Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].[Na].S(=O)(=O)(O)O>CCOCC>[F:13][C:14]([F:21])([F:20])[C:15](=[O:16])[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2][C:1]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(=O)CCC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CC(C(=O)OCC)C(=O)C(F)(F)F
Temperature: 80 °C

Procedure:
200 g of diethyl succinate and 82 g of ethyl trifluoroacetate were mixed together and 13.2 g of sodium and 200 ml of ether were added over 5 minutes. The reaction medium was heated for 18 hours at 80° C., and then poured into 200 ml of iced 10N sulfuric acid. After decanting, drying and concentrating, the expected product was obtained which was used as is for the following step.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(O)=O.CN.Cl.[BH3-][C:20]#[N:21].[Na+]>CO>[CH3:20][NH:21][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCC2(CC1)OCCO2
Reaction time: 2 h
Yield: 54 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (10.0 g, 64.10 mmol, 1.0 eq.) was dissolved in MeOH (100 ml); AcOH (0.1 ml) and CH3NH2.HCl (8.65 g, 128.21 mmol, 2.0 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (10.0 g, 160.256 mmol, 2.5 eq.) was added in portions at 0° C. and the mixture was then stirred for 16 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Alox, 5% MeOH in DCM). Yield: 54% (6.0 g, 35.08 mmol)
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=2[F:19])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[N:20]([O-])=O.[Na+].[Sn](Cl)[Cl:25]>Cl.O>[ClH:25].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][NH2:20])[C:13]=2[F:19])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: CCCCc1ccc(-c2cccc(N)c2F)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A mixture of dioxane (16 mL) and N-methylpyrrolidinone (8 mL) is deoxygenated by passing a stream of nitrogen through it for 15 minutes. A sample of 3-chloro-2-fluoroaniline (3 g, 20.6 mmol) is charged to a 250 mL round-bottom flask which is equipped with a screw-top adapter capable of sealing the vessel via a 3 way stopcock. The aniline is then treated with 4-butylphenylboronic acid (5.5 g, 30.9 mmol), cesium fluoride (7.82 g, 51.5 mmol) and bis-(tri-tert-butyl phosphiono) palladium (527 mg, 1.03 mmol). The flask is evacuated, back filled with nitrogen, and sealed. The flask is placed into an oil bath which has been preheated to 130° C. and stirred for 4 hours. After cooling, the reaction is filtered through a pad of celite which is subsequently rinsed with EtOAc. The organics are then removed by rotary evaporation. The crude reaction is diluted with water, and extracted with EtOAc. The phases are separated, and the organics are dried over MgSO4, filtered, and concentrated. The resulting oil is diluted with diethyl ether and treated with an excess of a 4 M solution of HCl in dioxane. The resulting solid is collected, washed with diethyl ether, and dried to give 4′-butyl-2-fluoro-biphenyl-3-ylamine hydrochloride as a white solid: LC/MS calculated for [M+H]+ C16H19FN: 244.3, found: 244.2. A 0° C. mixture of 4′-butyl-2-fluoro-biphenyl-3-ylamine hydrochloride (5.4 g, 0.019 mol) in concentrated aqueous HCl (50 ml) is treated with the drop wise addition of sodium nitrite (1.3 g, 0.019 mol) in H2O (20 ml) over 10 minutes. The resulting solution is stirred at 0° C. for 1 hour and then treated with the drop wise addition of a 0° C. solution of tin (II) chloride (13.0 g, 0.058 mol) in concentrated aqueous HCl (14 ml). This mixture is stirred for 15 min and then filtered. The isolated solid is washed with cold saturated aqueous NaCl and then suspended in 50% NaOH. The resultant slurry is diluted with H2O and extracted with Et2O. The organic phase is dried over MgSO4, filtered, and concentrated. The resulting residue is dissolved in 100 ml of Et2O and cooled to 0° C. 4.0 M HCl in dioxane (15 ml) is added drop wise to this solution and the resulting precipitate collected to yield 4.58 g (81%) of the desired hydrazine hydrochloride. LC/MS calculated for C16H20FN2: 259.3 found: 259.2
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13](=[O:29])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:27][OH:28].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:29])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH:27]=[O:28]
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
A solution of oxalyl chloride (0.15 mL, 1.76 mmol) in CH2Cl2 (11.0 mL) was added to a solution of DMSO (0.16 mL, 2.25 mmol) in CH2Cl2 (1.0 mL) at −78° C. After 15 min at −78° C., a solution of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid methyl ester (240 mg, 0.88 mmol) in CH2Cl2 (1.5 mL) was added via cannula. After 20 min at −78° C., triethylamine (0.37 mL, 2.65 mmol) was added. After 20 min at −78° C., the mixture was allowed to warm to 0° C. After 30 min at 0° C., the reaction was allowed to warm to rt. After 45 min at rt, saturated aqueous NaHCO3 (15 mL) was added and the mixture was extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (40%→70% EtOAc/CH2Cl2, gradient) afforded 96 mg (40%) of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+].O>O1CCOCC1>[CH2:37]([O:36][C@@H:23]1[C@@H:22]([CH2:21][O:20][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
In 50 ml of dioxane was dissolved 10 g of 2'-deoxy-5'-O-trityl-5-fluorouridine. To the solution were added 2.9 ml of benzyl bromide and 14.6 g of particles of potassium hydroxide. The mixture was stirred at room temperature for 1 hour. Thereto was added 40 ml of water. The mixture was adjusted to a pH of about 3 to about 4 and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The sodium sulfate was separated by filtration and the solvent was distilled off, giving as an intermediate 16.0 g of 2'-deoxy-3'-O-benzyl-5'-O-trityl-5-fluorouridine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]1[N:26]([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24][N:23]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:22]12>>[CH2:1]([N:8]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[CH2:25][CH2:24][N:23]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:22]2[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Reactant: COc1cc(NCc2ccccc2)cc(OC)c1OC
Product: COc1cc(N(Cc2ccccc2)C(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC

