Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10]O)[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4].C(N(CC)C(F)(F)C(F)C(F)(F)[F:31])C>C(Cl)Cl>[Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:31])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4]
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: CC1(C)O[C@H](c2ccc(S(C)(=O)=O)cc2)[C@@H](CO)N1C(=O)C(Cl)Cl
Solvent: ClCCl
Product: CC1(C)O[C@H](c2ccc(S(C)(=O)=O)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 22.5 °C

Procedure:
(4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIIa) (81 g, 0.2050 moles) in methylene chloride (450 ml) reacts with N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (73.2 g, 0.328 moles) at 95-105° C. for 2-4 hours. Cooling to 20-25° C., quenching with 25% aqueous sodium hydroxide and water (2000 mL) and separation of the methylene chloride layer gives a solution of (4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIIIa) for use as an intermediate for the next step in the process.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[O:19][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1ccc(CC2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(4-chlorophenyl)prop-1-ene (9.0 g) in chloroform (100 ml) was added portionwise metachloroperbenzoic acid (12.2 g), and the solution was stirred for 5 h at room temperature. The mixture was poured into water, the water layer was separated and the organic layer washed successively with sodium bicaronate, sodium sulphite and water. After drying, evaporation of the solvent gave 1-(4-chlorophenyl)-2,3-epoxypropane as a pale yellow oil. (9.51 g). NMR in CDCl3 :
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]([OH:14])=[O:6]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(C=O)c(O)c1F
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)O)c(O)c1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a mixture of 3-fluoro-2-hydroxy-4-methoxybenzaldehyde (10.0 g) and sodium dihydrogenphosphate (22.9 g) in DMSO (100 mL) and water (25.0 mL) was added dropwise an aqueous solution (30.0 mL) of sodium chlorite (14.5 g), and the mixture was stirred at 20° C. for 16 hr. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate (×6). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.42 g).
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].[Li]C(C)(C)C.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:31][CH:30]=1)[C:22](N(OC)C)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCOC(C)=O>C1COCC1>[C:40]([O:39][C:37]([NH:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C@H:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22](=[O:23])[C:2]([CH3:4])=[CH2:3])=[CH:30][CH:31]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CON(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reactant: C=C(C)Br
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C

Procedure:
2-Bromopropene (3.5 eq., 14.0 mmol, 1.25 mL) was dissolved in THF (50 mL) and cooled to −78° C. tBuLi (6.5 eq., 26.0 mmol, 16.3 mL; 1.6 M in hexane) was added slowly and the mixture was stirred for 1 hour at −78° C. after which Weinreb amide 11 (1 eq., 4.0 mmol, 1.89 g) was added in THF (5 mL). The mixture was allowed to warm to −20° C. in 6 hours after which TLC analysis indicated complete consumption of the Weinreb amide. A saturated aqueous NH4Cl solution and EtOAc were added and the layers were separated. The organic layer was extracted with brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (20%→50% EtOAc/PE) as a colourless oil (yield: 1.71 g, 3.77 mmol, 94%). 1H NMR (400 MHz, CDCl3): δ=7.33-7.24 (m, 5H), 7.11 (d, J=7.87 Hz, 2H), 6.97 (d, J=8.00 Hz, 2H), 6.03 (s, 1H), 5.85 (s, 1H), 5.77 (d, J=8.18 Hz, 1H), 5.30 (dd, J=14.10, 6.11 Hz, 1H), 5.12-5.08 (m, 1H), 5.04 (dd, J=26.54, 12.35 Hz, 2H), 4.21 (d, J=5.41 Hz, 2H), 3.09 (dd, J=13.79, 5.88 Hz, 1H), 2.89 (dd, J=13.76, 5.97 Hz, 1H), 1.84 (s, 3H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=199.28, 155.66, 155.34, 141.99, 137.40, 136.13, 134.60, 129.27, 128.17, 127.80, 127.71, 126.50, 79.01, 66.45, 55.13, 43.96, 38.76, 28.14, 17.44 ppm. HRMS: calcd. for C26H32N2O5 453.23840 [M+H]+. Found 453.23818.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([CH2:32][CH2:33][CH2:34]O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59].N(C(OC(C)C)=O)=NC(OC(C)C)=O>CCOC(C)=O.C1COCC1>[C:58]([O:62][C:63](=[O:64])[N:65]=[C:66]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:67][CH2:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:9])[CH3:10])=[CH:12][N:13]=2)=[C:30]([F:31])[CH:29]=1)([CH3:61])([CH3:60])[CH3:59]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(CCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 8 h
