Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:25])[CH:10]([NH:18][C:19](=O)[CH2:20][CH2:21][S:22][CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>ClCCl>[CH3:7][O:8][C:9]([CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19]([CH2:20][CH2:21][S:22][CH3:23])=[N:18]1)=[O:25]
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)CCSC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2C(CCSC)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.882 mL (10.07 mmol) of oxalyl chloride was added dropwise to a solution of 2-(3-methylsulfanyl-propionylamino)-3-phenyl-propionic acid methyl ester (from previous step) in 30 mL of dichloromethane and stirred at room temperature for 1 h. This reaction mixture was then cooled to −10° C. and treated with 1.82 g (11 mmol) of FeCl3 at this temperature in portions. This reaction mixture was allowed to warm up to room temperature overnight. 30 mL of 2 N aq. HCl was added slowly while stirring for 1 h. 20 mL of dichloromethane was added and separated, washed again with water (50 mL), and dried over sodium sulfate. The organic solvents were evaporated in vacuo. The residual red solid was mixed with 30 mL of methanol and 1.5 mL of conc. H2SO4 and heated under reflux overnight. Water was added to the reaction mixture and the methanol was evaporated under reduced pressure Ammonium hydroxide was added to adjust pH to basic. The aqueous layer (˜50 mL) was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel gave 923 mg (38%) of 1-(2-methylsulfanyl-ethyl)-3,4-dihydro-isoquinoline-3-carboxylic acid methyl ester. LCMS: 264 (M+1)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[CH3:18][C:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C1COCC1>[OH:23][C:22]([C:19]1([CH3:18])[CH2:21][CH2:20]1)=[CH:16][C:15](=[O:17])[CH:14]=[CH:13][O:12][CH3:11]
Reactant: COC=CC(C)=O
Reactant: CC1(C(=O)Cl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=CC(=O)C=C(O)C1(C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
LiHMDS (1M in THF, 88 mL, 2 eq) is added dropwise to a cold (−78° C.) solution of 4-methoxy-3-buten-2-one (8.8 mL, 88 mmol, 2 eq) in THF (300 mL). After a 30 min stirring at −78° C., a solution of 1-methyl-cyclopropanecarbonyl chloride (Step 40.8) (5.19 g, 44 mmol) in THF (100 mL) is added. The resulting mixture is allowed to warm to rt over 2 h and quenched by addition of a saturated solution of NH4Cl. THF is removed under vacuum. The concentrated mixture is extracted with Et2O. The organic phase is washed with brine (2×150 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5) to afford 5.68 g of the title compound as a yellow oil: ESI-MS: 183.1 [M+H]+; TLC: Rf=0.32 (Hex/EtOAc, 9:1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.O>C1(C)C=CC=CC=1.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>[F:15][C:14]([F:17])([F:16])[CH:13]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:12]=[CH:11]/[C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH:27]=[CH2:28])[CH:10]=1
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)O
Yield: 55.1 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (600 mg, 1.23 mmol) in dry toluene (10 mL) was added tributyl(vinyl)stannane (470 mg, 1.48 mmol) and the mixture was degassed with argon for 15 min Pd(PPh3)4 (72 mg, 0.06 mmol) was added and the reaction mixture was refluxed for 2 h. The reaction mixture was brought to ambient temperature, water was added and the mixture extracted with EtOAc. The organic layer was washed with 2N HCl and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica eluting with 30% EtOAc in petroleum ether to afford the title compound as brown solid (295 mg, 55%): 1H NMR (300 MHz, DMSO-d6) δ 13.05 (bs, 1H), 7.91 (s, 2H), 7.81-7.75 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.48 (dd, J=17.4, 10.8 Hz, 1H), 7.03 (dd, J=15.9, 8.7 Hz, 1H), 6.84 (d, J=15.6 Hz, 1H), 5.88 (d, J=16.5 Hz, 1H), 5.39 (d, J=12.3 Hz, 1H), 4.89-4.82 (m, 1H); ESIMS m/z 432.18 ([M−H]−); IR (thinfilm) 3418, 1689, 1114, 747 cm−1.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[C:15]([O:23][CH2:24][CH2:25]Cl)(=[O:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19]>CN1C(=O)CCC1>[C:4]([O:6][CH2:25][CH2:24][O:23][C:15](=[O:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: COC(=O)/C=C/C(=O)OCCCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)/C=C/C(=O)OC
Yield: 17 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.22 g, 1.7 mmol) in NMP (4 mL) was reacted with CsHCO3 (0.38 g, 1.9 mmol) and chloroethyl methyl(2E)but-2-ene-1,4-dioate (0.27 g, 1.4 mmol) to afford 0.068 g (17% yield) of the title compound (45) after purification by silica gel flash chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:3). 1H NMR (CDCl3, 400 MHz): δ 7.03 (q, J=5.2 Hz, 1H), 6.90 (d, J=16.0 Hz, 1H), 6.82 (d, J=16.0 Hz, 1H), 3.82 (s, 3H), 1.60 (d, J=5.2 Hz, 3H).
Reaction SMILES: [C:1]1([P:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](Cl)(Cl)(Cl)Cl.[H][H]>[S]>[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [S]
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 250 °C
Yield: 86.8 %

