Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH2:9])=[N:6][CH:7]=1>CCO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:6][CH:7]=1
Reactant: C=C(NC(C)=O)c1ccc(F)cn1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(C)c1ccc(F)cn1
Temperature: 27.5 °C
Reaction time: 1.5 h
Yield: 103535.5 %

Procedure:
10% Pd/C (100 mg) was added to a solution of N-(1-(5-fluoropyridin-2-yl) vinyl)acetamide (440 g, 2.2 mmol) in EtOH (10 mL) and the mixture was stirred continuously under hydrogen atmosphere at 20-35° C. for 1.5 h. The reaction mixture was filtered over a celite bed-and the filtrate was concentrated under reduced pressure to afford 415 g of the title compound as a yellowish brown liquid. MS (ESI): m/z 183 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.I[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2].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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Reactant: Ic1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cnccn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a solution of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.352 g, 1.0 mmol) in 4 mL of dry THF, at −78° C. under Ar, was added n-butyllithium solution (1.6M in hexanes, 0.75 mL, 1.2 mmol) dropwise. After 15 min, a solution of freshly fused ZnCl2 in 1.2 mL of dry THF was added dropwise and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. To this mixture was then added 2-iodopyrazine (0.119 mL, 1.2 mmol) and (Ph3P)4Pd (0.058 g, 5 mol %) and the reaction vessel was sealed and then heated at 90° C. for 16 h. The cooled mixture was quenched with saturated aqueous NH4Cl and then it was partitioned with EtOAc-water. The organic phase was washed (brine), dried (Na2SO4) and evaporated to give a dark brown gum. Flash chromatography of this material [SiO2/1-2% MeOH—NH4OH (9:1) in CH2Cl2] afforded the title compound (0.237 g, 68%) as a light yellow solid:
Reaction SMILES: [NH2:1][C@H:2]([P:6](=[O:9])([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].O>[CH2:21]([O:28][C:29]([NH:1][C@H:2]([P:6](=[O:8])([OH:7])[OH:9])[CH:3]([CH3:5])[CH3:4])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)[C@H](N)P(=O)(O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
A slurry of (1R)-(+)-(1-amino-2-methylpropyl)phosphonic acid (2.57 g, 16.8 mmol), NaHCO3 (2.82 g, 33.6 mmol), and Na2CO3 (3.58 g, 33.8 mmol) in 16 mL of 2N NaOH and 3 mL of H2O was cooled in an ice water bath. To this was added benzyloxycarbonyl chloride (2.4 mL, 16.8 mmol). During the next 2 hours, two additional aliquots of benzyloxycarbonyl chloride were added (2.4 mL each). After stirring at ambient temperature for 16 hours, 40 mL of 2N NaOH was added and the mixture was partitioned between water and ether. The aqueous portion was washed with ether, acidified to pH 2 with concentrated HCl, and extracted with ethyl acetate (2×) and with methylene chloride (2×). The combined organic extracts were washed with saturated NaCl, dried over MgSO4, filtered, and concentrated in vacuo to give 4.41 g (91%) of (1R)-(+)-(1-benzyloxycarbonylamino-2-methylpropyl)phosphonic acid as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: OC1Cc2ccccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC1Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 0.26 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 was dissolved in 10 ml of tetrahydrofuran. To the obtained solution were added 0.2 g of 2-hydroxyindane, 0.75 ml of diisopropyl azodicarboxylate (40% toluene solution) and 0.31 g of tri(n-butyl)phosphine, and the mixture was stirred at 50° C. After 3 hours, 0.2 g of 2-hydroxyindan, 0.75 ml of diisopropyl azodicarboxylate (40% toluene solution) and 0.31 g of tri(n-butyl)phosphine were further added thereto, and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:dichloromethane=1:1:1), and recrystallized from acetone/diisopropyl ether to give 0.13 g of colorless powdery 3-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([CH3:15])[CH:9]=1>CCOCC>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([Cl:7])=[CH:9][C:10]=1[CH3:15])=[O:6]
Reactant: Cc1cc(Cl)ccc1N
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-chloroethyl isocyanate, 28.3 g. (0.27 mole) in 100 ml. of ether is added dropwise to a solution of 4-chloro-2-methylaniline, 38.0 g. (0.27 mole), in 500 ml. of ether. The solution is stirred 16 hours at room temperature, and the solid product is filtered and air dried, giving 47.2 g. (71% of theory) of the desired product, m.p. 190°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14](Br)=[C:13](Br)[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1ncc2c(ccn2Cc2cccc(OC)c2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 327 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[F:40][C:41]([F:51])([F:50])[CH:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[NH2:43]>>[F:51][C:41]([F:40])([F:50])[CH:42]([NH:43][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[N:8]=1)=[O:20])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1
Reactant: NC(c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 503173-14-6) as starting materials, MS (EI): m/e=436.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:14][O:15][C:16](=[O:28])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1Br>O1CCCC1.[Cl-].[Cl-].[Zn+2].Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:15][C:16](=[O:28])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)OC)c(-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
4-Bromotoluene (6 g) was dissolved in tetrahydrofuran (20 ml). To this solution at -78° C. under N2 was added over a ten minute period, 1.7M tBuLi (42 ml). After two hours at room temperature, the reaction mixture was cooled to 0° C. and 1M ZnCl2 (36 ml) was added over a ten minute period. After one half hour at room temperature, bis(triphenylphosphine)nickel(II) chloride (1.32 g) was added followed by dimethyl-2-bromo-terepthalate (6 g) in tetrahydrofuran (20 ml) dropwise over a five minute period. The reaction mixture was stirred at room temperature for two hours. The tetrahydrofuran was removed under reduced pressure. The residue was treated with ethyl acetate and 1N HCl and the layers separated. The organic phase was washed with water, brine, dried over magnesium sulfate and evaporated gave the crude product. Chromatography on silica gel using 5% hexanes/methylene chloride gave the desired product (5.33 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[NH:11][C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[N:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(-c2ccccc2)c2ncnn12
Reaction time: 16 h
Yield: 102 %

