Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl.[CH2:34]([N:36]([CH2:42][CH3:43])[CH2:37][CH2:38][C:39](O)=[O:40])[CH3:35].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(#N)C.CCOCC>[CH2:34]([N:36]([CH2:42][CH3:43])[CH2:37][CH2:38][C:39]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:40])[CH3:35]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CCN(CC)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)CCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), N,N-diethyl-β-alanine hydrochloride (0.24 g, 1.43 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature. The mixture was then diluted with acetonitrile:ether (1:1) and filtered. The solids were dissolved in a minimum amount of methanol and purified by chromatography (silica gel, 5 to 20% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (70 mg), melting point: 167° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(Br)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
The product from Example 44A (995 mg, 3.77 mmol) was reacted with 4-chloro-3-nitro-phenol (650 mg, 3.77 mmol) in 15 mL of DMF with K2CO3 (10.4 g, 3.77 mmol) at 80° C. for 3 h. Cooled to room temperature and diluted with water. Extracted with CH2Cl2, washed four times with water. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.24 g, 92%).
Reaction SMILES: Cl[C:2]1[N:3]2[CH:19]=[N:18][N:17]=[C:4]2[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[N:10]=1.[OH-:20].[Li+].O>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4]3=[N:17][N:18]=[CH:19][N:3]3[C:2](=[O:20])[NH:10][C:9]1=2
Reactant: Clc1nc2c(ncn2C2CCCCO2)c2nncn12
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2c(ncn2C2CCCCO2)c2nncn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 5-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-[1,2,4]triazolo[3,4-i]purine (0.17 g, 0.50 mmol) in THF (10 mL) was added lithium hydroxide (420 mg, 18 mmol) and water (10 mL). After stirring at room temperature for 10 minutes, the reaction mixture was concentrated under reduced pressure to give the product, which is used for next step without further purification. LCMS calculated for C11H13N6O2 (M+H): 261.1. found: 261.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:31]([CH3:34])([CH3:33])[CH3:32])(=O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH:13]=[C:14]([O:17][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:15][CH2:16]1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (Step 1, 250 g, 1.05 mol) and triethylamine (223 g, 2.20 mol) in toluene (4.2 liter) at 0° C. is slowly added trimethylsilyl trifluoromethanesulfonate (TMS-OTf, 280 g, 1.26 mol) via addition funnel. The stirring is continued for 30 min and the mixture allowed to warm to ambient temperature. Water (5 liter) is added and the aqueous layer extracted with EtOAc (3×500 ml). The organics are combined, dried over MgSO4 and the solvent removed under reduced pressure. Hexane (4×500 ml) is added and the solvent removed under reduced pressure. At the fourth co-distillation, a slurry forms (˜300 ml). The mixture is cooled to 0° C. and the solids filtered. The filtrate is concentrated to a slurry, cooled and filtered (2nd crop). Solids are combined to give 273.7 g (84%) of the title compound as a yellow solid, 1H NMR (CDCl3) δ 0.21 (s, 9 H), 2.20 (brs, 2 H), 3.52 (brs, 2 H), 3.62 (brs, 2 H), 4.89 (brs, 1 H), 6.65 (t, 1 H), 7.67 (d, 1 H), 7.73 (d, 1 H).
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][S:11][C:12]1[N:17]=[C:16](O)[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:16]1[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=[C:12]([S:11][CH3:10])[N:17]=1
Reactant: CSc1nc(O)n2nccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)n2nccc2n1
Reaction time: 0.17 h

Procedure:
To a mixture of 10 mL of phosphorus oxychloride and 1 mL of N,N-dimethylaniline was added 0.5 g of 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-ol (crude from previous step). The solution was refluxed for 30-60 minutes until all the solid dissolved. The excess phosphorus was removed under reduced pressure and the syrupy residue poured with vigorous stirring onto a mixture of ice water. After 10 minutes, the aqueous solution was extracted with ether. The ethereal layers were collected and washed with cold water, then dried with anhydrous Na2SO4. Filtration and concentration under reduced pressure gave the desired 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine. MS (ES+): 201.0 (M+1)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: Oc1ccnc2cc3ccccc3cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1ccnc2cc3ccccc3cc12