Yield: 126.3 %

Procedure:
To a solution of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)propan-1-ol (407 mg, 0.73 mmol) in anhyd THF (0.97 mL) were added PPh3 (285 mg, 1.08 mmol), 1,3-bis(tert-butoxycarbonyl)guanidine (384 mg, 1.45 mmol) and diisopropyl azodicarboxylate (DIAD) (225 μL, 1.08 mmol) sequentially. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (80% EtOAc/hexanes) to yield tert-butyl(tert-butoxycarbonylamino)(3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)propylamino)methylenecarbamate (740 mg), which was taken to the next step without further purification. MS (EI) m/z 802.50 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:11][N:12]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][C:20]=3[N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[O:23])[CH2:13][CH:14]2[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)c(-n2nccn2)c1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CC3CN(Cc4ccccc4)CC3C2)c(-n2nccn2)c1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a mixture of 2-benzyloctahydropyrrolo[3,4-c]pyrrole (282 mg, 1.4 mmol), 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (306 mg, 1.4 mmol), and TEA (0.21 mL, 1.5 mmol) in DMF (7.5 mL) was added HATU (583 mg, 1.5 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (1×). The combined organics were dried (Na2SO4) and concentrated to give a residue. Purification via Agilent prep system (Basic) gave 327 mg (58%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.79 (s, J=6.5 Hz, 2H), 7.50 (d, J=5.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.34-7.21 (m, 5H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.86-3.72 (m, 1H), 3.65-3.46 (m, 3H), 3.13 (s, 1H), 2.90-2.74 (m, 2H), 2.74-2.59 (m, 2H), 2.57-2.39 (m, 2H), 2.16 (dd, J=9.2, 4.2 Hz, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].C(Cl)Cl.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][C:8]([C:7]1[CH:6]=[C:5]([S:2]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])(=[O:4])=[O:3])[CH:19]=[CH:18][CH:17]=1)=[O:9]
Reactant: COC(=O)c1ccccc1N
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
To a mixture of 2.09 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate and 20 mL of methylene chloride were added 982 mg of methyl 2-aminobenzoate and 2.10 mL of pyridine under ice-cooling, followed by stirring at room temperature for 15 hours. To the reaction mixture was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.61 g of methyl 2-{[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}benzoate as a colorless oily substance.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:9][CH3:10])[CH3:7].[C:18]([OH:29])(=[O:28])[CH2:19][CH2:20][S:21][S:22][CH2:23][CH2:24][C:25]([OH:27])=O>C(C(C)=O)C(C)C>[CH2:9]([N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:25](=[O:27])[CH2:24][CH2:23][S:22][S:21][CH2:20][CH2:19][C:18]([O:29][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:28])[CH2:6][CH3:7])[CH3:10]
Reactant: O=C(O)CCSSCCC(=O)O
Reactant: CCN(CC)CCCCCCO
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: CCN(CC)CCCCCCOC(=O)CCSSCCC(=O)OCCCCCCN(CC)CC
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
1.3 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 2.3 g of the obtained 6-(N,N-diethyl)amino-1-hexanol. After stifling for 10 minutes, 1.4 g of 3,3′-dithiodipropionic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 4 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di[6-(N,N-diethyl)aminohexyl]3,3′-dithiodipropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: c1c[nH]cn1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccnc2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 25 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (2.0 g), 60% sodium hydride in oil (0.50 g, degreased with hexane), imidazole (0.50 g) and dimethylformamide (25 ml), the title