Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH2:20])[CH:14]=2)=[N:11][N:12]=1.[OH2:32].OO.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][OH:32])[CH:14]=2)=[N:11][N:12]=1
Reactant: O
Reactant: C=Cc1cccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CCO)c4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a solution of 4-[5-amino-6-[5-(3-vinylphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (100 mg, 0.2425 mmol) in THF (9.172 mL) at 0° C., borane-THF complex (606.3 μL of 1 M, 0.6063 mmol) was added dropwise and the reaction mixture stirred overnight at room temperature. Water (43.69 mg, 43.69 μL, 2.425 mmol) was added to the reaction mixture followed by hydrogen peroxide (299.9 μL of 27.5% w/v, 2.425 mmol) and NaOH (606.5 μL of 2 M, 1.213 mmol) and the mixture stirred vigorously for 1 h. The mixture was partitioned between ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL) and combined organic extracts dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (5.8 mg, 11% yield); 1H NMR (400 MHz, DMSO) d 2.89 (t, 2H), 2.98 (m, 6H), 3.70 (q, 2H), 4.75 (t, 1H), 7.55-7.62 (m, 4H), 7.80 (br s, 2H), 8.01 (m, 2H), 8.17 (m, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 431.24
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=2)[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]
Reactant: COc1ccc(-c2cccc(N)c2)cc1OC
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1OC
Temperature: 25 °C
Yield: 18.4 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,4′-Dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.005 g of product in 19% yield: LCMS (ESI) m/z 418 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH3:10][C:11]1[N:12]=[C:13]([NH:16][C:17](=O)[O:18]C2C=CC=CC=2)[S:14][CH:15]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17]([NH:16][C:13]2[S:14][CH:15]=[C:11]([CH3:10])[N:12]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Cc1csc(NC(=O)Oc2ccccc2)n1
Reactant: Nc1ccc(F)c(Br)c1
Solvent: C1CCOC1
Product: Cc1csc(NC(=O)Nc2ccc(F)c(Br)c2)n1

Procedure:
Step 2 A solution of 3-bromo-4-fluoroaniline (250 mg, 1.316 mmol) in THF (6 mL) was stirred on ice and treated with TEA (0.367 mL, 2.63 mmol), then with phenyl 4-methylthiazol-2-ylcarbamate (308 mg, 1.316 mmol) and the resulting solution was stirred at rt for 70 h. The mixture was concentrated and the residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, rinsed with water and dried under vacuum to provide 1-(3-bromo-4-fluorophenyl)-3-(4-methylthiazol-2-yl)urea as an off white solid (400 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H) 7.94 (dd, J=6.3, 2.5 Hz, 1H) 7.37-7.45 (m, 1H) 7.32 (t, J=8.7 Hz, 1H) 6.67 (d, J=1.1 Hz, 1H) 2.23 (d, J=1.1 Hz, 3H). Mass spectrum m/z 330, 332 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[O:22][CH3:23]>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[O:22][CH3:23])[CH3:2]
Reactant: CCOC(CO)OCC
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(N)cc1OC)OCC
Reaction time: 18 h