Procedure:
Under a nitrogen atmosphere, benzo[g]quinolin-4-ol (6) (100 mg, 0.51 mmol) was refluxed in 2 ml of phosphorus oxychloride (0.25 M) in the presence of N,N-dimethylaniline (0.25 mL, 3.8 equivalents) until deemed complete by TLC. Removal of the excess phosphorus oxycloride in vacuo and flash chromatography (gradient: 9:1 to 8:2 to 7:3 hexanes:EtOAc) afforded 108 mg of clean 4-chlorobenzo[g]quinoline (7b) in quantitative yield.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1>>[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:30]1
Reactant: OCC1CCCNC1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCCC(CO)C4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 3-hydroxymethylpiperidine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.75 (4H, brm), 2.87 (1H, dd, J=12.91, 9.89 Hz), 3.05 (1H, m), 3.13 (1H, d, J=5.22 Hz), 3.54 (2H, brm), 3.88 (2H, brd, J=2.91 Hz), 7.14 (1H, dt, J=7.42, 1.10 Hz), 7.19 (1H, d, J=9.34 Hz), 7.42 (2H, ddd, J=7.41, 2.20, 1.92 Hz), 7.79 (1H, d, J=9.34 Hz), 8.21 (2H, ddd, J=7.69, 1.92, 1.10 Hz), 8.52 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]([C:18](=[NH:21])[NH:19][OH:20])([CH3:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N(CC)CC)[CH3:24].C(Cl)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]([CH3:17])([C:18]1[N:21]=[C:23]([CH3:24])[O:20][N:19]=1)[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(CS(C)(=O)=O)(NC(=O)OCc1ccccc1)C(=N)NO
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of [1-(N-Hydroxycarbamimidoyl)-2-methanesulfonyl-1-methyl-ethyl]-carbamic acid benzyl ester (Example 109b, 2.04 g, 6.19 mmol) in dry DMF (30 mL) were added triethylamine (1.73 mL, 12.4 mmol) and acetyl chloride (572 μL, 8.05 mmol). the reaction was stirred 30 minutes at room temperature. Reaction was then stirred at 130° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.21 g, 55%) as yellow oil. MS (ESI, m/z): 354.5 (M+H+).
Reaction SMILES: O[CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3].[C:10]([O:16]CC)(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[Na]>>[C:10]([O:16][CH2:3][CH2:2][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(O)N1CCCC1=O
Agent: [Na]
Product: CC(=O)CC(=O)OCCN1CCCC1=O
Yield: 4 %

Procedure:
A mixture of 20 g (0.16 mol) of 1-hydroxyethyl-2-oxo-pyrrolidine, 40 g (0.31 mole) of ethyl acetoacetate and 100 mg of sodium was heated at 140°-150° C. for six hours. Residual ethanol was removed in vacuo and the resultant oil was kugelrohr distilled (200° C./1 mm) to give 1.38 g (40%) of the product. NMR: (CDCl3) δ 2.1 (7H, m), 3.4 (6H, m) 4.1 (2H, t)
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[Cl:37][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][N:13]=1
Reactant: OCc1ccc(COc2ccccc2)cn1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(COc2ccccc2)cn1
Temperature: 25 °C

