Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[O:18][CH2:19][CH2:20][CH:21]=[O:22])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Sulfur trioxide pyridine complex (240 mg, 1.5 mmol) was added to a solution of 3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propanol (190 mg, 0.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.2 mL, 1.6 mmol) and anhydrous dimethyl sulfoxide (0.1 mL, 1.4 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (30 mL). The mixture was extracted into dichloromethane (3×30 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (30 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (3:1 ethyl acetate/dichloromethane) to give the title compound as a colorless oil (135 mg, 72%). 1H-NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 9.46 (s, 1H), 8.80 (d, J=6.2 Hz, 1H), 8.59 (d, J=5.8 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 6.56 (s, 1H), 6.32 (s, 1H), 6.24 (s, 1H), 4.09 (t, J=6.0 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.[I:12]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[I:12]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1cc2[nH]ncc2cc1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc2[nH]nc(I)c2cc1Br
Temperature: 70 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
To a solution of 10.0 g of 5-bromo-6-fluoro-1H-indazole in 150 mL of N,N-dimethylformamide was added 10.5 g of N-iodosuccinimide at room temperature, and stirred at 70° C. for 2 days. Then the solution was diluted with ethyl acetate, washed successively with aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crystals precipitated by adding diethyl ether to the residue were collected by filtration. The filtrate was further concentrated and purified and separated by silica gel column chromatographsy (ethyl acetate:n-hexane=1:10-1:5) and combined with the previous crystals, to afford 14.5 g of the title compound as colorless crystals.
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=CC=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([CH3:36])[CH:27]=[CH:26][C:25]([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])=[CH:24][CH:23]=1.C(C1CCCCC1)C#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH3:36])=[CH:27][CH:26]=2)[CH:14]=[C:13]([CH2:12][CH:11]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[O:35]1)[CH3:33]
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(O)C#Cc1ccc(C)cc1
Agent: [Au]
Agent: C#CCC1CCCCC1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(C)cc2)C=C(CC2CCCCC2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]|SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen p-tolylethynylphosphonate (67.3 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, prop-2-ynylcyclohexane (73.2 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-tolyl-6-(cyclohexylmethyl)-1,2-oxaphosphorin 2-oxide (66.5 mg, 64%) which is a title compound.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C(OC1C=CC=C[N+]=1C)C1C=CC=CC=1.F[C:25](F)(F)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:34]([O:39][C@@H:40]1[C@@H:48]([CH2:49][CH2:50][OH:51])[C:47](=[O:52])[O:46][CH2:45][C@H:44]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:43](=[O:61])[O:42][C@H:41]1[CH3:62])(=[O:38])[CH:35]([CH3:37])[CH3:36]>>[C:34]([O:39][C@@H:40]1[C@@H:48]([CH2:49][CH2:50][O:51][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:47](=[O:52])[O:46][CH2:45][C@H:44]([NH:53][C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[C:43](=[O:61])[O:42][C@H:41]1[CH3:62])(=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: FC(F)(F)c1ccccc1
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Agent: C[n+]1ccccc1OCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOCc1ccccc1
Temperature: 83 °C
Yield: 36 %

Procedure:
