Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][CH:6]1[CH2:14][OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:15][CH2:14][CH:6]1[CH2:7][N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][CH:5]1[CH2:4][OH:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)N1CC(CO)C(CO)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CC(CO)C(COCc2ccccc2)C1
Temperature: -12 °C
Reaction time: 0.08 h
Yield: 58.9 %

Procedure:
To a suspension of 60% NaH (66 mg, 1.64 mmol) in DMF (3 ml) was added a solution of ([3RS,4RS]-4-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl)-methanol (327 mg, 1.56 mmol) in DMF (5 ml) at −12° C. After 5 min, benzylbromide (286 mg, 1.64 mmol) was added and the mixture was stirred at −12° C. for 30 min. The mixture was allowed to warm to room temperature. The solvent was evaporated. Water was added and extracted with dichloromethane. The organic phase was dried, filtered and evaporated. Flash chromatography (hexane/EtOAc 2:1=>1:1) gave 275 mg (58%) of ([3RS,4RS]-4-benzyloxymethyl-1-methanesulfonyl-pyrrolidin-3-yl)-methanol as a colorless oil, MS: 358 (M+OAc)−.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C@@H:7]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2nc(N[C@@H](C)C3CCCCC3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1nc2ccc(O)cc2s1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a solution of (S)—N-(1-cyclohexylethyl)-6-methoxybenzo[d]thiazol-2-amine (3.39 g, 10 mmol) in 30 mL of DCM was added 1 M boron tribromide in DCM (20 mL, 20 mmol) slowly at 0° C. The reaction solution was stirred at 0° C. for 20 min and then at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (400 mL) and water (90 mL) and stirred at room temperature for 10 min. To the mixture was added excess solid NaHCO3 until basic. Stirring was continued at room temperature for 1 hour. The separated aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed water (50 mL), saturated NaCl solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography with EtOAc/hexanes (3/7) provided the title compound as a solid (2.0 grams). ES/MS m/z 277.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:23][CH3:24])[C:16]([CH2:25][CH3:26])=[CH:15][CH:14]=1)(=[O:11])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:46][CH2:47][CH2:48][C:49]#[CH:50].CN(C)C>C1COCC1.[Pd](Cl)Cl.[Cu]I>[CH2:25]([C:16]1[C:17]([O:23][CH3:24])=[C:18]([C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[C:50]#[C:49][CH2:48][CH2:47][OH:46])(=[O:11])=[O:10])=[CH:14][CH:15]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:26]
Reactant: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2Br)c(C(=O)OC)c1OC
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CN(C)C
Solvent: C1CCOC1
Product: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2C#CCCO)c(C(=O)OC)c1OC
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A solution of Example 615A (0.446 g, 1.0 mmol), bis(triphenylphosphine))palladium dichloride (35 mg, 0.05 mmol), triphenylphosphine (6.5 mg, 0.025 mmol), 4-hydroxy-1-butyne (0.14 g, 2.0 mmol) and trimethylamine (0.2 mL, 1.5 mmol) in anhydrous THF (6 mL) in a scintillation vial was shaken at ambient temperature for 20 minutes. Copper (I) iodide (5 mg, 0.025 mmol) was added. The mixture was purged with argon, sealed and shaken at 75° C. for 8 hours, treated with ethyl acetate (30 mL), washed with brine (2×10 mL), dried (MgSO4), filtered, and concentrated. The residue was purified on a silica gel column eluting with 30% ethyl acetate in hexanes to provide the desired product, 304 mg, 69.9%. 1H NMR (DMSO-d6) δ 1.11 (t, 3H), 2.55 (q, 2H), 2.61 (t, 2H), 3.63 (t, 2H), 3.73 (s, 3H), 5.25 (t, 1H), 6.86 (d, 1H), 7.25 (d, 1H), 7.32 (t, 1H), 7.52 (d, 2H), 7.82 (dd, 1H), 9.59 (s, 1H); MS (ESI(−)) m/e 434 (M−H)−.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.[OH-].[Na+]>[CH2:8]([N:6]1[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 1.0 g (10 mmol) (R)-2-methylpiperazine, 1.3 g (10 mmol) benzyl chloride and 4.1 g (30 mmol) potassium carbonate in 10 ml ethanol was heated at reflux over night. After cooling to room temperature the reaction mixture was diluted with a 0.5 M aqueous solution of sodium hydroxide and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 0.93 g (49%) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[CH3:20][N:21]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:22]([C:24]1[S:25][C:26]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:28]=1)=[O:23]>>[CH3:20][N:21]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:22]([C:24]1[S:25][C:26]([C:29]([NH:31][N:32]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[S:10][CH:11]=2)[CH3:17])=[O:30])=[CH:27][CH:28]=1)=[O:23]
Reactant: CN(Cc1ccccn1)C(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Product: CC(=NNC(=O)c1ccc(C(=O)N(C)Cc2ccccn2)s1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O