Procedure:
To an oven-dried 50-ml autoclave liner were added 16.68 g of triphenylphosphine oxide (.06 mole) and 0.057 g of sulfur (.0018 mole). The solids were treated with 11.12 g of silicon tetrachloride (.066 mole) and the mixture was placed in an autoclave which was then charged to a pressure of 715 p.s.i.g. (48 atm.) with hydrogen. The mixture was heated to 250°C for 15 hours at a maximum pressure of 77 atm. After cooling and venting, the reaction mixture was worked up by first partitioning between warm 30% by weight aqueous sodium hydroxide solution and toluene. The aqueous layer was extracted once with toluene and the combined organic layers were washed with water and with brine and dried over anhydrous sodium sulfate. Filtration and solvent removal gave 13.66 g (86.9%) of crude triphenylphosphine, mp 68°-77° which contained 2% triphenylphosphine oxide and 3% triphenylphosphine sulfide by gas-liquid chromatographic (glc) analysis. Recrystallization from methanol gave 11.25 g (71%) of purified triphenylphosphine, mp 75°-9°, still containing 1-2% triphenylphosphine sulfide by glc analysis.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[C:58]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:57][CH:56]=[CH:55][N:54]=1)[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[C:58]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:57][CH:56]=[CH:55][N:54]=1)[CH3:51]
Reactant: CCOc1ncccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
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: CCOc1ncccc1-c1cccc(NC(=O)c2cc3cccc(OC)c3oc2=O)c1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
DIEA (0.013 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-Ethoxy-pyridin-3-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.025 g of product in 86% yield: LCMS (ESI) m/z 417 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([CH2:9][C:10]([CH3:12])=[CH2:11])[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1.[I:20]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[I:20][CH2:11][C:10]1([CH3:12])[O:1][CH2:2][C@@H:3]2[CH2:4][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7][N:8]2[CH2:9]1
Reactant: O=C1CCC(=O)N1I
Reactant: C=C(C)CN1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN2CC(C)(CI)OC[C@@H]2C1
Temperature: 25 °C
Yield: 106.4 %