A mixture of 2-benzyloxy-1-methylpyridinium triflate (255 mg, 0.73 mmol), α,α,α-trifluorotoluene (PhCF3, 0.75 mL), MgO (30 mg, 0.74 mmol), and (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-hydroxyethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (150 mg, 0.36 mmol) was heated at 83° C. for 1 day (d). The reaction mixture was cooled to room temperature (about 22° C.) and filtered through Celite®. The filtrate was concentrated under vacuum and purified by column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (66 mg, 36%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.21 (m, 5H), 5.28 (m, 2H), 5.06 (t, J=10.0 Hz, 1H), 4.95-4.73 (m, 2H), 4.69 (s, 2H), 4.42 (s, 2H), 3.52-3.33 (m, 3H), 2.77 (td, J=11.5, 2.8 Hz, 1H), 2.60 (dq, J=14.0, 7.0 Hz, 1H), 1.42 (s, 9H), 1.26 (d, J=6.2 Hz, 3H), 1.19 (dd, J=7.0, 2.5 Hz, 6H); ESIMS m/z 530 ([M+Na]+).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 25.72 mL (336 mmol) of diketene in 100 mL of toluene was added dropwise at 90° C. to a solution of 51.0 g (288 mmol) of 4-bromoaniline in 200 mL of toluene and the reaction mixture was kept at this temperature for 5 hours. The reaction solution was cooled in the ice bath, and the precipitate formed was filtered and washed with toluene until the product was virtually colorless. Subsequently it was dried at 50° C. in the circulating air dryer until a constant weight was obtained. Yield: 50.0 g (68% of theoretical); C10H10BrNO2 (M=256.096); calc.: molpeak (M+H)+: 256/258 (Br); found: molpeak (M+H)+: 256/258 (Br); HPLC-MS: 4.7 minutes (method B).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].CI.[C:14](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[CH3:14][O:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[Cl:3]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Sodium hydride (60% dispersion, 3.0 g, 77 mmol) was added in three portions to a solution of 2-chloro-5-methylphenol (10.0 g, 70.1 mmol) in DMF (100 mL) at 0° C. under nitrogen. Methyl iodide (5.0 mL, 77 mmol) was added and the solution was warmed to RT. After 1 h, 10% aqueous citric acid (200 mL) and EtOAc (1.0 L) were added. The layers were separated and the aqueuos layer was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (12 g, 100%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:11]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16]3[C:22]4=[C:23]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=6)=[C:30]([Cl:43])[CH:29]=5)[N:24]=[CH:25][N:26]=[C:21]4[S:20][C:17]=32)=[N:12]1)[CH:9]=[CH2:10]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:43][C:30]1[CH:29]=[C:28]([NH:27][C:23]2[N:24]=[CH:25][N:26]=[C:21]3[S:20][C:17]4[C:18]5[C:13]([CH2:14][CH2:15][C:16]=4[C:22]=23)=[N:12][N:11]([CH2:8][CH2:9][CH3:10])[CH:19]=5)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1
Reactant: C=CCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.7 %

Procedure:
To a solution of 2-allyl-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine trifluoroacetate (25.0 mg, 0.05 mmol) in ethyl acetate (1.50 mL) was added Pd/C (2.0 mg, 10%) under nitrogen. The reaction was stirred at rt under hydrogen atmosphere (balloon, 1 atm) for 4 h. The Pd/C residue was removed by filtering through a pad of celite and pad was washed with EtOAc (2×3 mL). The combined EtOAc layers were dried over sodium sulfate and the solvent was removed in vacuo. The residue was then separated by preparative HPLC to give (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-propyl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine trifluoroacetate (salt) (3.4 mg, 15%) as a yellow solid. 1H NMR (CD3CN) δ 8.33 (s, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.65 (s, 1H), 7.49 (dd, J=2.3, 8.9 Hz, 1H), 7.45 (m, 1H), 7.33 (t, 1H), 7.28 (d, J=10 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 7.12 (dt, 1H), 5.23 (s, 2H), 4.08 (t, 2H), 3.40 (t, 2H), 3.04 (t, 2H), 1.88 (m, 2H), 0.94 (t, 3H); LCMS RT=3.91 min, [M+H]+=520.1.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH3:1][NH:2][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: CN