Procedure:
To a solution of carbon tetrachloride (20 mL) of a known compound (5-phenoxymethyl-pyridin-2-yl)-methanol (1.4 g) was added triphenylphosphine (2.1 g) at room temperature, which was heated to reflux for 6 hours and 15 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (1.3 g).
Reaction SMILES: CN/[C:3](/[CH3:9])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].[OH2:28]>C1COCC1>[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([CH:4]([C:3](=[O:28])[CH3:9])[C:5]([O:7][CH3:8])=[O:6])=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CN/C(C)=C/C(=O)OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C(C(C)=O)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(E)-methyl 3-(methylamino)but-2-enoate (12.9 g, 100 mmol) was dissolved in 300 mL anhydrous THF and 12 mL pyridine was added into the solution dropwise. The reaction was cooled in ice bath, and 4-nitrobenzoyl chloride (18.7 mL in 50 mL anhydrous THF) was added into the solution slowly. The reaction was warmed up to room temperature and stirred for overnight. After adding 300 mL water into the reaction, the solution was extracted by ethyl acetate for 3 times. The combined organic layer was further washed with water and brine, dried over Na2SO4, and removed under the vacuum to give methyl 2-(4-nitrobenzoyl)-3-oxobutanoate as the solid without further purification (25.2 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([S:11][CH3:12])[CH3:10])=[CH:5][N:4]=1.[N:15]#[C:16][NH2:17].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[Cl:1][C:2]([F:13])([F:14])[C:3]1[N:4]=[CH:5][C:6]([CH:9]([S:11]([CH3:12])=[N:17][C:16]#[N:15])[CH3:10])=[CH:7][CH:8]=1
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(F)(F)Cl)nc1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Product: CC(c1ccc(C(F)(F)Cl)nc1)S(C)=NC#N
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a stirred solution of 2-[chloro(difluoro)methyl]-5-[1-(methylthio)-ethyl]pyridine (E) (0.32 g, 1.35 mmol) and cyanamide (0.058 g, 1.35 mmol) in THF (7 mL) was added iodobenzene diacetate (0.44 g, 1.35 mmol) in one portion at 0° C. and the resulting mixture was stirred at this temperature for 1 hr and then at room temperature for 2 hr. The solvent was then removed under reduced pressure and the resulting mixture was dissolved in CH2Cl2, washed with half-saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified on silica gel using 50% acetone in hexane to give 0.175 g of (1-{6-[chloro-(difluoro)methyl]pyridin-3-yl}ethyl)(methyl)-λ4-sulfanylidenecyanamide (F) as light-yellow oil in 48% yield. 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.4, 1.8 Hz, 1H) 7.78 (d, J=8.4 Hz, 1H), 4.42 (q, J=6.9 Hz, 1H), 2.64 (s, 3H), 1.92 (d, J=6.9 Hz, 3H); LC-MS: mass calcd for C10H10ClF2N3S [M+1]+ 278. Found 278.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([OH:30])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:40]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:56]([O:55][C:54]([NH:53][C@H:40]1[C@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:39]1)=[O:60])([CH3:57])([CH3:58])[CH3:59]
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (0.005 g, 0.01 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.0064 g, 0.015 mmol), and HATU (0.012 g, 0.031 mmol) in DMF (0.2 mL) and DIPEA (0.0064 mL, 0.037 mmol) was stirred at room temperature for 2 h. The mixture was quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.05% TFA, at a flow rate of 30 mL/min.) to afford the sub-title compound (0.0032 g, 30%). LCMS calc. for C44H60N7O7Si [M+H]+: m/z=826.4. found: 826.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH3:10].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:32]C)C=C4)N(CC2)C1.CS(N)(=O)=O.CC(O)(C)C.[OH2:79]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:32])[C@H:9]([OH:79])[CH3:10]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C/c1ccccc1Cl
Reactant: O
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Product: C[C@@H](O)[C@H](O)c1ccccc1Cl
Reaction time: 8 h
Yield: 90 %

Procedure:
1-(2-chlorophenyl)-trans-1-propene (2.5 g, Preparation Example 1) was dissolved in 50 mL of the mixture of t-BuOH/H2O (1:1(V/V)). At 0° C., AD-mix-α (Aldrich, U.S.A.) (23.5 g) and methane sulfone amide (CH3SO2NH2, 1.27 g, 0.013 mol) were added thereto and stirred for overnight. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na2SO3) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (2.96 g, yield 90%).
Reaction SMILES: NC1N=CC([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=CC=1OCC1C(F)=CC=C(F)C=1Cl.Br[C:29]1[CH:30]=[C:31]([O:36][CH:37]([C:39]2[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:46])[CH3:38])[C:32]([NH2:35])=[N:33][CH:34]=1.COC(C1C=CC(B(O)O)=CC=1)=O>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:30][C:31]=1[O:36][CH:37]([C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH3:38]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)ccc(F)c1Cl
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)cccc1Cl
Agent: COC(=O)c1ccc(B(O)O)cc1
Product: CC(Oc1cc(-c2ccc(C(=O)O)cc2)cnc1N)c1c(Cl)cccc1Cl