Procedure:
To a suspension (20 mL) of 3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), phenylboronic acid (0.31 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.47 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.61 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:15]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[N:7]=[C:2]([C:34]3[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=3)[N:3]=2)[CH:20]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
(S)-4-(2-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 10) (350 mg, 0.91 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (239 mg, 1.09 mmol), Pd(PPh3)2Cl2.DCM (37 mg, 0.05 mmol) and Na2CO3 (145 mg, 1.36 mmol) were dissolved in a mixture of DME:H2O (4:1) and stirred at 120° C. under microwave for 30 mins. The reaction mixture was partitioned between H2O and DCM. The organic layer was recovered, dried over MgSO4, filtered and the solvent removed in vacuo to yield the title compound as a brown solid (128 mg, 0.29 mmol, 32% yield).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:11]1([O:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)n1cc(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(NC(=O)Oc2ccccc2)cn1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution containing 1-tert-butyl-1H-pyrazol-4-amine (0.995 g, 7.16 mmol) in THF (20 mL), phenylchloroformate (1.00 mL, 8.02 mmol) and K2CO3 (1.32 g, 9.52 mmol) were added at room temperature. After stirring overnight, the mixture was filtered and the solid washed with THF. The filtrate was concentrated to dryness and the residue was dissolved in DCM and the organic solution was washed with brine and dried over MgSO4 to yield phenyl 1-tert-butyl-1H-pyrazol-4-ylcarbamate as a solid (1.65 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.30 (6H, m), 1.60 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1
Yield: 98.4 %

Procedure:
4-Chloronitrobenzene (80 mg, 0.51 mmol) reacted with o-methylphenylboronic acid (85 mg, 0.63 mmol) using 0.5/1.0 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.55 mmol) in THF solvent at 50° C. for 22 h to give the title compound (107 mg, 98%): 1H-NMR (500 MHz, CDCl3): δ 8.30 (d, 2H, J=6.90 Hz, aryl coupling 1.8 Hz), 7.51 (d, 2H, J=6.92 Hz, aryl coupling 1.8 Hz), 7.35-7.23 (m, 4H), 2.29 (s, 3H, Ar—CH3). 13C{1H}-NMR (125 MHz, CDCl3): δ 148.80, 146.86, 139.60, 135.04, 130.70, 130.09, 129.39, 128.45, 126.11, 123.40, 20.31. GC/MS(EI): m/z 213 (M+), 165, 152.
Reaction SMILES: [I-].[O:2]([CH2:9][CH:10]1[NH+:14]([CH3:15])[C:13]([CH3:17])([CH3:16])[CH2:12][O:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC=CC=1.C(N(CC)CC)C.[N:31]([C:33]1[C:42]([OH:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][CH:37]=[N:38]2)=O>O>[O:2]([C:9]1[C:10]2([N:14]([CH3:15])[C:13]([CH3:17])([CH3:16])[CH2:12][O:11]2)[O:43][C:42]2[CH:41]=[CH:40][C:39]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]=2[N:31]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[NH+]1C(COc2ccccc2)OCC1(C)C
Reactant: O=Nc1c(O)ccc2ncccc12
Agent: [I-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(C)(C)COC12Oc1ccc3ncccc3c1N=C2Oc1ccccc1
Reaction time: 8 h
Yield: 2.8 %

