Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH2:10]Cl)=[O:7])=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.N>O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NCCCl)c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: N
Solvent: O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
5.45 G. of p-chloro-N-(2-chloroethyl)-benzamide and 8.7 g. of morpholine are stirred together for 2 hours at 100° C. The mixture is cooled to room temperature and 50 ml. of water are added. Then, the mixture is rendered basic with 10% ammonia solution and extracted three times with 50 ml. of methylene chloride each time. The methylene chloride extract is dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 2.2 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13](=[O:14])[C:8]2=[CH:7][NH:6]1)(C)(C)C>FC(F)(F)C(O)=O>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[N:10]=[C:9]2[N:5]=[N:6][CH:7]=[C:8]2[C:13](=[O:14])[N:12]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc2n(C(C)(C)C)[nH]cc-2c(=O)n1
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccccc1C1=NC(=O)C2=CN=NC2=N1
Yield: 79.9 %

Procedure:
A mixture of 1-tert-butyl-6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one 1/100 hydrate (0.68 g, 2.1 mmol) and trifluoroacetic acid (50 ml) was heated on a steam bath for 3.5 hours. The reaction mixture was stripped to dryness and the residue was purified by column chromatography on silica gel eluting with ether to afford 0.45 g (79%) of 6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one.1/4 hydrate, m.p. 170-171° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:18][C:19]1[CH:20]=[C:21]2[C:26](=O)[O:25][C:23](=[O:24])[C:22]2=[CH:28][CH:29]=1.C(OCC)(=O)C.CCCCCC>C(O)(=O)C.O>[CH2:16]([O:15][C:9]1[CH:8]=[C:7]([CH:2]([N:1]2[C:26](=[O:25])[C:21]3=[CH:20][C:19]([CH3:18])=[CH:29][CH:28]=[C:22]3[C:23]2=[O:24])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])[CH3:17]
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A stirred solution of 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.00 g, 12.5 mmol) and 4-methylphthalic anhydride (2.13 g, 12.5 mmol, 95%) in acetic acid was heated to reflux under nitrogen for 18 hours. The mixture was allowed to cool to room temperature. The solvent was removed in vacuo to give an oil. The resulting oil was stirred with ethyl acetate (10 mL), hexane (10 mL) and water (30 mL) for 30 minutes. The resulting suspension was filtered. The solid was washed with water (3×10 mL) and hexane (3×10 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to give 3-(3-ethoxy-4-methoxyphenyl)-3-(4-methylphthalimido)propanoic acid as a white solid (3.4 g, 71% yield): mp, 134.0-136.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 2.47 (s, 3H, CH3), 3.23 (dd, J=6.7, 16.5 Hz, 1H, CHH), 3.50 (dd, J=9.2, 16.5 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.58 (dd, J=6.7, 9.1 Hz, 1H, NCH), 6.90-6.95 (m, 2H, Ar), 7.01 (br s, 1H, Ar), 7.61-7.76 (m, 3H, Ar), 12.4 (br s, 1H, OH); 13C NMR (DMSO-d6) δ14.65, 21.32, 36.09, 50.04, 55.45, 63.72, 111.79, 112.15, 119.29, 123.08, 123.58, 128.51, 131.35, 131.49, 134.95, 145.63, 147.75, 148.53, 167.67, 167.78, 171.72; Anal Calcd for C21H21NO6: C, 65.79; H, 5.52; N, 3.65. Found: C, 65.46; H, 5.57; N, 3.31.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]3[C:25]4[C:20](=[CH:21][C:22]([N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=4)[C:18](=[O:19])[O:17]3)=[CH:11][C:10]=2C2[C:4]1=[CH:5]C=CC=2)[CH3:2].[CH2:29]([N:33]([CH2:49]CCC)[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]([CH2:45]CCC)[CH2:41]CCC)[CH:35]=1)CCC>>[CH3:49][N:33]([CH3:29])[C:34]1[CH:35]=[C:36]([N:40]([CH3:41])[CH3:45])[CH:37]=[CH:38][C:39]=1[CH:16]([C:25]1[CH:24]=[CH:23][C:22]([N:26]([CH3:28])[CH3:27])=[CH:21][C:20]=1[C:18]([OH:19])=[O:17])[C:12]1[CH:13]=[CH:14][C:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:10][CH:11]=1
Reactant: CCn1c2ccccc2c2cc(C3OC(=O)c4cc(N(C)C)ccc43)ccc21
Reactant: CCCCN(CCCC)c1cccc(N(CCCC)CCCC)c1
Product: CCN(CC)c1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)cc1