Procedure:
To a solution of 2,2-diethoxyethanol (50 mmol, 6.71 g) was added 60% sodium hydride (50 mmol, 2.0 g) and the solution was stirred for 10 minutes at which point a solution of 2-chloro-5-nitroanisole (50 mmol, 9.38 g ) in DMF was added dropwise. The reaction mixture was stirred for 18 h. The DMF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated. The principal component was purified by silica gel column chromatography. The product was subjected to reduction over 18 h using 1 atm hydrogen and 10% Pd on carbon. After the reaction took up a theoretical amount of hydrogen the catalyst was removed by filtration.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[C:18](O[K])(C)(C)C.CI>ClCCl>[CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]([CH3:18])([CH:9]=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)O[K]
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Solvent: ClCCl
Solvent: CI
Product: CN(C)C1(c2ccccc2)CCC(C)(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the title compound from step 1 (11.6 g, 50.0 mmol) in abs. dichloromethane (200 mL) was mixed with tert-BuOK (6.50 g, 58.0 mmol) and methyl iodide (3.42 mL, 55.0 mmol) at 0° C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was washed with water and saturated NaCl solution (50 mL), dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH 20:1.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12.N#N.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Ethynylimidazo[1,2-a]pyridine (37 mg, 0.26 mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (103.4 mg, 0.2 mmol), (prepared as in Example 2), Pd[(PPh3)4] (11.6 mg, 5mol %), and Cul (2.9 mg, 7.5 mmol %) was placed in a vial with rubber septum. The mixture underwent 3 cycles of vacuum/filling with N2, and DMF (1.5 ml) and N,N-diisopropylethylamine (53 mL, 0.3 mmol) was added. The mixture was stirred at rt for 16 h, and the reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in methylene chloride, MeOH was pre-saturated with ammonia gas), giving the titled compound as an off-white solid (53%, 56 mg): MS (M+H)+ 532.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:30]1[CH:34]=[CH:33][CH2:32][CH2:31]1.N>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:31]2[CH2:32][CH2:33][CH2:34][O:30]2)=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: C1=COCC1
Reactant: CCCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCCn1nnn(-c2cc(OC3CCCO3)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To a stirred solution of 1.0 g (0.0035 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (Example 10, Step A) and 0.05 g (0.00026 mole) of 4-methylphenylsulfonic acid in 40 mL of p-dioxane was added slowly 0.88 g (0.0126 mole) of dihydrofuran in 20 mL of p-dioxane. The mixture was stirred at room temperature for approximately 18 hours, and an additional 0.88 g of dihydrofuran was added. The mixture was stirred at room temperature for an additional 48 hours. One mL of methanol saturated with ammonia was added to the mixture and stirring was continued for a short period of time. The reaction mixture was evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 0.58 g of 1-[2,4-dichloro-5-(2-tetrahydrofuranyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 89°-90° C.
Reaction SMILES: O.[CH2:2]([O:9][C:10](Cl)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([O:9][C:10]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CCCO)CC1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a stirred mixture of methylene chloride (400 ml) and water (40 ml) are added dropwise benzyloxycarbonyl chloride (100 g) and a solution of 3-(4-piperidyl)propanol (84 g) and triethylamine (65 g) in methylene chloride (100 ml) for 45 minutes at room temperature. After addition is completed, stirring is continued for further 1 hour. The methylene chloride layer is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Vacuum distillation of the oily residue is carried out to remove the low boiling material (50°-60° C./5 mmHg). 3-(1-Benzyloxycarbonyl-4-piperidyl)propanol (110 g) is obtained as a yellow oily residue.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:24]C(=O)OC(C)(C)C)([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>Cl.O1CCOCC1>[NH2:24][C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])=[CH:10][CH:11]=2)=[N:20][CH:19]=1)([CH3:22])[CH3:23]
Reactant: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)NC(=O)OC(C)(C)C)cn2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)N)cn2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
tert-butyl 2-(6-(4-(diethoxyphosphoryl)phenyl)pyridin-3-yl)propan-2-ylcarbamate (5.3 g, 11.8 mmol) was dissolved in HCl in dioxane (30 ml), the mixture was stirred at 50° C. for 4 hours. Then evaporated the solvent and the residue diluted with H2O (5 ml), extracted with ethyl acetate and the water phase was adjusted to pH=9 with 1N aqueous NaOH, extracted with ethyl acetate and the organic phase washed with brine and dried, concentrated under vacuo to give the product 33-g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([CH3:9])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:10][C:3]1[C:2]([F:1])=[CH:8][C:6]([NH2:7])=[C:5]([CH3:9])[CH:4]=1
Reactant: Cc1ccc(F)cc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)c(F)cc1N
Yield: 102.1 %

Procedure:
To a solution of 49.0 g of 5-fluoro-o-toluidine in 600 mL of dichloromethane was added 69.7 g of N-bromosuccinimide at 0° C., and stirred at this temperature for an hour. Then sodium thiosulfate aqueous solution was added, and the reaction solution was evaporated and diluted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. Then the solvent was evaporated, and the precipitated crystals were washed with diethyl ether:n-hexane=1:10, to afford 81.6 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH2:27][CH2:28][CH:29]=1)CCC.CCN(CC)CC>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:25]2[O:26][CH2:27][CH2:28][CH:29]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C2=CCCO2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (10 g, 25.8 mmol) in dioxane were added tributyl-(4,5-dihydro-furan-2-yl)-stannane (13.9 g, 38.7 mmol), (Ph3P)4Pd then Et3N (4.52 mL, 32.3 mmol). The reaction mixture was heated at reflux for 18 h to give a brown suspension that was allowed to cool to r.t. The reaction mixture was filtered through a sintered funnel and the filtrate was concentrated under in vacuo. The residue was purified by flash column chromatography (silica gel, 1:4 EtOAc/hexanes) to give the title compound (7.3 g, 86%) as beige crystals, m.p.: 120-125° C., API-ES: m/z 330 [M+H]+
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:7]([CH2:22][CH2:23][CH3:24])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:9])[CH2:5][CH3:6]>C1COCC1.O.Cl>[CH2:22]([N:7]([CH2:4][CH2:5][CH3:6])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
Lithium hydroxide monohydrate (0.0680 g, 1.6 mmol) is added to a mixture of methyl 3-[(dipropylamino)carbonyl]-5-ethylbenzoate (PREPARATION 20, 0.450 g, 1.6 mmol) in a mixture of THF/methanolwater (2/1/1, 8 mL). The mixture is stirred at 20-25 degrees C. for 3 hours. The mixture is then diluted with water (20 mL) and hydrochloric acid (1 N) is added to bring the pH to less than 3. The aqueous mixture is extracted with ethyl acetate. The organic phase is separated and washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound, MS (ESI+) for C16H23NO3 m/z (M+H)+=278.2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: C#CCOc1cc(F)c(CO)c(F)c1
Product: C#CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 67 %

