Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:37]=[CH:38][CH:39]=1)[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:3]1[N:2]([CH2:6][C:7]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[C:11]([Cl:10])[CH:12]=3)[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1
Reactant: O=C(O)Cn1nccn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 268, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)(=[O:4])[CH2:2][CH3:3].[BH4-].[Na+]>C(O)C.C1COCC1>[OH:4][CH:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(O)c1ccc2c(c1)NC(=O)C(C)O2
Yield: 95 %

Procedure:
6-(Propionyl)-2-methyl-1,4-benzoxazin-3-(4H)-one (1.1 g) is stirred with a half equivalent of sodium borohydride in 30 ml of ethanol/THF 1:1 for three hours at room temperature. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. A yield of 95% results.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH2:10][O:11][C:12](/[CH:14]=[CH:15]/[CH2:16]P(OCC)(OCC)=O)=[O:13].[CH:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[N:37]2[CH:38]=[N:39][CH:40]=[C:36]2[CH:35]=[CH:34][CH:33]=1)=O>O1CCCC1>[CH2:10]([O:11][C:12]([CH:14]=[CH:15][CH:16]=[CH:25][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[N:37]2[CH:38]=[N:39][CH:40]=[C:36]2[CH:35]=[CH:34][CH:33]=1)=[O:13])[CH3:9]
Reactant: O=CCCCCCc1cccc2cncn12
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=CCCCCCc1cccc2cncn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of lithium diisopropylamide (prepared from 3.8 ml of n-butyllithium in hexane and 0.84 ml of diisopropylamine) in 10 ml tetrahydrofuran at -70° C., is added 1.35 g of triethyl 4-phosphonocrotonate in a dropwise manner over a 15 minute period. On completion of the addition, 6.0 g of 5-(5-formylpentyl)imidazo[1,5-a]pyridine is added in a dropwise manner. The reaction mixture is allowed to stir at room temperature for 15 minutes. The reaction mixture is quenched with methanol and the solvent evaporated under reduced pressure to yield 5-(9-ethoxycarbonyl-nona-6,8-dienyl)-imidazo[1,5-a]pyridine as an oil.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]4)=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2)CC1
Yield: 19.1 %

Procedure:
The title compound (8.6 mg, 19%) was prepared from [4-(1-pyrrolidinylcarbonyl)phenyl]boronic acid (21.9 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 451 (M+H).
Reaction SMILES: CC(C)(C)C(Cl)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][C:10]=1[F:19].[Li]CCCC.[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([F:19])[CH:11]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
Trimethylacetyl chloride (1.68 g, 13.9 mmol) was added to a solution of 2-(4-chloro-3-fluorophenyl)acetic acid (2.50 g, 13.3 mmol) and TEA (d. 0.726; 2.00 mL, 14.3 mmol) in dry THF (100 mL) at 0° C. and stirred at room temperature. In a separate flask, n-BuLi (6.424 mL, 14.58 mmol) was added to (R)-4-benzyloxazolidin-2-one (2.47 g, 13.9 mmol) in dry THF (100 mL) at −78° C. The reaction was strirred for 20 minutes at −78° C., and then the (R)-4-benzyloxazolidin-2-one solution was added dropwise to the 0° C. mixed anhydride solution. The reaction was allowed to stir overnight at room temperature. The reaction was quenched with water (100 mL) and diluted with ethyl acetate (100 mL). The layers were separated, and the organics were washed with brine, dried (MgSO4) and concentrated to a residue. The resulting residue was purified by flash chromatography to give (R)-4-benzyl-3-(2-(4-chloro-3-fluorophenyl)acetyl)oxazolidin-2-one (2.79 g, 8.02 mmol, 60.5% yield). 1H NMR (400 MHz, CDCl3) 7.37 (t, J=8.2 Hz, 1H), 7.33-7.26 (m, 3H), 7.18-7.12 (m, 3H), 7.07 (d, J=8.2 Hz, 1H), 4.73-4.65 (m, 1H), 4.33-4.18 (m, 4H), 3.27 (dd, J1=3.5 Hz, J2=13.3 Hz, 1H), 2.77 (dd, J1=9.4 Hz, J2=13.7 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH:6]2[C:11]([O:13]C)=[O:12])[O:4][CH2:3][CH2:2]1.[OH-].[K+]>C(O)C>[O:4]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH:6]2[C:11]([OH:13])=[O:12])[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CSCCC12OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CSCCC12OCCO2
Yield: 63 %

