Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: N#Cc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
5-Fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzonitrile (5v) (0.20 g, 0.59 mmol) was dissolved in THF (4 mL) and cooled to 0° C. A solution of lithium aluminum hydride in THF (1.0 mL, 1.0 mmol) was added slowly and the reaction was allowed to warm to room temperature. After 1 h, the reaction was cooled to 0° C. and an additional portion of LAH in THF was added (0.9 mL, 0.9 mmol). The reaction was allowed to stir 20 minutes. The reaction was then quenched by the portion-wise addition of sodium sulfate decahydrate at 0° C. until gas evolution ceased. THF was added and the mixture was filtered through celite and eluted with EtOAc. The solution was concentrated to provide 5-fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzylamine (6v) (0.15 g) which was used in the next step without further purification. MS (APCI+) m/z 342 (M+H) detected.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:3]=2[O:2]1.[H][H]>[Ni].C(O)CC>[CH2:10]([OH:11])[C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Ni]
Solvent: CCCO
Product: OCc1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 10 h
Yield: 30.2 %

Procedure:
In a 500-ml autoclave were placed 90 g (0.60 mol) of heliotropin, 270 ml of 1-propanol and 3 g of a Raney nickel catalyst (Raney-Ni). Hydrogen gas was filled therein up to 4 MPa. The autoclave contents were stirred at 90° C. for about 10 hours. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 27.6 g of piperonyl alcohol as white crystals (yield: 30.3%, G.C. purity: 98.4%)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:7][CH:6]=1.[F:38][C:39]([F:44])([F:43])[CH2:40][CH:41]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([CH2:41][CH2:40][C:39]([F:44])([F:43])[F:38])[CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: O=CCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CCC(F)(F)F)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of 150 mg of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine, 33 mg 3,3,3-trifluoropropanal and 5 mg of acetic acid in 2 ml dichloromethane was added 94 mg of sodium triacetoxyborohydride. After 1 h at rt 33 mg 3,3,3-trifluoropropanal and 94 mg of sodium triacetoxyborohydride were added and the reaction was stirred overnight. Then another 33 mg 3,3,3-trifluoropropanal and 94 mg of sodium triacetoxyborohydride were added and the reaction was stirred overnight. The reaction was diluted with ethyl acetate and water. The pH was adjusted to 8, and the phases were separated. The aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo. 167 mg (94%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.C(=O)(O)[O-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)Cc3ccc(F)cc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg) in DMF (9 mL) and dichloromethane (18 mL) was added sodium bicarbonate (153 mg), (4-fluorophenyl)acetic acid (155 mg) and HATU (521 mg). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 120 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:45][CH2:46][CH:47]4[CH2:49][CH2:48]4)=[C:17]([NH:20][C:21](=[O:44])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([N:31]([CH2:36][C:37]([O:39][C:40]([CH3:43])(C)C)=[O:38])[CH2:32][C@H](O)C)[CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.CO.FC(F)(F)C(O)=O.C(OCC)(=O)C.CO>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:45][CH2:46][CH:47]4[CH2:49][CH2:48]4)=[C:17]([NH:20][C:21](=[O:44])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([N:31]5[CH2:32][C@@H:40]([CH3:43])[O:39][C:37](=[O:38])[CH2:36]5)[CH2:29][CH2:30]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H](O)CN(CC(=O)OC(C)(C)C)C1CCN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(C2CCN(CC=CC(=O)Nc3cc4c(Nc5ccc(F)c(Cl)c5)ncnc4cc3OCC3CC3)CC2)CC(=O)O1