Procedure:
The procedure is as for Example 2 using as substrate benzyl-(3,4,5-trimethoxyphenyl)-amine and the compound obtained in Step B of Example 2.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:16]=2)=[C:11]([F:31])[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[F:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:18][N:17]([CH2:26][C:27]([F:28])([F:29])[F:30])[N:16]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Yield: 77.7 %

Procedure:
To 4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridine (900 mg) was added trifluoroacetic acid (5.25 ml) and anisole (1.15 ml) and the reaction mixture heated at reflux for 18 h. The reaction mixture was quenched with with 1N NaOH, extracted 3× tetrahydrofuran, dried magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC eluting with 5% methanol/1% ammonium hydroxide/ethyl acetate provided the title compound (552 mg). MS: (M+H m/z=338.2).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[Li+].[OH-].Cl.CCOCC>O1CCCC1.CO>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)[C@H]1CC[C@H](c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C

Procedure:
To a solution of methyl trans-4-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (Example 21-11, 91 mg, 0.197 mmol) in tetrahydrofuran (2.00 mL) and methanol (0.75 mL) was added aqueous 1N LiOH (0.590 mL, 0.590 mmol). The resultant solution was stirred 20 minutes at room temperature and then 30 minutes at 50° C. The solution cooled to room temperature and was quenched with HCl (0.571 mL, 0.571 mmol) and then aqueous 25% NH4OAc solution (to pH=7). The mixture was extracted with 2-Me-THF. The combined organic fractions were washed with brine, dried (Na2SO4), and were filtered before concentration to dryness. The residue was triturated in hot ethyl acetate. The product was collected by filtration (wash with ethyl acetate, then ether and then hexanes) to yield trans-4-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (37.6 mg 0.084 mmol, 43%) as a yellowish solid. MS APCI [M+H]+ m/z 449.1. 1H NMR (400 MHz, DMSO) δ 12.12 (s, 1H), 10.34 (s, 1H), 8.86 (d, J=4.9, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.66 (d, J=8.0, 1H), 7.39 (t, J=7.9, 1H), 7.35-7.29 (m, 2H), 3.07-2.89 (m, 1H), 2.30 (ddd, J=11.5, 6.8, 2.5, 1H), 2.16 (d, J=10.4, 2H), 2.09-1.96 (m, 2H), 1.66-1.41 (m, 4H). rhSYK Activity: +++
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:12]=[CH:11][C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH3:26][O-:27].[Na+].CO>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[N:8][N:7]([C:9]3[C:10]([OH:23])=[C:11]([CH2:10][C:11]4[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([N:7]5[N:6]=[C:5]6[CH:24]=[CH:25][CH:2]=[CH:3][C:4]6=[N:8]5)[C:26]=4[OH:27])[CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:14]=3)[N:6]=2)[CH:5]=[CH:24][CH:25]=1
Reactant: C[O-]
Reactant: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)OCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3cccc(Cl)c3n2)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3′-N,N-diethylaminomethyl-2′-hydroxy-5′-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 11.1 g (31.0 mmols) of 5-chloro-2-(2′-hydroxy-5′-methacryloyloxyethylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate•methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this stage were separated through filtration, and recrystallized from chloroform to obtain 13.1 g of 6-(4-chloro-2H-benzotriazol-2-yl)-4-methacryloyloxyethyl-2-[3′-(2H-benzotriazol-2-yl)-2′-hydroxy-5′-methylphenyl]methylphenol (hereinafter abbreviated as “RUVA-2” as white crystals (yield 70.3%, purity 98.