Procedure:
A solution of 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxylic acid, methyl ester (prepared according to Baldwin, J. J. et al. U.S. Pat. No. 4,803,286; 30.00 g, 0.137 mol) in ethanol (500 mL) and a solution of potassium hydroxide (16.80 g, 0.299 mol) in ethanol (300 mL) were combined and heated under reflux for 7 h. The solution was concentrated in vacuo and water was added. The mixture was extracted with ether, and the ether layer was discarded. The aqueous layer was made acidic and extracted with ether. The ether layers were washed, dried, and evaporated, and the residue was recrystallized from benzene/hexane to give 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxylic acid (17.8 g, 63%) as white crystals, mp 99–101° C.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.C[N:11]([C:13]([N:15]=NC(N(C)C)=O)=O)C.[C:22]1([N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:13]([NH:15][C:32](=[O:33])[CH2:31][CH2:30][C:29]([NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:34])#[N:11]
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Reactant: O=C1CCC(=O)N1c1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: N#CNC(=O)CCC(=O)Nc1ccccc1

Procedure:
Using high temperature NMR techniques (150° C., nitrobenzene), the rapid conversion of the diamide to N-phenylsuccinimide was observed.
Reaction SMILES: Cl.[CH2:2]1[O:13][C:12]2[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][C:4]=2[O:3]1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>ClCCCl>[O:13]1[C:12]2[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][C:16](=[O:17])[CH2:15][Cl:14])=[CH:5][C:4]=2[O:3][CH2:2]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCCl
Product: O=C(CCl)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.5 %

Procedure:
3,4-Methylenedioxyphenethylamine hydrochloride (101 mg, 0.5 mmol) was dissolved in DCE (2 mL) and TEA (70 μL). Next, chloroacetyl chloride (48 μL, 0.6 mmol) was added and the reaction was allowed to stir at room temperature for 16 hours. After this time, the solution was concentrated down under N2. The residue was redissolved in DCM, washed with sat. NaHCO3 (aq) and dried over Na2SO4. The crude residue was purified by Prep-LCMS to afford 32 mg (27%) of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-chloro-acetamide. 1H-NMR (400 MHz, CDCl3) δ 6.75-6.62 (m, 3H), 5.92 (s, 2H), 4.01 (s, 2H), 3.52-3.47 (m, 2H), 2.79-2.72 (t, 2H).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.I[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:15][CH2:16][OH:17])[CH:1]=[O:13]
Reactant: OCCI
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OCCO
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Syringaldehyde (1.0 g,5.49 mmole), 2-iodo-1-ethanol (1.90 g,10.98 mmole) and potassium carbonate (1.90 g, 13.77 mmole) were added to 15 ml dry DMF and stirred for 24 hours at 80° C. under an argon atmosphere. The reaction mixture was added to 100 ml H2O and acidified with 10% HCl. The product was extracted into CHCl3, dried over MgSO4, and concentrated to an oil in vacuo. The remaining oil was purified by flash column chromatography using 1:1 hex/ethyl acetate as eluent (1.009 g, 81%). NMR: (CDCl3) 3.23,t,1H; 3.73,m,2H; 3.93,s,6H; 4.20,t,2H; 7.13,s,2H; 9.87,s,1H M.S. (CI): 227 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])=[C:8]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)[O:9][C:5]=2[CH:4]=1.[H-].[Na+].Cl.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>CS(C)=O>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:13]1[CH:14]=[C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:30]=[CH:29][C:6]=3[C:7]=2[C:15]([C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:11]=[N:12]1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn[nH]c3)oc2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cnn(CCN(C)C)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.6 %