Procedure:
Prepared by lactonizing the intermediate product ((R)-4-[(3-chloro-4-fluorophenyl)amino]-6 ({4-[4-[N-(tert-butyloxycarbonylmethyl)-N-(2-hydroxypropyl)amino]piperidin-1-y]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, melting point: from 115° C. (with foaming); Rf value: 0.53 (silica gel, methylene chloride/methanol 9:1)) in the presence of 5 equivalents of trifluoroacetic acid in acetonitrile under reflux; melting point: from 126° C. (with foaming); mass spectrum (ESI+): m/z=623, 625 [M+H]+; Rf value: 0.29 (silica gel, ethyl acetate/methanol 4:1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]1[CH3:11])=[O:4].[S-:12][C:13]#[N:14].[K+].[I-].[Na+]>C(O)C>[S:12]([CH2:2][C:3]([N:5]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]1[CH3:11])=[O:4])[C:13]#[N:14]
Reactant: N#C[S-]
Reactant: CC1CCC(C)N1C(=O)CCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC1CCC(C)N1C(=O)CSC#N
Reaction time: 2 h

Procedure:
1-(α-Chloroacetyl)-2,5-dimethylpyrrolidine (10 grams; 0.057 mol), potassium thiocyanate (10.1 grams), sodium iodide (a few crystals) and ethanol (100 ml) were charged into a glass reaction flask equipped with mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about 2 hours. After this time the reaction mixture was cooled and filtered. The filtrate was stripped of ethanol under reduced pressure resulting in a solid product. The solid was extracted with two 125 ml portions of hot benzene. The benzene extracts were combined and were evaporated to yield 1-(α-thiocyanoacetyl)-2,5-dimethylpyrrolidine as a light brown oil having a refractive index at 25° C. of 1.5185 and having the following elemental analysis as calculated for C9H14N2OS.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17](O)=[O:18])[C:14]([N+:20]([O-:22])=[O:21])=[C:13]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[N:6][C:5]([C@@H:8]([NH:10][C:11]2[N:12]=[C:13]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:14]([N+:20]([O-:22])=[O:21])=[C:15]([C:17]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:18])[N:16]=2)[CH3:9])=[N:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(C(=O)O)c2[N+](=O)[O-])n[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(C(=O)N3CCOCC3)c2[N+](=O)[O-])n[nH]1
Reaction time: 8 h

Procedure:
To a solution of 2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidine-4-carboxylic acid (Intermediate 50, 406 mg, ˜1 mmol), in DMF (5 ml) were added DIPEA (˜0.3 ml), HATU (456 mg) and morpholine (0.130 ml) at ambient temperature. The resulting mixture was stirred overnight. The mixture was diluted with H2O and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, saturated NaHCO3 (aq) solution, dried and evaporation of the volatiles under reduced pressure gave a colored residue. Purification by column chromatography (ISCO, 50%→70% EtOAc/hexanes) gave the title compound. LCMS: 473 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.Cl>CC(C)=O>[Br:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[Cl:10]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc(Cl)c(Br)c(Cl)c1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 5.0 grams (0.028 mole) of 1,3-dichloro-5-methoxybenzene (commercially available) in 35 mL of acetone was stirred and 5.0 grams (0.028 mole) of N-bromosuccinimide, then one mL of aqueous 10% hydrochloric acid were added. Upon completion of additions the reaction mixture was stirred at ambient temperature during a 30-minute period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was slurried in 20 mL of hexane and an insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, yielding 4.8 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(C)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
Solutions of methyl 3-(4-methylpiperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (249.7 mg, 0.55 mmol, 1.00 equiv.) in THF/MeOH (1:1) (20 mL) and sodium hydroxide (138 mg, 3.45 mmol, 5.00 equiv) in water (1.5 mL) were placed in a 50-mL round bottom flask, stirred for 3 hrs at 30° C. in an oil bath, concentrated under vacuum, and washed with DCM. This resulted in 90 mg (45%) of 3-(4-methylpiperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O-:26])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[CH3:27]N(C=O)C>CCN(CC)CC.[Pd]>[CH3:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1C#Cc1ccccc1CC(=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10% Pd/C (53% water; 0.020 g) was added to a solution of methyl 2-(2-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-ylethynyl)phenyl)acetate (A115) (0.115 g, 0.318 mmol) in DMF (5 mL) and Et3N (0.5 mL) and the resulting suspension placed under a hydrogen atmosphere and stirred at room temperature for 18 hours. The mixture was filtered through Celite, washing with EtOAc (250 mL). The combined filtrates were washed with water (100 mL) then brine (100 mL) and the washing repeated 3 times. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure and the resulting oil purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A116 as a yellow solid (0.097 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.83 (s, 1H), 7.46 (s, 1H), 7.25-7.17 (m, 4H), 6.75 (s, 1H), 3.89 (s, 3H), 3.72 (s, 2H), 3.67 (s, 3H), 3.09 (dd, J=9.5, 6.3 Hz, 2H), 2.91 (dd, J=9.5, 6.4 Hz, 2H), 2.07 (s, 3H). LCMS-A: rt 5.160 min; m/z 366 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:12])[CH:6]=[CH:5]2.BrC1C=C2C(=CC=1[Cl:24])C=NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:24])[CH:8]=[N+:7]([O-:12])[CH:6]=[CH:5]2
Reactant: Clc1cc2cnccc2cc1Br
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Product: [O-][n+]1ccc2cc(Br)c(Cl)cc2c1