compound (0.57 g) was obtained as a tan amorphous solid, MS, m/z: 389 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[F:35][C:36]([F:43])([F:42])[CH2:37][S:38](Cl)(=[O:40])=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:35][C:36]([F:43])([F:42])[CH2:37][S:38]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=3)[CH:11]=[C:2]([CH3:1])[C:3]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:17]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NS(=O)(=O)CC(F)(F)F)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A flask containing a solution of 29 (0.30 g, 0.85 mmol), Et3N (0.26 g, 2.55 mmol) and DMAP (0.032 g, 0.26 mmol) in CH2Cl2 (5 mL) was added trifluoroethanesulfonyl chloride (0.39 g, 2.13 mmol), dropwise, at RT and the reaction allowed to stir overnight at RT. After 18 h the reaction was diluted with 15 mL CH2Cl2 and rinsed with 10% aq. HCl (25 mL). The CH2CO2 layer was dried (MgSO4), concentrated to a dark amber oil, and purified by silica gel column chromatography with 10% EtOAc/hexanes to afford 270 mg (64%) of the title compound, 273, as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 3.88 (s, 3H), 4.33 (q, J=9.8 Hz, 2H), 6.58 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.08 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 7.18-7.36 (m, 5H), 7.61 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 10.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=3)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(CN)on1
Reactant: Cc1ccc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)cc1Cl
Product: COc1cc(CNC(=O)c2cc(-c3ccc(C)c(Cl)c3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BM) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 456.0934 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:6])=[O:4]>[Pt]=O.C(O)C>[NH2:14][C:13]1[C:8]([O:7][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH3:6])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C(C)Oc1ncccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)C(C)Oc1ncccc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A mixture of 1.7 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine, 102 mg of platinum oxide, and 7.5 ml of ethanol was stirred at room temperature under an atmosphere of hydrogen gas for 3.5 hours. The gas in the atmosphere on the reaction system was replaced with nitrogen gas, and the reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 1.16 g of 3-amino-2-{1-(methoxycarbonyl)ethoxy}pyridine. 1H-NMR (CDCl3, 300 MHz) δ(ppm): 1.63 (d, 3H, J=6.8 Hz), 3.74 (s, 3H), 3.84 (bs, 2H), 5.38 (d, 1H, J=6.8 Hz), 6.72 (dd, 1H, J=7.7, 5.0 Hz), 6.90 (dd, 1H, J=7.7, 1.4 Hz), 7.48 (dd, 1H, J=5.0, 1.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>[Cu].O>[N:9]1([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=Cc1cc(Br)cs1
Reactant: c1c[nH]cn1
Agent: [Cu]
Solvent: O
Product: O=Cc1cc(-n2ccnc2)cs1
Temperature: 60 °C

Procedure:
In a three-necked-20-l-reaction bulb aquipped with a thermometer, a reflux cooler and a KPG-stirrer, 1.911 kg (10 mole) of 4-bromothiophen-2-aldehyde, 4.084 kg (60 mole) of imidazol of 99% purity and 0.065 kg (about 1 mole) of powderous copper metal are added to 10 l of water. The reaction mixture is stirred and boiled to reflux for 5 hours. After cooling the reaction mixture to 60° C., the reaction mixture is extracted several times with a total of 26 l of chloroform. The combined chloroform solutions are washed three times mit 15 l of water. The washed chloroform phase is mixed with 10 l of water and then brought to a pH of smaller than 1 by the addition of about 750 ml of 25% hydrochloric acid with vigorous stirring. The aqueous acidic phase is added with 30 l of chloroform at 40° C. Subsequently, about 600 g of NaHCO3 is added thereto slowly with vigorous stirring, until the aqueous phase reaches a pH larger than 7.5. In order to extract completely the precipitated product, the chloroform phase is separated and the aqueous phase is again extracted with 20 l of chloroform. The combined chloroform phases are evaporated to a final volume of about 4 l and is added to 9 l of petrol ether (b.p. 40° to 60° C.) with vigorous stirring. The resulting precipitate is filtered off with suction and is dried at 50° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:14]([C:28]([F:31])([F:30])[F:29])=[CH:13][C:12]=1[NH2:32])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl-].C([O:43][C:44](=O)[C:45](O)=[O:46])C.Cl.C([NH+](CC)CC)C>O1CCCC1>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:11]2[C:12](=[CH:13][C:14]([C:28]([F:30])([F:31])[F:29])=[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:16]=2)[NH:32][C:44](=[O:43])[C:45]1=[O:46])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOC(=O)C(=O)O