Procedure:
To a stirred solution of [6-Methoxy-2-(1H-pyrazol-4-yl)-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (45 mg, 0.11 mmol) in dry DMSO (1.5 mL) was added sodium hydride (60% dispersion in mineral oil, 13 mg, 0.33 mmol) and the reaction was stirred at room temperature for 20 minutes. After this time the resulting yellow suspension was treated with 2-chloroethyl-dimethylamine hydrogen chloride (24 mg, 0.17 mmol) and heated to 35-40° C. for 5 h. The reaction was quenched with water (15 mL) and ethyl acetate (20 mL) and the aqueous layer was washed with further portions of ethyl acetate (2×10 mL). The combined organic layers were dried over magnesium sulphate and the solvent was removed under vacuum. The crude residue was purified by flash chromatography (alumina activated with 1.2% water, sequential elution—1:1 DCM:hexane, 9:1 DCM:ethyl acetate) to afford the product as a yellow resinous gum (23 mg, 44% yield). 1H-NMR (CDCl3) δ 8.17 (s, 1H), 8.00 (s, 1H), 7.12 (s, 2H), 7.11 (d, J=8.7 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.79 (dd, J=8.7, 2.2 Hz, 1H), 4.23 (t, J=6.7 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.77 (s, 6H), 2.78 (t, J=6.7 Hz, 2H), 2.27 (s, 6H). 13C-NMR (CDCl3) δ 190.3, 158.1, 153.6, 152.9, 142.2, 139.0, 133.7, 130.4, 121.7, 120.9, 113.7, 112.5, 112.2, 111.5, 106.9, 95.5, 61.0, 58.7, 56.1, 55.7, 50.4, 45.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=2)=[CH:4][CH:3]=1.[OH-:25].[K+]>C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:24])=[O:25])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1cc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)ccn1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.44 g (4.6 mmoles) of 4-[3-(4-Fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridine-2-carbonitrile is stirred at room temperature in 8 mL of t-butanol in the presence of 1.03 g (18.3 mmoles) of powdered potassium hydroxide. The reaction is stirred at room temperature for 4 hours, concentrated under vacuum and poured into water and ethyl acetate (1/1). Chlorhydric acid 2N is added to the solution to reach pH=5 and the solution is extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration 800 mg of 4-[3-(4-Fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridine-2-carboxylic acid amide are obtained as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Product: CC(=O)NC(C)c1cc2cc(CCc3ccc(OCC4CC4)cc3)ccc2o1
Yield: 32 %

Procedure:
Using N-(1-{5-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (328 mg, 1.01 mmol) obtained in Example 157 and (bromomethyl)cyclopropane (3.97 g, 29.3 mmol) and in the same manner as in Example 158, the title compound was obtained (122 mg, yield 32%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35]Cl)[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH:30]=1
Reactant: ClCc1cc(Cl)ccn1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cc(Cl)ccn4)cc3)no2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To 4-(5-(6-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 177-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.9 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of the solid obtained above and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (13.3 mg, 0.08 mmol) described in Manufacturing Example 51-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (7.2 mg, 25%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:29]2[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]3[CH2:45][NH:44][C:43](=[O:46])[CH2:42]3)[CH3:40])[C:32]3[N:33]([N:35]=[CH:36][CH:37]=3)[CH:34]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[C:1]([N:26]1[CH2:25][CH2:24][N:23]([C:22]2[CH:21]=[CH:20][C:19]([C:29]3[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]4[CH2:45][NH:44][C:43](=[O:46])[CH2:42]4)[CH3:40])[C:32]4[N:33]([N:35]=[CH:36][CH:37]=4)[CH:34]=3)=[CH:18][C:17]=2[O:16][CH3:15])[CH2:28][CH2:27]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(C)=O)CC1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Acetic anhydride (5 μL, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(3-methoxy-4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.48 (22.4 mg, 0.04 mmol) and triethylamine (0.05 ml, 0.33 mmol) in dichloromethane (1.8 mL) at room temperature. After two hours, reaction mixture was loaded directly onto silica and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.49 (15.9 mg).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][P:22](=[O:25])([OH:24])[OH:23])C1C=CC=CC=1>CO>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][P:22](=[O:23])([OH:24])[OH:25]
Reactant: O=P(O)(O)OCCCCCCCCCCCCOCc1ccccc1
Solvent: CO
Product: O=P(O)(O)OCCCCCCCCCCCCO