Procedure:
The title compound was prepared by the method, described for 6-Bromo-isoquinoline 2-oxide (4), starting with 6-Bromo-7-chloro-isoquinoline (9). Rt=1.05 min (Method C). Detected mass: 258.1/260.2 (M+H+).
Reaction SMILES: O[CH2:2][CH:3]([CH3:12])[CH2:4][CH2:5][CH:6]([O:10][CH3:11])[CH:7]([CH3:9])[CH3:8].S(Cl)([Cl:15])=O.C1C=CC=CC=1>CN(C)C=O>[Cl:15][CH2:2][CH:3]([CH3:12])[CH2:4][CH2:5][CH:6]([O:10][CH3:11])[CH:7]([CH3:9])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: COC(CCC(C)CO)C(C)C
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(CCC(C)CCl)C(C)C

Procedure:
A mixture of 3.4 g. of 1-hydroxy-5-methoxy-2,6-dimethylheptane and 3 g. of thionyl chloride and 60 ml. of dry benzene is treated with 0.2 ml. of dry dimethylformamide and then refluxed for 6 hours. After cooling, the mixture is decanted and 1-chloro-5-methoxy-2,6-dimethylheptane isolated by filtration through silica gel and distillation.
Reaction SMILES: [CH3:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:54]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:59]=[CH:58][C:57]([CH:60]([NH:68][CH3:69])[CH2:61][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:55]=[CH:56][C:57]([CH:60]([N:68]([CH3:69])[C:11](=[O:13])[CH2:10][N:6]2[C:5]3[CH:14]=[C:15]([O:16][CH3:17])[C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:7]2=[O:9])[CH2:61][N:62]2[CH2:63][CH2:64][O:65][CH2:66][CH2:67]2)=[CH:58][CH:59]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc2c(cc1C)oc(=O)n2CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C)oc(=O)n2CC(=O)N(C)C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.8 %