Procedure:
To a round bottom flask charged with (S)-tert-butyl 3-(hydroxymethyl)-4-(2-methylallyl)piperazine-1-carboxylate (0.1 g, 0.370 mmol) in acetonitrile (3.70 ml) was added N-iodosuccinimide (0.125 g, 0.555 mmol) and potassium carbonate (0.077 g, 0.555 mmol). The reaction mixture was stirred at rt ON. The reaction mixture was quenched with 20% sodium thiosulfate solution and stirred 30 min. The mixture was transferred to a separatory funnel and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. (9aS)-tert-butyl 3-(iodomethyl)-3-methylhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.156 g) was isolated as a yellow oil. Material used crude in subsequent chemistry.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:25]=[CH:24][C:13]([O:14][C:15](=[CH2:23])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[H][H].C([O-])(=O)CC>C(O)CCC.[Pd]>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]([CH3:23])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: C=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCCCC
Agent: [Pd]
Agent: CCC(=O)[O-]
Solvent: CCCCO
Product: CCCCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The product (15 g) from Step 3 in n-butanol (300 ml) was hydrogenated at room temperature and atmospheric pressure using a 10% palladium on carbon catalyst. When the uptake of hydrogen ceased, the catalyst was filtered off and the filtrate evaporated under reduced pressure. The residue was purified by short-path distillation (at 140°-150°/0.2 mmHg) to afford a main fraction (11.6 g) containing 57% w/w of the desired propionate which was recrystallised from cold hexane to give n-butyl 2-[4-(5-trifluoromethylpyrid-2-yloxy)-phenoxy]propionate. The propionate may then be obtained substantially pure by recrystallisation from cold hexane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:23])[CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:20].[Cl:20][C:19]1[CH:18]=[C:17]([C:21](=[O:23])[CH3:22])[CH:16]=[N:15][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(5-acetyl-3-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (c) above (0.65 g, 1.92 mmol) and satd solution of HCl in EtOAc (50 mL) was stirred at room temperature for 4 h. The solution was evaporated in vacuo to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 240 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:13]=3[S:14][C:15]=2[C:16]([O:18]C)=[O:17])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:13]=3[S:14][C:15]=2[C:16]([OH:18])=[O:17])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2c(C(=O)O)sc3cc(C(F)(F)F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a stirred solution of 4-(2-Methoxycarbonyl-6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (1.1 g, 2.7 mmol) in THF (7.0 mL) was added 1 N NaOH (2.97 mL). The resulting mixture was stirred at room temperature overnight when the mixture was diluted with water (50 mL) and washed with ether (100 mL). The aqueous layer was acidified with the addition of 3 N HCl and the product was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated yielding 960 mg (92%) of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: C1CNCCN1
Reactant: COc1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: COc1ccnc(N2CCNCC2)c1
Temperature: 115 °C

Procedure:
To 756 mg (5.29 mmol) of 2-Chloro-4-methoxypyridine and 2.27 g (26 mmol) of piperazine in a pressure flask was added 2.7 mL dimethylformamide, and the mixture was heated at 115° C. for 5 hours. The solution was allowed to cool before opening the flask, and the resulting slurry was partitioned between ethyl acetate and water. The phases were separated, and the aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over Na2SO4, filtered, and the filtrate was acidified with 2M HCl in ether. The product crystallized over night, and the solids were isolated by filtration to yield product as a white solid: 1H NMR (D2O, 400 MHz) 7.72 (d, 1H), 6.61 (d, 1H), 6.48 (s, 1H), 3.88 (s, 3H), 3.79 (m, 4H), 3.36 (m, 4H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]12[CH2:15][O:14][C@H:13]3[CH2:16][C:12]13[CH2:11][N:10]([C@@H](C1C=CC=CC=1)C)[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]12[CH2:15][O:14][C@H:13]3[CH2:16][C:12]13[CH2:11][NH:10][CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1CC2(NC(=O)OC(C)(C)C)CO[C@H]3CC32C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC12CNCC13C[C@@H]3OC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
An [(S)-5-[(R)-1-Phenylethyl]tetrahydro-2-oxa-5-azacyclopropa[c]pentalen-3a-yl]carbamic acid tert-butyl ester (480 mg, 1.39 mmol) was dissolved in dioxane (10 ml) and 20% palladium hydroxide catalyst (20 wt. % Pd on carbon, wet; cat.) was added. The mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 3 days. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was taken up in dichloromethane, and washed with 1N aq. NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the crude title compound as a white solid (280 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>CN(C)C=O.C(OCC)(=O)C>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)[CH:7]=1)([O-:22])=[O:21]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine (191 mg) in N,N-dimethylformamide (10 mL), and 3-(trifluoromethyl)benzylamine (210 mg). The resulting solution was stirred overnight at 50° C. The resulting mixture was dissolved in 50 mL of ethyl acetate and washed with 2×50 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography to give 186 mg of product as yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:14]([NH:18][NH2:19])(=O)[CH2:15][CH3:16]>C(O)CCC>[CH2:15]([C:14]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[CH3:16]
Reactant: CCC(=O)NN
Reactant: Clc1ccc(-c2cccnc2)nn1
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3cccnc3)nn12