Procedure:
This compound was prepared from 2,6-difluoro-4-prop-2-ynyloxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (336 mg; 67%); MS (ISP): 456.5 (M+NH4)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.ClC1C=CC=CC=1CC(Cl)=O>>[C:12]1([CH:2]2[CH2:3][NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1O
Reactant: c1ccc2c(c1)NCCO2
Agent: O=C(Cl)Cc1ccccc1Cl
Product: c1ccc(C2CNc3ccccc3O2)cc1

Procedure:
By a procedure similar to that described for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine (Example 142), o-aminophenol and 2-chlorophenylacetyl chloride produces 3,4-dihydro-2-phenyl-2H-1,4-benzoxazine, m.p. 113°-116° which, according to the reaction scheme of Example 110 is converted to the title compound, m.p. 311°-313°.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.Br[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: O=Cc1ccc(Br)cc1
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc(C=O)cc3)ccc21

Procedure:
In a manner similar to Example 1(a) above, by the reaction of 5.3 g (15 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 3.1 g (16.5 mmol) of 4-bromobenzaldehyde, 2.4 g of the expected aldehyde of melting point 75-6° C. were obtained after purification by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:16][N:17]=2)=[N:8][CH:9]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:16][N:17]=2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1ccnc1CCCc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccnc1CCCc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A solution of the compound 134 (50 mg, 0.15 mmol) in EtOAc (10 mL) was added Pd/C (10 mg, 10%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at room temperature for 2 h. The suspension was filtered and the solid was washed by EtOAc. The filtrates were concentrated to dryness to give compound 135 (45 mg, 99%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ8.02-8.05 (m, 1H), 7.28-7.31 (m, 1H), 6.92-7.02 (m, 2H), 6.82-6.86 (m, 1H), 3.05 (t, 2H, J=7.6 Hz), 2.81 (t, 2H, J=7.6 Hz), 2.10-2.20 (m, 2H), 1.62 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[C:13]([Cu])#[N:14].C(OCC)(=O)C.O>CN(C=O)C>[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([OH:12])[CH:5]=1)[C:13]#[N:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(O)cc(Br)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(O)cc(C#N)c1
Temperature: 170 °C
Reaction time: 1.25 h
Yield: 68.2 %

Procedure:
A solution of 403 mg of 3-bromo-5-tert-butylphenol and 200 mg (1.28 mmol) of CuCN in 5 mL of DMF was stirred at 160° C. After 75 min. 365 mg of CuCN was added and stirring was continued at 160° C. After about 1 h, the temperature was increased to 170° C. and the mixture was refluxed for 19 h. Ethyl acetate and H2O were added, and the mixture was filtered through a Buchner funnel, and the layers were separated. The organic layer was washed with 10 mL of H2O and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided 153 mg of 3-tert-butyl-5-hydroxybenzonitrile as an orange solid in 49% yield.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:7])=[O:5])#[N:2].[H][H]>[Ni].N.CO>[NH2:2][CH2:1][CH2:3][C:4]([N:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CN(C(=O)CC#N)C1CCCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN(C(=O)CCN)C1CCCCC1

Procedure:
A mixture of 2-cyano-N-cyclohexyl-N-methyl-acetamide (3.96 g, 0.022 mol), a known compound, (which may be prepared as disclosed in Osdene, Thomas S. et al. Journal of Medicinal Chemistry (1967), 10(2), 165-7; Osdene, Thomas S.; Santilli, Arthur A. U.S. Pat. No. 3,138,595) and Raney nickel (3 g) in NH3/MeOH (300 mL) was hydrogenated at normal pressure. After 2 equivalents of hydrogen were consumed, the catalyst was removed by filtration. The filtrate was evaporated, and toluene was added to the residue and then evaporated to yield a residue.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>CN(C=O)C.O>[NH2:9][C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: N#Cc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cccnc2c1N
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-chloropyridine-2-carbonitrile (C-1) (1.01 g, 7.29 mmol) and K2CO3 (1.10 g, 7.96 mmol) in DMF (10 mL) and water (1 mL) was added methyl thioglycolate (0.709 mL, 7.93 mmol) dropwise. The reaction mixture was stirred at 40° C. for 3 h. The mixture was quenched with cold water (70 mL) and placed on ice to enhance precipitation. The precipitate was collected by filtration to afford the title compound. MS (m/z): 209 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:17])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH3:17])=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:26][CH2:25]2)=[CH:21][CH:20]=1
Reactant: Cc1c(-c2ccccc2)nc2ccc(Cl)nn12
Reactant: Fc1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2ccc(N3CCN(Cc4ccc(F)cc4)CC3)nn12
Temperature: 180 °C
Yield: 47 %

Procedure:
A solution of 6-chloro-3-methyl-2-phenylimidazo[1,2-b]pyridazine (1.00 g, 4.35 mmol) and 1-(4-fluorobenzyl)piperazine (Sigma-Aldrich, 1.54 g, 4.35 mmol) in acetonitrile (50 mL) containing triethylamine (13.0 mmol) is heated at 180° C. in the microwave for 5 hours. The reaction mixture is concentrated to dryness and then purified via chromatography (hexanes to EtOAc) to afford the title product (0.82 g, 81%) as an off-white solid: Rf 0.30 (EtOAc); LCMS (m/z)=402.4 [M+H]+, tR=1.74 min. (compound same as Example 134)