Procedure:
Employing a procedure similar to that described in Example 1, part B above, 3-(9-ethyl-3-carbazolyl)-6-dimethylaminophthalide from A is interacted with N,N,N',N'-tetrabutyl-m-phenylenediamine to obtain 2-[α-(9-ethyl-3-carbazolyl)]-α-[2,4-bis(dibutylamino)phenyl]methyl-5-dimethylaminobenzoic acid (Formula III: R=CH3 ; X=H; Y=9-C2H5 -3-carbazolyl; Z=2,4-[(C4H9)2N]2C6H3).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[H][H]>CO.[Pd]>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:2]=1[OH:1]
Reactant: Cc1ccc2c(c1O)CCC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1O)CCC2
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a suspension of 4-Hydroxy-5-methyl-indan-1-one (8 gm) in Methanol (80 ml), added 10% w/w Pd—C. Hydrogenation was carried out for 5 hours at 55-60° C. in an autoclave at 200-250 psi using Hydrogen gas. The reaction mixture was filtered through hyflow bed and filtrate was distilled under vacuum to give a 6.0 gm of desired product as white solid.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([CH3:25])[N:21]=[CH:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([CH3:7])([CH3:6])[CH3:5]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:4]([C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([CH:25]=[O:2])[N:21]=[CH:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2cn1
Reactant: O=[Se]=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ncc3c2)CC1
Temperature: 200 °C

Procedure:
Selenium dioxide (2.25 g, 20.3 mmol) was added to a solution of 7-(trans-4-tert-Butyl-cyclohexyloxy)-3-methyl-isoquinoline (2.01 g, 6.76 mmol) in Diphenyl ether (50 mL, 300 mmol) and the mixture was heated at 200° C. in a sealed tube for 4 hours. The reaction was then cooled to room temperature. Silica gel was added and the flask was placed in a cold water bath to solidify the diphenylether solvent. This solid mixture containing the crude product was purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound in 50% yield. ESI-MS (M+H+): 312.27
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:21])[C:10]=2C(O)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:39][C:10]1[C:11]([CH3:21])=[N:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1N
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 38.7 %

Procedure:
A mixture of 4-(3-cyanophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid (3.7 g), diphenylphosphoryl azide (3.24 g), triethylamine (1.19 g) and t-butanol (35 ml) was refluxed for 5 hours. After the organic solvent was evaporated, chloroform (40 ml) and a saturated aqueous solution of sodium bicarbonate (40 ml) were added to the residue. The separated organic layer was washed with water and brine, dried and concentrated in vacuo. The residue containing 3-(t-butoxycarbonylamino)-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine was dissolved with ethanol (35 ml). After conc. hydrochloric acid (2 ml) was added to the solution at 0° C., the mixture was stirred at 0° C. for 1.5 hours and further at 80° C. for 7.5 hours. The mixture was concentrated, dissolved with chloroform (40 ml) and water (40 ml) and adjusted to pH 9 with 5N sodium hydroxide. The organic layer was separated, washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (70 g) eluting with a mixture of chloroform and methanol (100:1 V/V). The fractions containing the desired compound were combined and concentrated in vacuo. The residue was triturated with diethyl ether to give 3-amino-4-(3-cyanophenyl)-2-methyl-6-phenylpyridine (1.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70].FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)C1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and ethyl piperidine-2-carboxylate in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [O:1]1[C@H:5]2[CH2:6][O:7][CH2:8][C@H:4]2[NH:3][C:2]1=[O:9].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[Ar]>[Cl:10][C:11]1[N:12]=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:15]([N:3]2[C@@H:4]3[CH2:8][O:7][CH2:6][C@@H:5]3[O:1][C:2]2=[O:9])[CH:16]=1
Reactant: O=C1N[C@@H]2COC[C@@H]2O1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1O[C@H]2COC[C@H]2N1c1cc(Cl)nc(N2CCOCC2)n1
Temperature: 85 °C
Yield: 88.6 %