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:28]([O-])=O)=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:14]=2)[CH:9]1[CH2:31][C:32]1[CH:37]=[C:36]([Br:38])[C:35]([O:39][CH3:40])=[C:34]([Br:41])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(OCC)(=O)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH2:28])=[C:13]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:14]=2)[CH:9]1[CH2:31][C:32]1[CH:33]=[C:34]([Br:41])[C:35]([O:39][CH3:40])=[C:36]([Br:38])[CH:37]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(COc2cc3c(cc2[N+](=O)[O-])C(Cc2cc(Br)c(OC)c(Br)c2)N(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc3c(cc2N)C(Cc2cc(Br)c(OC)c(Br)c2)N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3,5-dibromo-4-methoxybenzyl)-6-(4-methoxy-benzyloxy)-7-nitro-1,2,3,4-tetrahydro-isoquinoline-2-carboxylic acid tert-butyl ester (8.31 g, 0.012 mol) in 120 mL of ethyl acetate and 12 mL of pyridine was added powder tin (II) chloride dihydrate (27.08 g, 0.12 mol). The reaction mixture was stirred for 5 h at 55° C., cooled and filtered. The filtrate was washed 2 times with 1N NaOH. Water phase was extracted with chloroform. The extracts and ethyl acetate solution were combined, dried over Na2SO4 and concentrated. The product was purified by column chromatography (silica gel, ethyl acetate-hexanes mixture (1:4)), evaporated with ethyl ether and dried in vacuum. Yield 4.864 g (61%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.[Fe]>[Cl:1][C:2]1[C:3]([O:4][CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:13][CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1Cl
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccc(OCCN2CCOCC2)c1Cl
Temperature: 23 °C
Reaction time: 1.25 h
Yield: 63.2 %

Procedure:
4-(2-(2-chloro-3-nitrophenoxy)ethyl)morpholine (873 mg, 3.1 mmol) was dissolved in toluene (12 mL). Ammonium formate (866 mg, 13.7 mmol) was dissolved in H2O (12 mL) and added. Iron powder (<10 micron, 766 mg, 13.7 mmol) was added and the reaction was placed in a 120° C. oil bath. After 1.25 h, the solution was cooled to 23° C. and filtered over a pad of celite eluting with 10% MeOH/dichloromethane (250 mL). The filtrate was concentrated in vacuo and the residue was purified via flash column chromatography to give 2-chloro-3-(2-morpholinoethoxy)aniline (503 mg, 75%) as a golden oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=Cc1ccc(Oc2cccnc2)cc1
Yield: 44.1 %

Procedure:
A mixture of 25 g of 3-bromopyridine, 20 g of 4-hydroxybenzaldehyde, 60 g of potassium carbonate and 150 ml of hexamethylphosphoramide was heated at a temperature of 130° to 135° C. for 11 hours. After cooling, the mixture was poured into water and extracted with diethyl ether. The ether extract was washed with water and extracted with 10% hydrochloric acid. The aqueous layer was washed with diethyl ether, rendered alkaline with sodium hydroxide and extracted with diethyl ether. The ether extract was washed with water and dried over sodium sulfate. The solvent was distilled off and the resulting oily substance was purified by silica gel chromatography (eluted with diethyl ether) to obtain 13.9 g (45% yield) of 4-(3-pyridyloxy)benzaldehyde as a colorless oil having a boiling point of 135°-140° C./2-3 mmHg.
Reaction SMILES: C(OC(N1CCC(CCC(OCC)=O)CC1)=O)C1C=CC=CC=1.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[CH2:41][CH2:40]3)=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:37]([N:39]3[CH2:40][CH2:41][CH:42]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:43][CH2:44]3)=[O:38])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Agent: CCOC(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1

