2[C:35]([OH:37])=[O:36])=[CH:43][CH:44]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1COc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CC3C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product from Example 284A was added 2N hydrochloric acid (1 mL), tetrahydrofuran (0.5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature overnight. Water (2 mL) was added. The solution was neutralized with 1N hydrochloric aid until pH=2˜3. The product was extracted with ethyl acetate (2 mL), dried in vaccuo, and purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.01-12.29 (br.s, 1 H), 8.95 (s, 1 H), 7.23 (m, 8 H), 7.03 (m, 1 H), 6.94 (m, 4 H), 6.69 (m, 1 H), 6.50 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (m, 1 H), 3.80 (m, 1 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 1.67 (m, 1 H), 1.57 (m, 1 H), 1.05 (m, 1 H), 0.92 (m, 1 H); MS (APCI+) m/z 587.1 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:22]=[C:23]([NH:35][NH2:36])[C:24]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:25]=2[N:26]=1)[CH3:13].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:12]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:22]=[C:23]([NH:35][NH:36][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:24]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:25]=2[N:26]=1)[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCSc1ccccc1-c1nc(NN)c2ncc(C(F)(F)F)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc(NNS(=O)(=O)c2ccc(C)cc2)c2ncc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
152 mg of p-toluenesulfonyl chloride was added to a mixture of 246 mg of [2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidin-4-yl]-hydrazine, 74 mg of pyridine and 5 ml of acetonitrile, under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was washed with t-butyl methyl ether and n-hexane, and then dried to obtain 156 mg of 1-[2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidin-4-yl]-2-tosylhydrazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:9]2[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14](Cl)[CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:24][NH2:25]>O1CCOCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:9]2[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:25][CH3:24])[CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCn1c(=O)c(-c2c(Cl)ccc(N)c2F)cc2cnc(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1c(=O)c(-c2c(Cl)ccc(N)c2F)cc2cnc(NC)cc21
Temperature: 100 °C
Yield: 87.8 %

Procedure:
A solution of 3-(3-amino-6-chloro-2-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (0.45 g, 1.150 mmol) in dioxane (5 mL) was treated with methylamine (40% in water, 7.14 g, 92 mmol) and heated at 100° C. overnight. The mixture was cooled to RT, treated with brine and extracted with EtOAc (2×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-(3-amino-6-chloro-2-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (350 mg, 88% yield) as a white amorphous solid. 1H NMR (500 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.74 (s, 1H), 7.07 (q, J=4.9 Hz, 1H), 7.03 (dd, J=8.7, 1.3 Hz, 1H), 6.77 (t, J=9.0 Hz, 1H), 6.25 (s, 1H), 5.30 (s, 2H), 4.15-4.13 (q, J=7.0 Hz, 2H), 2.87 (d, J=4.9 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 347.1 [M+H]+.
Reaction SMILES: Cl[C:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=O.CC1C=CC(C2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)=CC=1>>[NH:24]1[C:25]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:2]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[N:23]1
Reactant: Cc1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: CCOC(=O)c1ccc(C(=O)Cl)cc1
Product: CCOC(=O)c1ccc(-c2n[nH]c3ccccc23)cc1
Yield: 88.9 %

Procedure:
Ethyl 4-(chlorocarbonyl)benzoate was treated as in the preparation of 10 to afford 11 (0.94 g, 88.9%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.ClCCl.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnccc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1cnccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
4-Phenylamino-3-nitropyridine (1.40 g, 6.51 mmol) was dissolved in the mixed solvent of 15 ml of ethanol and 10 ml of dichloromethane. After the atmosphere was replaced with nitrogen, 0.10 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane: methanol=2:1 (v/v)] to obtain 1.07 g of a light brown solid (yield: 88.7%).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[CH:1]1[C:6]2[CH:7]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(C2Nc3ccccc3Oc3ccccc32)cc1
Yield: 67 %