Procedure:
Synthesis was carried out in the same manner as in Synthetic Example 7 by using 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid methyl-2-picolylamide prepared in Reference Synthetic Example 10.
Reaction SMILES: Br[CH2:2][CH2:3]Br.C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[C:13]([F:22])=[C:14]([OH:21])[C:15]([OH:20])=[C:16]([O:18][CH3:19])[CH:17]=1.Cl>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[O:20][CH2:2][CH2:3][O:21][C:14]=2[C:13]=1[F:22]
Reactant: COc1cc(Br)c(F)c(O)c1O
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(F)c2c1OCCO2
Temperature: 80 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
After adding 830 mg of 1,2-dibromoethane and 1.4 g of potassium carbonate to a solution of 880 mg of 4-bromo-3-fluoro-6-methoxybenzene-1,2-diol in 10 ml of DMF, the mixture was stirred at 80° C. for 6 hours. Next, 1N hydrochloric acid was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (549 mg) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.S(O)(=O)(=O)C.O[CH2:39][CH:40]1[O:44][N:43]=[C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:39][C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:41]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: OCC1CC(c2ccccc2)=NO1
Agent: CS(=O)(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3cc(-c4ccccc4)no3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(oo) In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 61 (c)] with 5-hydroxymethyl-3-phenyl-4,5-dihydro-isoxazole mesylate, prepared according to a generally known procedure, there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-phenyl-isoxazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 591 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]([O:16]CC)=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[Br:1][C:2]1[C:3]([C:14]([NH:24][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Br
Solvent: CCO
Product: O=C(NC1CCCC1)c1noc(-c2ccc(Cl)cc2)c1Br

Procedure:
A mixture of ethyl 4-bromo-5-(4-chlorophenyl)isoxazole-3-carboxylate (213 mg, 0.70 mmol) and cyclopentylamine (0.70 mL, 7.0 mmol) in absolute ethanol (8 mL) was heated to reflux overnight. The volatiles were removed in vacuo and the compound was purified by silica gel chromatography eluting with 2% methanol with dichloromethane to afford the title compound: (0.21 g, 0.57 mmol). MS (ESI) m/z (M+H+): 370.9/368.8.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=[N:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH3:21][N:22]1[C:26]([C:2]2[C:11]3[O:10][CH2:9][CH:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]4[C:18](=[O:20])[NH:19][C:5]([C:6]=34)=[CH:4][CH:3]=2)=[CH:25][CH:24]=[N:23]1
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CO3
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
7-Bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (100 mg, 0.3 mmol) was dissolved in 1,4-dioxane (2.4 mL). A solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (94 mg, 0.45 mmol) and potassium phosphate (100 mg, 0.6 mmol) in water (0.60 mL) was added. Reaction was deoxygenated with nitrogen. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (7 mg, 0.009 mmol) was added and deoxygenated with nitrogen. The reaction mixture was stirred at 100° C. for 4 h. Water and EtOAc were added and the layers were separated. The organic layer was concentrated under reduced pressure. Purification on silica using EtOAc/hexanes gave the title compound (61 mg). LCMS calc. for C19H17N4O2 (M+H)+: m/z=333.1. found: 333.2. 1H NMR (300 MHz, DMSO-d6): d 7.40 (s, 1H); 7.31 (m, 3H); 7.13 (m, 2H); 6.92 (m, 1H); 6.79 (m, 1H); 6.22 (s, 1H); 5.49 (s, 1H); 4.59 (m, 1H); 4.41 (m, 1H); 3.60 (s, 3H).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:18][N:19]([CH3:36])[CH2:20][CH2:21][S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31](F)(F)F)=[CH:26][CH:25]=1.C1N2CCN(CC2)C1.O>C(Cl)Cl>[CH3:18][N:19]([CH3:36])[CH2:20][CH2:21][S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([O:35][S:1]([C:4]2[C:16]3[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH3:31])=[CH:26][CH:25]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CN(C)CCSSc1ccc(C(O)C(F)(F)F)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: CC(OS(=O)(=O)c1cccc2c(N(C)C)cccc12)c1ccc(SSCCN(C)C)cc1
Reaction time: 4 h