Procedure:
Into a dry 250 ml three-necked flask kept under dry nitrogen and fitted with a distillation column and internal thermometer was added 2-phenoxymethyl-3,4,4-trimethyl-1,3-oxazolidinium iodide (6.00 grams, 18.1 mmole) and 80 ml dry benzene. To the heterogeneous stirred solution was added in one portion triethylamine (3.64 grams, 36 mmole) followed by 5-nitroso-6-quinolinol (2.61 grams, 15 mmole). The solution was heated to reflux and maintained at reflux for 3 hours during which time water that formed during the course of the reaction was azeotropically removed. The solution was cooled with stirring overnight, decanted away from the tarry residue, and concentrated in vacuo. The product was isolated by flash chromatography to yield 0.16 grams of 2'-phenoxy-3,4,4-trimethylspiro[oxazolidine-2,3'-[3H]pyrido[3,2-f] [1,4]benzoxazine], which was characterized by appropriate spectral techniques. A toluene solution of the product changed to red when irradiated with ultraviolet light. The solution returned to its original hue after the UV light was removed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C.CN(C)C1C=CN=CC=1>[F:23][C:20]([F:21])([F:22])[C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:24]=[C:2]([NH:1][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH:3]=[CH:4][C:5]=2[OH:25])[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 40.5 %

Procedure:
5-Amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (100.2 mg, 0.28 mmol) was dissolved in acetonitrile (4 ml). 4-Dimethylaminopyridine (3 mg) and phenylisocyanate (30 μl, 0.28 mmol) were added, and the mixture was stirred at 60° C. for 5 minutes. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound (54.8 mg, 41.2%) as a light brown solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH3:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[S:51][CH2:52][C:53]1[N:57]([CH2:58][CH2:59][CH3:60])[CH:56]=[N:55][CH:54]=1)[NH2:47]>O1CCCC1.N1C=CC=CC=1.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:47][C:46]4[CH:48]=[CH:49][C:50]([S:51][CH2:52][C:53]5[N:57]([CH2:58][CH2:59][CH3:60])[CH:56]=[N:55][CH:54]=5)=[C:44]([CH3:43])[CH:45]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cncc1CSc1ccc(N)cc1C
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (350 mg) in tetrahydrofuran (10 ml) was added a drop of DMF. Then, after adding thionyl chloride (0.073 ml), the mixture was stirred under nitrogen atmosphere for 1 hour. The solution was slowly added dropwise to a solution of 3-methyl-4-[((1-propylimidazol-5-yl)methyl)sulfanyl]aniline (223 mg) in pyridine (10 ml) at 0° C. under nitrogen atmosphere. After stirring the mixture at room temperature under nitrogen atmosphere overnight, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (444 mg) as a yellow amorphous material (Compound 38).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C3CC3)c2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.22) (0.30 g, 0.55 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.219 g, 0.94 mmol) according to the general procedure VI. Obtained as an off-white solid (0.250 g, 80%). MS (ISP) 432.3 [(M+H)+]; mp 130-135° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O1CCCC1>[C:1]([NH:11][C@H:12]([C:14]([Cl:18])=[O:16])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Cl

Procedure:
(1)A solution of carbobenzoxy-L-alanine (4.48 g) in tetrahydrofuran (15 ml) is mixed with phosphorus pentachloride (4.58 g) to give a solution of carbobenzoxy-L-alanyl chloride in tetrahydrofuran, which is added to a solution of 1-(2-benzoyl-4-chlorophenyl)-2-(1-amino-1-dimethylcarbamoylmethylene)hydrazine (3.45 g) in tetrahydrofuran (70 ml) and dimethylformamide (20 ml). The resultant mixture is stirred at room temperature for 1 hour, mixed with potassium carbonate (1.38 g), stirred for 4 hours, and allowed to stand overnight. The reaction mixture is mixed with water and evaporated under reduced pressure to remove the solvents, and the residue is extracted with ethyl acetate. The organic layer is dried and evaporated to remove the ethyl acetate, whereby 1-(2-benzoyl-4-chlorophenyl-2-[1-(carbobenzoxy-L-alanylamino)-1-dimethylcarbamoylmethylene]hydrazine is obtained as a residue. The residue is mixed with acetic acid (30 ml) without purification, and the resultant solution is refluxed for 2 hours under heating. The reaction mixture is evaporated under reduced pressure to remove the acetic acid. The residue is extracted with chloroform, and the chloroform layer is washed with aqueous sodium bicarbonate and water in order, dried and evaporated to remove the chloroform. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate. The eluate is evaporated to give 5-chloro-2-[3-dimethylcarbamoyl-5-(1-carbobenzoxyaminoethyl)-1H-1,2,4-triazol -1-yl]benzophenone (1.4 g) as a gelatinous material.