Procedure:
Title compound 4 was dissolved in ethanol (25 mL) and THF (5 mL). Platinum (IV) oxide (0.075 g, 10% wt) was added. The mixture was stirred at room temperature for 3 h under 1 atmosphere of hydrogen. The catalyst was filtered and the filtrate was concentrated under reduced pressure to one third volume. The precipitate was filtered to afford title compound 5 (510 mg, 67%) as a white solid. LRMS (ESI): (calc) 345.14. (found) 346.3 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.88 (d, J=8.4 Hz, 2H), 7.48 (dd, J=7.5, 1.7 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.33 (td, J=7.7, 1.8 Hz, 1H), 7.19 (td, J=7.4, 1.2 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.90-6.83 (m, 3H), 6.77 (dd, J=7.9, 1.4 Hz, 1H), 6.50 (td, J=7.3, 1.6 Hz, 1H), 5.55 (d, J=6.1 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:35][CH2:34]1
Reactant: COc1cc(F)c(N2CCN(C(=O)CCc3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=C(CCc1ccccc1)N1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 74.7 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-(2,5-difluoro-4-methoxyphenyl)-1-(3-phenylpropanoyl)piperazine (344 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=15:1) to provide 4-(2,5-difluoro-4-hydroxyphenyl)-1-(3-phenylpropanoyl)piperazine (247 mg).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:3]=1.IC.[C:17](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:17])[CH:5]=[C:4]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:3]=1
Reactant: O=C(NCCO)c1c[nH]c(=O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cc(C(=O)NCCO)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (400 mg, 1.532 mmol), iodomethane (0.114 mL, 1.839 mmol), and potassium carbonate (212 mg, 1.532 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 1-30% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:2]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]([S:23]([CH3:26])(=[O:24])=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1)(=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Yield: 108.3 %

Procedure:
A solution of 7-{[4-(1-hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid (88 mg, 0.21 mmol) and Dess-Martin reagent (145 mg, 0.34 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 72 h. Sodium thiosulfate solution was added and the reaction mixture was stirred until all solids were dissolved. The aqueous layer was extracted with CH2Cl2 (2×), and the organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (CH2Cl2 to 5% MeOH/CH2Cl2) provided the title compound (93.6 mg). 1H NMR (400 MHz, CDCl3) δ7.92 (d, 2H), 7.43 (d, 2H), 4.40 (s, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 2.85 (s, 3H), 2.28 (t, 2H), 1.71 (m, 2H), 1.50 (m, 4H), 1.15-1.40 (m, 8H), 0.85-0.95 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Cc2ccccc2)C1
Reactant: COC(=O)CBr
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: COC(=O)CC1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C

Procedure:
A solution of the product from Step A of Example 21 above (1320 mg, 4.56 mmol), pyrrolidine (972 mg, 13 mmol) and p-toluenesulfonic add (33 mg) in benzene (30 ml) was refluxed through 3A molecular sieves for about 17 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in benzene (10 ml) and cooled to about 0° C. Methyl bromoacetate (1530 mg, 10 mmol) was added dropwise. The reaction mixture was slowly allowed to warm to room temperature and then was heated under reflux for about 17 h at which point H2O (5 mL) was added. After refluxing for about another 2 h, the reaction mixture was cooled to room temperature and extracted with EtOAc (3×100 ml). The combined organic extracts were dried and concentrated in vacuo. The crude residue was chromatographed on SiO2-gel using 15% ethyl acetate/hexanes to give 280 mg of product. 1H NMR (250 MHz, CDCl3): d 7.35 (m, 5 H), 4.5 (m, 1H, 3.8 (s, 3H), 3.4 (dd, 1 H), 3.1 (m, 1 H), 2.85 (m, 4H), 2.6 (m, 1H, 2.4 (m, 1 H), 1.5 (s, 9 H); MS (APCI): 362 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([N:33]6[CH2:38][CH2:37][O:36][CH2:35][CH2:34]6)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)Cl)s5)nn34)ccnc2c1
Reactant: C1COCCN1
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)N6CCOCC6)s5)nn34)ccnc2c1
Temperature: 25 °C

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carbonyl chloride (0.100 g, 0.21 mmol) in dichloromethane (2 mL) at 0° C. was added morpholine (0.19 g, 2.1 mmol). The solution was stirred at room temperature twenty minutes, then was concentrated and purified by MPLC chromatography (eluted with 3% methanol in dichloromethane) to yield a yellow solid. Trituration in acetonitrile and filtration afforded the product as a white solid. MS m/z=517.2 [M+1]+. Calc'd for C26H24N6O4S: 516.2.