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methylamine (5.7 mL of a 2.0 M in THF, 11.4 mmol) was added to a solution of 4-phenylcyclohexanone 1 (2.0 g, 11 mmol) in anhydrous THF (30 mL), and the mixture was stirred at room temperature for 4 hours. BH3—SMe2 1.6 mL, 16 mmol) was added, and stirring was continued overnight. After quenching the reaction with MeOH, the solvents were removed under reduced pressure. The crude solid was dissolved in MeOH (10 mL), HCl (15 mL of a 1.0 M solution in Et2O, 15 mmol) was added, and the mixture concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1:0.1 CH2Cl2: MeOH:NH4OH) gave trans-1-(methylamino)-4-phenylcyclohexane 6 (0.80 g, 39%) as a white solid: 1H NMR (300 MHz, CD3 OD) δ 7.27-7.11 (m, 5H), 2.64 m, 1H), 2.51 (obs m, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 2.11 (br d, J=11 Hz, 2H), 1.93 (br d, J=11 Hz, 2H), 1.59 (dddd, J=11, 11, 2, 2 Hz, 2H), 1.42 (dddd, J=11, 11, 2, 2 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](N)C(O)C(C)(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (40 mg, 1 eq, 0,14 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.12 mL, 4.9 eq, 0.69 mmol) followed by (3RS,4S)-4-amino-2,2-dimethyl-hexan-3-ol (57 mg, 2.8 eq, 0.39 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 7.2 mg (13%). (53% de 4S,3R: 47% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.99-1.04 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.56+1.58 (2×d, 6H, J=6.63+6.79 Hz, —CH(CH3)2), 1.64-1.87 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.57 (d, 1H, J=1.42 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.73-3.86 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.57-4.69 (m, 1H, —CH(CH3)2), 4.78-4.86 (m, 2H, —HNCH2-Bz), 5.22-5.34+5.95-6.08 (2×m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.26-7.44 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.53 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 411 ([M+H]+, 85), 323 (100). Accurate Mass (N+H): Actual: 411.2872, Measured: 411.2860.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>O>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reaction time: 1 h

Procedure:
13.7 g of p-aminobenzoic acid was dispersed in a solution of 100 cc of water and 30 cc of 30% hydrochloric acid in an ordinary manner and the dispersion was cooled with ice. A solution of 8.3 g of sodium nitrite in 50 cc of water was added dropwise to the dispersion to effect the diazotization reaction. A solution of 10.1 g of sodium azide in 70 cc of water was added dropwise to the mixture, stirred for about one hour, filtered and vacuum-dried to obtain p-azidobenzoic acid. 5.4 g of the thus obtained p-azidobenzoic acid was dissolved in 10 cc of dimethylformamide and 25 g of thionyl chloride was added dropwise to the solution. The mixture was stirred for about one hour and the product was added dropwise to ice-water. After filtration followed by washing with water and vacuum drying, p-azidobenzoyl chloride was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:14])([O-])=O.[H][H]>[Pd].CO>[F:11][C:10]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:14])[C:4]=1[NH2:1]
Reactant: Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(F)(F)F)c1N

Procedure:
A slurry of 2-nitro-3-trifluoromethyl-phenylamine (0.678 g, 3.2 mmol) and 10% palladium on carbon (0.067 g) in methanol (20 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated under vacuum to obtain the title compound as off white solid (0.420 g, 73.17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[O:19])=[CH:15][CH:14]=[C:13]([OH:28])[CH:12]=2)=[O:10])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([O:39][CH2:40]C)=[O:38]>CN(C=O)C.CCOC(C)=O.O>[CH3:40][O:39][C:37](=[O:38])[CH2:36][O:28][C:13]1[CH:14]=[CH:15][C:16]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[O:19])=[C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH:12]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(O)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a mixture of compound N-(5-chloro(2-pyridyl)){6-[(4-cyanophenyl)-carbonylamino]-3-hydroxyphenyl}carboxamide (50 mg, 0.13 mmol) and Cs2CO3 (83 mg, 0.25 mmol) in DMF (1 mL) at room temperature was added ethyl bromoacetate (15 μL, 0.13 mmol). The mixture was stirred for 1 hour before diluted with EtOAc (20 mL) and water (10 mL). The organic layer was washed with brine dried and evaporated to give 70 mg of the crude compound, which was used without farther purification. MS found for C24H19ClN4O5 (M+H)+: 479.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH:45]1[C:50]#[N:51]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:47]2[CH2:48][CH2:49][NH:44][CH:45]([C:50]#[N:51])[CH2:46]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1NCC(=O)O