Procedure:
In a single-neck flask with a reflux condenser, 12-diethoxyphosphoryl benzoate (4.0 g, 9.3 mmol) is weighed and concentrated HCl (10 mL) is added. The mixture is brought to a temperature of 100° C. and left stirring under a static head of nitrogen. After 72 hours ethyl acetate (80 mL) and distilled water (40 mL) are added. Separation is carried out in a separating funnel and the water is extracted three more times with ethyl acetate (3×50 mL). The combined organic phases are washed with a saturated solution of NaCl, anhydrified with anhydrous sodium sulphate and concentrated in the Rotavapor and in the high vacuum pump. Column chromatography is performed on silica gel with eluant petroleum ether/ethyl acetate 1/1. The benzoic acid subproduct is isolated first and then, after changing to pure methanol as eluant, the product 12-benzyloxydodecyl phosphoric acid. Continuing column chromatography, the total hydrolysis product 12-hydroxydodecyl phosphoric acid is also isolated. The last two products (about 2.0 g) are kept together and used in the next stage.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12](CC2C=CC(OC)=CC=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:32]([O:34][CH:35]([Cl:37])[CH3:36])=[O:33]>C(Cl)Cl>[Cl:37][CH:35]([O:34][C:32]([N:12]1[CH2:13][CH2:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11]1)=[O:33])[CH3:36]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc(CN2CCC(CNC(=O)OC(C)(C)C)(c3ccccc3)CC2)cc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of [1-(4-methoxy-benzyl)-4-phenylpiperidin-4-ylmethyl]carbamic acid tert-butyl ester (3.2 mmol) in CH2Cl2 is added 1-chloroethyl chloroformate (4.7 mmol), then the mixture is stirred at room temperature for 2.5 h. After the bulk of solvent is concentrated in vacuo, the residue suspended in ether and filtered. After the filtrate is concentrated in vacuo, the residue is suspended in hexane and filtered. The filtrate is concentrated in vacuo to give the 4-(tert-butoxycarbonylaminomethyl)-4-phenylpiperidine-1-carboxylic acid 1-chloroethyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:15]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
tert-Butyl piperazine-1-carboxylate (45.8 mmol, 8.53 g) and 4-(3-(cyclopropylmethyl)ureido)benzoic acid (45.8 mmol, 10.73 g) were mixed in dichloromethane (200 mL) and triethylamine (103 mmol, 14.36 ml, 10.43 g) added followed by 1-propanephosphonic acid cyclic anhydride (68.7 mmol, 40.7 mL, 43.7 g, 50% solution in ethyl acetate). The reaction was stirred for 1 hour and then was poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the title compound (17.13 g).
Reaction SMILES: [C:1]1([NH:11][CH2:12][C:13]([O:15]CC)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([NH:11][CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CNc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNc1cccc2ccccc12
Yield: 46.6 %

Procedure:
In 5 ml of THF, 500 mg of 1-naphthylamine was added, then 168 mg of sodium hydride (60% in oil) was added and the resultant mixture was stirred for 30 min under ice cooling. To the reaction mixture, 0.46 ml of ethyl bromoacetate was added and the mixture was refluxed for 5 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was re-dissolved in ethyl acetate. The obtained solution was washed with 5% sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated. under reduced pressure and subjected to a silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give 720 mg of ethyl 1-naphthylaminoacetate. In 10 ml of ethanol, 460 mg of the ester was dissolved, 3.78 ml of 1N-NaOH aqueous solution was added and the resultant mixture was stirred for 1 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N-HCl and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and crystallized by the treatment with ether to give 188 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A mixture of 4-fluoronitrobenzene (7.05 g), 4-pyridylpiperazine (8.15 g), anhydrous sodium bicarbonate (10.0 g) and dry N,N-dimethylformamide (100 ml) was heated under reflux with stirring for 3 hours and then cooled and poured into water. The solid was filtered off, washed with water and crystallised from ethanol to give 1-(4-nitrophenyl)-4-(4-pyridyl)piperazine (7.34 g), m.p. 213°-216° C. Further recrystallisation raised the m.p. to 219°-221° C. Found: C,63.76; H,5.85; N,19.96. C15H16N4O2 requires: C,63.36; H,5.67; N,19.71%.