Procedure:
To a solution of (3aR,6aR)-tetrahydrofuro[3,4-d]oxazol-2(3H)-one (500 mg, 3.87 mmol), 4-(4,6-dichloropyrimidin-2-yl)morpholine (1088 mg, 4.65 mmol) and Cs2CO3 (2.14 g, 6.58 mmol) in dioxane (20 mL) was added after degassing with argon 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (157 mg, 0.271 mmol) and Pd2(dba)3 (70.9 mg, 0.077 mmol) and the reaction mixture was heated for 6 h at 85° C. The reaction mixture was added to 10% aqueous NaHCO3 solution and extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated in MeOH overnight, filtered off and dried to afford the title compound as a colorless solid (1.12 g, 87%): tR=0.92 min (LC-MS 3); ESI-MS: 327, 329 [M+H]+ (LC-MS 3).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(N)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 3.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (110 mg, 0.34 mmol) and 3-amino-butyric acid (354 mg, 3.4 mmol) (Sigma-Aldrich Corp., St. Louis Mo.) in 0.5 M NaOMe/MeOH solution (5.4 mL<2.72 mmol) was refluxed overnight and then microwaved at 120° C. for 2 h. Reaction mixture was concentrated and residue was dissolved in water (60 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. The crude product was purified by silica gel chromatography, eluting with 5-100% EtOAc (with 0.075% acetic acid)/hexane (with 0.1% acetic acid). White solid was crystallized from fractions containing the desired produce. Solid was collected and rinsed with EtOAc and dried in vacuo to provide the title compound 5.1 mg (0.013 mmol) in 3.8% yield. LC-MS ESI−: 390.01 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[Cl:17].ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:48]([NH:51][C:52](=[O:68])[C:53]1[CH:58]=[C:57]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:56]=[CH:55][C:54]=1[NH:66][CH3:67])([CH3:50])[CH3:49]>C(Cl)Cl.C1COCC1>[Cl:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[O:7][CH2:6][C:5]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([N:66]([CH3:67])[C:54]1[CH:55]=[CH:56][C:57]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:58][C:53]=1[C:52]([NH:51][CH:48]([CH3:49])[CH3:50])=[O:68])=[O:14]
Reactant: CNc1ccc(Oc2ccccc2)cc1C(=O)NC(C)C
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2Cl)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C(=O)N(C)c3ccc(Oc4ccccc4)cc3C(=O)NC(C)C)cc2Cl)cc1OC
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A slurry of 1B (28 mg, 0.09 mmol) and trichloroacetonitrile (0.009 mL, 0.09 mmol) in CH2Cl2 (1 mL) at room temperature was treated with a solution of triphenylphosphine (22 mg, 0.09 mmol) in THF (0.25 mL). The reaction mixture was stirred for 30 minutes and additional trichloroacetonitrile (0.009 mL, 0.09 mmol) and triphenylphosphine (22 mg, 0.09 mmol) were added. The resulting solution was treated with 44B (16 mg, 0.06 mmol) in CH2Cl2 (0.5 mL). The stirring was continued for 2 hours, and then the reaction concentrated to dryness. The residue was purified by chromatography (SiO2, 50% to 75% EtOAc in hexanes) to afford 44C (31 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:38])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:20][CH2:21][OH:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]=1.[H-].[Na+].S(OC)(O[CH3:45])(=O)=O>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:38])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:20][CH2:21][O:22][CH3:45])[C:15]([N:17]([CH3:18])[CH3:19])=[O:16])[N:7]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC(CCO)C(=O)N(C)C)N2)n1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(O/N=C1\N[C@@H](c2ccc(F)cc2-c2cccc(OC)n2)Cc2nc(N)nc(C)c21)C(=O)N(C)C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
To a solution of 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (0.03 mmol, 16 mg) in THF (2 mL) was added 50% NaH (0.034 mmol, 1.65 mg) at 0° C. under N2 atmosphere. The reaction mixture was stirred for 15 minutes and dimethyl sulphate (4.08 μL, 0.043 mmol) was added. The reaction mixture was stirred at r.t. for 3 h. Quenched with MeOH (1 mL) and purified by LCMS to afford the title compound 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-methoxy-N,N-dimethylbutanamide (95, 3.6 mg, 25%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.81-2.06 (m, 2H) 2.47 (s, 3H) 2.70-2.80 (m, 1H) 2.83 (d, J=10.61 Hz, 3H) 3.05 (d, J=7.58 Hz, 3H) 3.07-3.17 (m, 1H) 3.20 (d, J=4.80 Hz, 3H) 3.31-3.39 (m, 2H) 3.40-3.49 (m, 2H) 3.87 (d, J=3.79 Hz, 3H) 4.80-4.93 (m, 1H) 5.06-5.22 (m, 1H) 6.83-6.90 (m, 1H) 7.20 (d, J=8.84 Hz, 1H) 7.23-7.32 (m, 2H) 7.44 (ddd, J=14.34, 8.91, 5.81 Hz, 1H) 7.85 (td, J=7.83, 3.28 Hz, 1H). MS (ES) [M+H] calculated for C27H33FN7O4, 538.58. found 538.40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][S:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([S:25][CH2:24][CH2:23][N:13]3[CH2:12][CH2:11][CH:10]([O:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:15][CH2:14]3)=[N:30][C:29]=2[CH:31]=1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Reactant: Clc1ccc2oc(SCCBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ccc(C(OC2CCN(CCSc3nc4cc(Cl)ccc4o3)CC2)c2ccccn2)cc1
Reaction time: 6 h
Yield: 53.9 %