Reactant: N#CC1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(Cl)cc1NCC(=O)N1CCNC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a mixture of 2-(4,5-dichloro-2-methoxyphenylamino)acetic acid (260 mg, 1.04 mmol), EDCI (273 mg, 1.43 mmol), HOBt (194 mg, 1.43 mmol) and Et3N (288 mg 2.85 mmol) in DCM (10 mL) at 0° C., piperazine-2-carbonitrile was added. The resulting mixture was stirred at RT for 8 h. The mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (108 mg, 30% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl(3R,4R)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[N+]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])([O-])=O>>[N+:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]=1[C:12]#[N:13])([O-:20])=[O:19]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCC(O)CC
Product: CCC(CC)Oc1cccc([N+](=O)[O-])c1C#N
Yield: 86.5 %

Procedure:
Prepared as in Example 111c from pentan-3-ol and 2,6-dinitrobenzonitrile in 86.5% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (t, J=7.6 Hz, 6H), 1.70 (m, 4H), 4.62 (m, 1H), 7.78 (dd, J=7.2, 2.4 Hz, 1H), 7.88 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:17][Si](C)(C)N[Si](C)(C)C>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)([OH:9])[CH3:17])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: CC(O)(c1ccc(O)cc1)c1ccc(Br)cc1

Procedure:
Ea) A mixture of 2.77 g of 4-hydroxyphenyl-(4-bromo-phenyl)-methanone and 50 ml of hexamethyidisilazane is heated under reflux for 4 h., then concentrated and dried. The resulting 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone is dissolved in 60 ml of toluene and treated at room temperature under argon with 11 ml of methylmagnesium chloride solution (22% in THF). The mixture is boiled under reflux. After cooling the mixture is treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and dried. After evaporation of the ethyl acetate extracts there are obtained 3.36 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-ethyl]-phenol, MS: m/e 293 (M+H+, 1Br).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:13](C)(C)[CH3:14])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:2].Cl.O1CCOCC1>CCO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C#N)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(C#N)cc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Combined tert-butyl 2-(4-cyano-2-fluorophenyl)acetate (227.3 mg, 0.966 mmol) with EtOH (5 mL) and added a 4M hydrogen chloride solution in dioxane (0.121 mL, 0.483 mmol) and stirred in a heating block at 60° C. for 16 h. Then the reaction mixture was concentrated via rotary evaporation and re-constituted in EtOH (5 mL). An additional portion of a 4M hydrogen chloride solution in dioxane (17.61 mg, 0.483 mmol) was added to the vial and the mixture was stirred at 60° C. for an additional 1 h. The reaction mixture was then concentrated via rotary evaporation and dried in vacuo to give the title compound (198 mg, 99% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.27 (t, J=7.07 Hz, 3H) 3.72 (d, J=1.26 Hz, 2H) 4.19 (q, J=7.24 Hz, 2H) 7.36-7.40 (m, 1H) 7.40-7.43 (m, 1H) 7.43-7.46 (m, 1H). MS m/z [M+H]+ 208.0.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:16])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1 g of 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (5.06 mmol) in DMF (20 ml) were carefully added 265 mg of sodium hydride (55% dispersion in oil, 6.07 mmol) at 0° C. and the mixture was stirred at RT for 30 min. Then 0.47 ml of methyl iodide (7.60 mmol) were added and stirring at RT was continued over night. Water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated and the remaining residue was purified by crystallization from heptane. This yielded 513 mg of 6-chloro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (48%) as an off-white solid. 1HNMR (DMSO-d6, 300 MHz): δ 3.45 (s, 3H), 7.47 (d, J=8.9 Hz, 1H), 7.89 (dd, J=8.9 and 2.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H).