Procedure:
Dansyl chloride (37.5 mg, 0.13 mmol) dissolved in dry CH2Cl2 (0.5 mL) was added to the crude 1-[4-(2-dimethylamino-ethyldisulfanyl)-phenyl]-2,2,2-trifluoro-ethanol obtained above. To this solution was added dropwise a solution of DABCO (157 mg, 1.4 mmol) dissolved in dry CH2Cl2 (0.25 mL). After 4 hours at room temperature, the reaction mixture was poured into H2O (30 mL) and extracted using ethyl acetate (3×30 mL). The combined organic phases were washed with H2O (3×30 mL), followed by brine (1×30 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation. The crude product thus formed was purified by using flash chromatography on silica gel using 0-2% CH2Cl2/MeOH to yield Compound 2 a yellow oil (8 mg). 1H NMR (400 MHz, CD3OD): δ 8.45 (m, 1H), 8.13 (m, 2H), 7.57 (m, 1H), 7.43 (m, 1H), 7.27 (m, 1H), 7.06 (m, 2H), 6.98 (d, J=8.47, 2H), 5.88 (q, J=6.5 Hz, 1H), 2.8 (s, 6H), 2.78 (m, 2H), 2.57 (m, 2H), 2.21 (s, 6H); 19F NMR (376 MHz, CH3OD): δ −78.1 (d, J=6.5 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[N:28]=[CH:27][N:26](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:25]=4)[CH:22]=3)[N:17](C3CCCCO3)[N:16]=2)[CH:10]=1)=[O:7]>O1CCOCC1.Cl>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:11]2[CH:10]=[C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:14]=[CH:13][CH:12]=2)=[N:25]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccco1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccco1
Reaction time: 18 h
Yield: 50 %

Procedure:
Hydrolysis was performed by stirring 2-furyl-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.150 g, 0.207 mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 18 hours. The title compound was purified by preparative HPLC (15–80% acetonitrile in water) (0.050 g, 50% yield): 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 8.6 (s, 1H), 8.3 (s, 1H), 8.0 (d, 1H), 7.8–7.7 (m, 4H), 7.5 (t, 1H), 7.3 (d, 1H), 6.6 (m, 1H); ES-MS (m/z) 371 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[CH:15][C:14]([O:13][CH3:12])=[O:35]
Reactant: COc1ccc(C=O)cc1C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C=Cc1ccc(OC)c(C)c1

Procedure:
Treatment of 3-methyl-4-methoxybenzaldehyde with methyl(triphenylphosphoranylidene)acetate in a procedure analogous to that described in Example 20, step a. provided methyl 3-methyl-4-methoxycinnamate which was recrystallized from hexane to give white crystals, mp 70°-73° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Yield: 35 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (R)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.19 g, 35%) was prepared as a tan powder: [α]25D−173.9° (c 1.00, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.50 (br s, 1H), 11.27 (s, 1H), 8.83-8.74 (m, 1H), 8.32-8.25 (m, 1H), 7.65-7.60 (m, 1H), 7.51-7.32 (m, 3H), 7.15-6.96 (m, 2H), 6.43-6.18 (m, 1H), 5.07-4.86 (m, 2H), 4.47-4.21 (m, 3H), 3.79-2.88 (m, 9H), 2.09-1.88 (m, 3H); MS (ESI) m/e 430 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](O)[CH:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)c2ccccc2n1
Product: FC(F)(F)c1cc(Cl)nc2ccccc12
Yield: 77.8 %