Procedure:
As for Example 2, a mixture of 3-chloro-6-(3-pyridyl)pyridazine (2.0 g.) and propionic acid hydrazide in 60 ml. of n-butyl alcohol is refluxed for 48 hours to give the product of the Example.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C1COCCN1
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Agent: CCOP(=O)(C#N)OCC
Product: O=C(c1cc2c(O)cccc2s1)N1CCOCC1
Yield: 105.9 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)benzo(b)thiophene-2-carboxylic acid (3.5 g), morpholine (1.0 g) and diethyl cyanophosphate (3.1 g), 4-(4-hydroxybenzo(b)thiophene-2-carbonyl)morpholine (3.2 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.1 g), the title compound (2.0 g) was obtained as brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH2:14][C:15]([CH3:17])=O)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]3[O:13][CH:14]=[C:15]([CH3:17])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)COc1cc(-c2ccc(F)cc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1coc2cc(-c3ccc(F)cc3)nn12
Temperature: 130 °C
Yield: 46.3 %

Procedure:
To a stirred solution of 1-{[3-(4-fluorophenyl)-1H-pyrazol-5-yl]oxy}acetone (0.25 g, 1.0 mmol) in toluene, equipped with dean stark apparatus, acetic acid (2 ml) and p-TsOH (25 mg, cat.) was charged at RT and the reaction mass was refluxed at 130° C. for 16 h. After completion, the reaction was diluted with EtOAc (50 ml) and washed with brine. The organic layer dried over sodium sulphate and concentrated under reduced pressure to get the crude which was then purified by column chromatography 100-200 mesh) eluted with 5-10% ethyl acetate in hexane as eluent to get compound 6-(4-fluorophenyl)-3-methylpyrazolo[5,1-b][1,3]oxazole (0.1 g, yield 43%).
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.O.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:18]([O:17][C:15]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)[CH2:2]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.5 %

Procedure:
A solution of 8.00 g (49 mmol) of 6-Methoxy-1,2,3,4-tetrahydro-isoquinoline in 196 mL of 48% hydrobromic acid was refluxed for 3 h. The mixture was then concentrated and coevaporated several times with ethanol. The resulting slurry was filtered and dried under vacuum to give 7.43 g of 1,2,3,4-Tetrahydro-isoquinolin-6-ol hydrobromide as a solid. To 7.38 g of the crude hydrobromide dissolved in 117 mL each of dioxane and water was added 6.34 g (35.3 mmol) of benzyl chloroformate with ice bath cooling. A 1 M solution of potassium carbonate was slowly added until a pH of 10 was maintained. The mixture was stirred overnight at room temperature. Excess dioxane was removed by evaporation, and the resulting aqueous mixture was acidified with 1 N HCl and the product extracted with ethyl acetate. The organic portion was washed with water and brine, dried over Na2SO4 and concentrated to give 10.4 g of an oil which was crystallized from ether/hexane to give 7.05 g of 7D as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:45][CH3:46])(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:36])[C:5]([CH2:45][CH3:46])([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][C:11]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C(CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)(CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Reaction time: 0.75 h
Yield: 12.3 %

Procedure:
A solution of the product from Example 108 (620 mg, 1.10 mmol) in N,N-dimethylformamide (2.5 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 48 mg, 1.21 mmol) in N,N-dimethylformamide (2.5 mL), and stirred for 45 minutes. Ethyl trifluoromethanesulfonate (0.140 mL, 1.10 mmol) was added dropwise and stirred for 14 hours at room temperature. The reaction was partitioned between diethyl ether (150 mL) and 1M aqueous hydrochloric acid (150 mL), the phases were separated and the aqueous layer extracted with diethyl ether. The combined organic layers were washed with 1N aqueous sodium hydrogencarbonate and brine, dried over MgSO4 and concentrated. The residue was chromatographed using a Biotage™ 40S column, eluting with 70/30 iso-hexane/acetone to give the title compound (80 mg).