Reactant: CCOP(=O)(CNc1cc(OCCOc2ccc(Cl)cc2)c(C(F)(F)F)cc1N)OCC
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(OCCOc3ccc(Cl)cc3)cc21)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 g of N-[2-amino-4-trifluoromethyl-5-(2(-4-chlorophenoxy)ethoxy)phenyl]-aminomethanephosphonic acid diethyl ester is introduced in 60 ml of tetrahydrofuran with 733 mg of triethylamine and mixed drop by drop at room temperature with a solution of 719 mg (0.59 ml) of oxalic acid ethyl ester chloride in 15 ml of tetrahydrofuran. Then, it is stirred for 2 hours at room temperature. After triethylammonium hydrochloride is suctioned out, the filtrate is concentrated by evaporation. The residue is taken up in 25 ml of ethanol and 25 ml of 1N hydrochloric acid and heated for 2 hours to a bath temperature of 120° C. After the ethanol is distilled off, it is diluted with water to 50 ml, and extracted three times with 50 ml of ethyl acetate each. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 810 mg of [(6-trifluoromethyl-7-(2(-4-chlorophenoxy)ethoxy)-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl]methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1.C(P(CCCC)CCCC)CCC.[CH3:30][O:31][C:32](=[O:46])[CH:33]([CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35].CCCCCCC>C1C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH:33]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:16][CH2:15][CH2:14][N:12]2[C:13]3[CH:1]=[N:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:43][CH:44]=1)[C:32]([O:31][CH3:30])=[O:46]
Reactant: OCCn1c2ccccc2c2ccncc21
Reactant: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: COC(=O)C(Cc1ccc(OCCn2c3ccccc3c3ccncc32)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
Under a nitrogen atmosphere, 2-β-carbolin-9-yl-ethanol (212 mg, 1.0 mmol), tributylphosphine (303 mg, 1.5 mmol) and 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (238 mg, 1.0 mmol) were successively dissolved in dry benzene (40 mL). Solid azodicarboxylic dipiperidide (ADDP) (378 mg, 1.5 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was chromatographed eluting with dichloromethane graduated with ethyl acetate to give 355 mg (82%) of the title compound; 1H NMR (300 MHz, CDCl3): δ 3.10 (d, 2H), 3.55 (t, 1H), 3.65 (s, 6H), 4.35 (t, 2H), 4.75 (t, 2H), 6.70 (d, 2H), 7.05 (d, 2H), 7.30 (t, 1H), 7.3-7.63 (m, 2H), 7.97 (d, 1H), 8.13 (d, 1H), 8.48 (d, 1H), 9.02 (s,1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](O)=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:60][N:61]1[C:69]([CH2:70][CH:71]2CCN[CH2:73][CH2:72]2)=[N:68][C:67]2[C:62]1=[N:63][C:64]([N:83]1[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=3[N:85]=[C:84]1[CH3:92])=[N:65][C:66]=2[N:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>>[CH3:60][N:61]1[C:69]([CH2:70][CH:71]2[CH2:11][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:73][CH2:72]2)=[N:68][C:67]2[C:62]1=[N:63][C:64]([N:83]1[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=3[N:85]=[C:84]1[CH3:92])=[N:65][C:66]=2[N:77]1[CH2:78][CH2:79][O:80][CH2:81][CH2:82]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of N-(tert-Butoxycarbonyl)-L-alanine (80.0 mg, 0.423 mmol) in N,N-Dimethylformamide (5.0 mL, 0.064 mol) was added HATU (0.154 g, 0.404 mmol), 1-hydroxybenzotriazole (HOBt, 0.00839 g, 0.0621 mmol) and triethylamine (0.10 mL, 0.72 mmol). The resulting yellow solution was stirred at room temperature for 5 minutes before the addition of 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine 520 (0.150 g, 0.310 mmol;). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between brine and EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH in DCM) to give tert-butyl 4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidine-1-carboxylate (0.15 g, 78%). LCMS m/z: 618.3 (MH+).