Procedure:
In a similar manner to that described in Example 103, ethyl 3-(1-benzyloxycarbonylpiperidin-4-yl)propanoate was converted to ethyl 3-[1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperidin-4-yl]propanoate. The following intermediates were isolated: ethyl-1-bromoacetylpiperidin-4-ylpropanoate. NMR(CDCl3): δ, 1.1-1.4(2H,m); 1.25(3H,t); 1.5-1.7(3H,m); 1.7-1.9(2H,t); 2.3(2H,t); 2.5-2.7(1H,td); 3.0-3.2(1H,td); 3.8-4.0(2H,d +1H,m); 4.15(2H,q); 4.55(1H,m); m/e 306/308(M+H)+, ethyl 3-[1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperidin-4-yl]propanoate. m.p. 90°-92° C.; NMR(d6DMSO): δ, 0.85-1.0(1H,m); 1.05-1.2(1H,m); 1.2(3H,t); 1.5(3H,m); 1.7(2H,m); 2.3(2H,t); 2.5(4H,br.s); 2.8-3.0(1H,t); 3.1(1H,d); 4.05(2H,q+1H,m); 4.3(1H,d); 6.8(2H,d); 8.15(2H,d); m/e 389 (M+H)+ 411 (M+Na)+ ; calculated for C21H32N4O3 ; C, 64.9; H, 8.3; N, 14.4; found: C, 65.0; H, 8.5; N, 14.4%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:39][C:40](C)([O-:42])C.[K+]>CCO>[CH2:40]([O:42][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1)[CH3:39]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 80 °C

Procedure:
In a 150 mL pressure vessel, to the stirred solution of 3-(2-Fluoro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 3BV (2.0 g, 4.0 mmole) in anhydrous EtOH (40 mL), solid potassium tert-butoxide (12 g, 10.0 mmole) was added under dry N2 gas. The pressure vessel was tightly sealed and heated at 80° C. for 24 hours. The pressure vessel was cooled to 0° C. in ice-bath before opening. The contents of the pressure vessel were transferred to 250 mL RBF and concentrated to a small volume. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated to dryness to give a crude solid 11BV (1.5 g, 71%).
Reaction SMILES: [SH:1][C:2]1[NH:6][CH:5]=[N:4][N:3]=1.[NH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1.Cl[C:15]1[C:16]2[N:24]=[C:23](Cl)[CH:22]=[CH:21][C:17]=2[N:18]=[CH:19][N:20]=1>>[N:9]1[CH:10]=[CH:11][N:12]=[CH:13][C:8]=1[NH:7][C:15]1[C:16]2[N:24]=[C:23]([S:1][C:2]3[NH:6][CH:5]=[N:4][N:3]=3)[CH:22]=[CH:21][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Nc1cnccn1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Sc1nnc[nH]1
Product: c1cnc(Nc2ncnc3ccc(Sc4nnc[nH]4)nc23)cn1

Procedure:
The compound of Example 64 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-4H-[1,2,4]triazole, 2-amino-pyrazine and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:13]([NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:36])[CH3:35])=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:35])[CH3:36])=[C:14]([O:16][CH2:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1OCC1CCNCC1
Yield: 72.6 %

Procedure:
A solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(2-(dimethylamino)acetamido)pyridin-4-yloxy)methyl)piperidine-1-carboxylate (24 mg, 0.047 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (10 mL) was stirred for 45 minutes. The solution was concentrated and the residue was loaded onto a MP-TsOH SPE cartridge. Elution with 2M ammonia in methanol gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethoxy)pyridin-3-yl)-2-(dimethylamino)acetamide as a yellow solid (14 mg, 72%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.ClC1[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]2C=N[NH:35][C:36](=O)[C:31]=2C=1I.CC1(C)C(C)(C)OB(C2C=NN(COCC[Si](C)(C)C)C=2)O1.C1(B(O)O)C=CC=CC=1>>[CH3:25][Si:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][O:21][CH2:20][N:4]1[C:5]2[CH:6]=[N:7][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:11])[C:10]=2[C:2]([C:31]2[CH:36]=[N:35][N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=2)=[CH:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Agent: OB(O)c1ccccc1
Product: C[Si](C)(C)CCOCn1cc(-c2cn(COCC[Si](C)(C)C)c3cnn(COCC[Si](C)(C)C)c(=O)c23)cn1
Yield: 46 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 31 except for using 289 mg (0.61 mmol) of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 20-(a) in place of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one, and using 619 mg (1.91 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazole obtained in Reference example 32-(a) in place of phenylboronic acid, respectively, whereby 166 mg of the title compound was obtained as a slightly yellowish oil. (Yield: 46%)