Procedure:
[6-Methyl-5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetic acid (59 mg, 0.25 mmol) and BOP reagent (133 mg, 0.30 mmol) were dissolved in CH2Cl2 (1 mL), and diisopropylethylamine (32 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 5 min, then 1-(4-biphenylyl)-N-methyl-2-(4-morpholinyl)ethanamine (74 mg, 0.25 mmol) was added. Stirring was continued for 16 h and then the mixture was concentrated. The residue was dissolved in CH3OH, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50×50 mm, 50 mL/min, A: acetonitrile B: water with NH4OH at pH=10, A: 20% to 70% during 12 min, UV detection at 214 nm) to give 32 mg (25%) of the title compound as a white solid. MS (ES) m/e 516 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:10][C:11]1[CH:22]=[CH:21][C:14]2[NH:15]C(=O)[O:17][C:18](=O)[C:13]=2[CH:12]=1.C[Al](C)C.Cl>C1(C)C=CC=CC=1>[NH2:15][C:14]1[CH:21]=[CH:22][C:11]([F:10])=[CH:12][C:13]=1[C:18]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[C:3]=1[CH3:9])=[O:17]
Reactant: Cc1c(N)cccc1Br
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A mixture of 3-bromo-2-methylaniline (1.50 g, 8.06 mmol) and 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.46 g, 8.06 mmol) in toluene (40 mL) was cooled on an ice-water bath and treated portionwise with 2 M trimethylaluminum in toluene (10.1 mL, 20.2 mmol). The mixture was stirred at room temperature for 30 min, then was heated at 70° C. overnight. The mixture was cooled to 0° C., carefully treated with 1M aqueous HCl, and extracted 3 times with EtOAc. The combined organic phases were washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated. The residue was subjected to column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 5-40%), to provide 2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide (0.893 g, 87% purity, 30% yield). Mass spectrum m/z 323, 325 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.54 (1H, dd, J=8.03, 0.99 Hz), 7.48 (1 H, dd, J=9.68, 3.08 Hz), 7.33 (1 H, d, J=7.26 Hz), 7.16 (1 H, t, J=7.92 Hz), 7.04-7.12 (1 H, m), 6.83 (1 H, dd, J=9.02, 4.62 Hz), 2.39 (3 H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:6]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:48][C@@H:49]([C:62]3[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=3)[C:50]3[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=3)=[O:16])=[CH:9][N:8]=2)[CH:6]=1
Reactant: O=C(O)c1cnc(-n2cc(F)cn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@@H](N)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 18.7 %

Procedure:
To a stirred solution of 28-g (2.8 g, 12 mmol) and Et3N (3.5 g, 34 mmol) in MeCN (30 ml) was added HATU (4.8 g, 12 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((S)-amino(4-fluorophenyl)methyl)phenyl(methyl)phosphinate, 19-d, (3.5 g, 1 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=l/1) to provide the product, 28-h, (1.2 g, 18.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([S:29](Cl)(=[O:31])=[O:30])=[CH:24]2.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([S:29]([N:11]1[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]1)(=[O:30])=[O:31])=[CH:24]2
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2c(Cl)cccc2c1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 69 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (193 mg, 3.888 mmol) with 5-chloronaphthalene-2-sulfonyl chloride (202.1 mg, 0.777 mmol) was carried out according to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.7 mL, 3.887 mmol) as base. 1-[(5-chloro-2-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 69% yield (256 mg) as white solid.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Cl:7][C:8]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=1>CO>[Cl:7][C:8]1[C:13]([C:14](=[N:5][OH:6])[NH2:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: NO
Reactant: N#Cc1cccnc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Sodium methoxide (150 mi of 0.25M solution in methanol, 37.5 mmol) was added to a solution of hydroxylamine hydrochloride (2.8 g, 39.7 mmol) in methanol (150 mL), and the reaction was stirred at room temperature for 30 minutes. The mixture was filtered, then 2-chloro-3-cyanopyridine (5.0 g, 36.1 mmol) was added, the reaction was stirred at room temperature for 16 hours and then heated to reflux for 2 hours. The reaction was cooled to room temperature, concentrated in vacuo to approximately 50 mL and filtered. The filtrate was concentrated to dryness in vacuo, the residue was triturated with dichloromethane and filtered to give the title compound as a white solid (6.2 g).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:22])=[CH:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([Br:1])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:22])=[CH:16]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: Cc1cc2cccc(OCc3ccccc3)c2[nH]c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(Br)ccc(OCc3ccccc3)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of bromine (0.57 g) in acetic acid (2 mL) is added dropwise to a solution of 8-benzyloxy-3-methyl-1H-quinolin-2-one (0.94 g) and sodium acetate (0.96 g) in acetic acid (12 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 hours, evaporated, the residue partitioned between water (5 mL) and ethyl acetate (5 mL), extracting a further 2× with ethyl acetate (5 mL). Combined organic extracts are dried over magnesium sulphate and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.