Procedure:
After 2.00 g (6.60 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 2.39 g (8.17 mmol) of 2-(2-bromoethylthio)-5-chlorobenzoxazole were dissolved in 10 ml of dioxane, 1.10 g (7.96 mmol) of potassium carbonate was added to the mixed solution, and the mixture was stirred at an oil bath temperature of 75° to 80° C. for 6 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with a mixed solution of chloroform and methanol in the volume ratio 50:1 as an eluent. The desired fraction was concentrated to give 1.83 g (54%) of 5-chloro-2-[2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethylthio]benzoxazole as an oily product.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]2[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:15]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]2[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:15]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (1.39 g) in tetrahydrofuran (30 ml) was added potassium tert-butoxide (437 mg) under nitrogen atmosphere at 0° C. After the mixture was stirred at 0°-5° C. for 1.5 hours, to this was added a solution of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (500 mg) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 4 hours and stood at room temperature overnight. Insoluble materials were filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel using dichloromethane as an eluant to give colorless crystals of 3-[2-(2-methylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (186 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH2:20])[CH:14]=1.NC[C@@H]1CCCN1CC.C(=O)C>>[NH2:8][CH2:9][C:10]([NH:20][CH2:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: NCc1cccnc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC=O
Agent: CCN1CCC[C@H]1CN
Product: NCC(=O)NCc1cccnc1

Procedure:
By using N-(t-butoxycarbonyl)glycine (1.0 g) and 3-picolylamine (577 μl) as starting materials, the title compound (892 mg) was obtained in the same manners as those of Reference Example 88, (1) and Reference Example 78, (3).
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]>CO.[Pd]>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)c1cccc(C=CC#N)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cccc(CCC#N)c1
Reaction time: 10 h
Yield: 83.9 %

Procedure:
To a solution of ethyl 3-(2-cyanovinyl)benzoate (800 mg, 4.0 mmol) in methanol (30 ml) was added cautiously 10% palladium/C and the mixture was stirred at 3 atm. for 10 hours under a hydrogen atmosphere. After the mixture was filtered to remove a solid, the filtrate was evaporated to yield ethyl 3-(2-cyanoethyl)benzoate (682 mg, 84%) as a colorless oil.
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:20])[C:17]([O-:19])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:55]([C:58]1[CH:63]=[CH:62][C:61]([NH:64][CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)=[CH:60][C:59]=1[C:71]([F:74])([F:73])[F:72])([O-:57])=[O:56]>CN(C)C=O.ClCCl.O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([CH3:20])[C:17]([N:68]3[CH2:69][CH2:70][CH:65]([NH:64][C:61]4[CH:62]=[CH:63][C:58]([N+:55]([O-:57])=[O:56])=[C:59]([C:71]([F:72])([F:73])[F:74])[CH:60]=4)[CH2:66][CH2:67]3)=[O:19])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CC(CN1CCN(c2ccc(Cl)cc2)CC1)C(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
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: C1CCOC1
Product: CC(CN1CCN(c2ccc(Cl)cc2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-propionic acid lithium salt (62 mg; 0.22 mmol, prepared in accordance with Example 60), diisopropylethyl amine (87 μL; 0.50 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (76 mg; 0.20 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (63 mg; 0.20 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 60 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (47 mg; 0.08 mmol). The structure was confirmed using Protocol I-A. Calculated mass=554; observed mass=554; HPLC retention time=3.45 min.