Procedure:
A round bottom was charged with 4-trifluoromethyl-quinolin-2-ol (1 g, 4.69 mmol) and POCl3 (10 ml, 107.28 mmol). The mixture was heated to reflux for 3 hours, and then concentrated to remove excess POCl3. The mixture was based with 5 N NaOH and extracted with DCM. The mixture was purified by flash chromatography to give intermediate 2-chloro-4-trifluoromethyl-quinoline (845 mg, 78%): LCMS found 232.22 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:29].[Na+].OO>C1COCC1>[F:17][C:16]([F:19])([F:18])[C:13]1[N:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:29])=[CH:8][CH:7]=2)=[CH:15][N:14]=1
Reactant: C=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
To a solution of 5-[(4-ethenylphenyl)oxy]-2-(trifluoromethyl)pyrimidine (100 mg, 0.376 mmol) and 9-BBN (1.503 mL, 0.751 mmol) in THF (5 mL) under nitrogen, which was stirred overnight was added NaOH (0.501 mL, 1.503 mmol) and H2O2 (0.460 mL, 4.51 mmol). The mixture was heated at 60° C. for 1 h, and then quenched with NH4Cl sat. solution after cooling. The organic layer was separated and washed with Na2SO3 solution and brine. The organic layer was dried by Na2SO4. Concentration then afforded the title compound (80 mg, 0.281 mmol, 74.9% yield). LCMS: rt=2.82 min, [M+H+]=285
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[H-].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCN(CC)C(=O)C(C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCN(CC)C(=O)C(C)(C)Oc1ccc(-c2ccc(N3CCCCC3)cc2)cc1

Procedure:
A mixture of 39 g. of 2-methyl-2-[4-(4-bromophenyl)-phenoxy]-propionic acid diethylamide [obtainable by bromination of 2-methyl-2-(4-phenylphenoxy)-propionic acid diethylamide], 8.5 g. of piperidine, 2.4 g. of NaH, and 60 ml. of HMPA is agitated overnight at 150°. After cooling and the usual working-up operation, 2-methyl-2-[4-(4-piperidinophenyl)-phenoxy]-propionic acid diethylamide is obtained, m.p. 100°-102°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[OH:14][CH2:15][C:16]1[C:17]([OH:28])=[C:18]([N:26]=O)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>C(O)C>[CH3:1][N:2]1[C:3]2([O:28][C:17]3[C:16]([CH2:15][OH:14])=[CH:25][C:24]4[C:19]([C:18]=3[N:26]=[CH:13]2)=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:4]([CH3:11])([CH3:12])[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: O=Nc1c(O)c(CO)cc2ccccc12
Solvent: CCO
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(CO)cc3ccccc13)O2
Yield: 20.9 %

Procedure:
In 100 ml of ethanol, 7.0 g (40 mmol) of 1,3,3-trimethyl-2-methyleneindoline and 8.0 g (40 mmol) of 3-hydroxymethyl-1-nitroso-2-naphthol were dissolved and the solution was heated to reflux for 3 hours. After removal of the solvent, purification was conducted by column chromatography and recrystallization from hexane to obtain 3.0 g of 1,3,3-trimethyl-5'-hydroxymethylspiro [indoline-2,3'-[3H]-naphtho[2,1-b](1,4)oxazine] as a white solid. In 50 ml of methylene dichloride, 1.1 g (3 mmol) of the thus obtained spirooxazine compound was dissolved and 4 ml of triethylamine was added thereto, and then 0.5 g (5 mmol) of methacrylic acid chloride was added dropwise thereto at room temperature and the mixture was allowed to react. After removal of solvent, purification was conducted by column chromatography and recrystallization from hexane to obtain 1.0 g of 1,3,3-trimethyl-5'-methacryloxymethylspiro[indoline-2,3'-[3H]-naphtho[2,1 -b](1,4)oxazine] as a light yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:10][C:9]3[CH:12]=[CH:13][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2cccs2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cccs4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(2-thienyl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.18 (1H, br m), 8.55 (1H, s), 7.15 (2H, dd, J=9, 5 Hz), 7.02 (2H, t, J=9 Hz), 6.96 (1H, s), 4.94 (2H, s), 4.11 (2H, s), 3.63 (2H, q, J=5 Hz), 3.56 (2H, t, J=5 Hz), 3.50 (2H, t, J=5 Hz), 3.44 (2H, t, J=5 Hz), 3.39 (3H, s), 1.68 (2H, m), 1.60-1.50 (4H, m); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2183.