Procedure:
4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid was prepared using the same procedure as 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid from 5-bromo-3-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[ClH:22].N([O-])=O.[Na+].[S:27]([O-:30])(O)=[O:28].[Na+]>C(O)(=O)C.O.[Cu](Cl)Cl>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:5]3[CH:20]=[CH:21][C:2]([S:27]([Cl:22])(=[O:30])=[O:28])=[CH:3][C:4]=3[O:9][C:8]([CH3:11])([CH3:10])[C:7]2=[O:12])=[CH:14][CH:15]=1
Reactant: Cl
Reactant: CC1(C)Oc2cc(N)ccc2N(c2ccc(F)cc2)C1=O
Reactant: O=S([O-])O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Oc2cc(S(=O)(=O)Cl)ccc2N(c2ccc(F)cc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-amino-4-(4-fluorophenyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 15, 50 mg) in acetic acid (465 μL)/concentrated hydrochloric acid (570 μL) was added a solution of sodium nitrite (13.3 mg) in water (115 μL) under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture was added a mixture of sodium hydrogen sulfite (182 mg), copper(II) chloride (23.5 mg), acetic acid (225 μL) and concentrated hydrochloric acid (115 μL) at the same temperature, and the mixture was stirred at room temperature for 2 hours. After ice-cooling, the reaction mixture was gradually poured to water with ice (15 mL) and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to give crude 4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-sulfonyl chloride.
Reaction SMILES: [CH:1]1([NH2+]C2CCCCC2)CCCC[CH2:2]1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][C:31]#[N:32])[C:26]([O-:28])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][C:31]#[N:32])[C:26]([O:28][CH2:1][CH3:2])=[O:27])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: N#CCC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.00 g (11.3 mmol) dicyclohexylammonium-(2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butanoate are stirred into in 100 ml of 5% citric acid solution and then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is distilled off i. vac. The residue is dissolved in 70 ml THF, 4.35 g (13.5 mmol) TBTU and 6.35 ml (33.8 mmol) DIPEA are added and the mixture is stirred for 10 minutes at ambient temperature. Then 50 ml of ethanol are added and the mixture is refluxed for 16 hours. Then the reaction mixture is evaporated down i. vac., taken up in ethyl acetate, washed with semisaturated sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: Cl.COCCOCCOC.II.[CH2:13]([O:15][C:16](=[O:19])[CH2:17]Br)[CH3:14].[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Zn]>[CH2:13]([O:15][C:16](=[O:19])[CH:17]=[C:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:14]
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: COCCOCCOC
Product: CCOC(=O)C=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95 %

Procedure:
21 g of (97.2%) zinc dust are treated, according to Example 4, with 2% (by weight) aqueous hydrochloric acid. The zinc activated in this manner is placed into 75 ml of diethylene glycol dimethyl ether, and 0.6 g of iodine is added. There is then added at 25° C. (if necessary with external cooling) a mixture of 16.7 ml of bromoacetic acid ethyl ester and 15.4 ml of benzonitrile. The mixture is stirred for 17 hours at room temperature, and subsequently processed basically analogously to Example 2. The β-aminocinnamic acid ethyl ester is obtained in 95% yield. When in the above Example the solvent diethylene glycol dimethyl ether is replaced by toluene or diethyl ether, the procedure being otherwise the same, there are likewise obtained good yields of β-aminocinnamic acid ethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CCO>[OH:3][CH:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(C(C)O)cc2s1
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of ethyl 6-acetyl-1-benzothiophene-2-carboxylate (2.0 g, 8.06 mmol) in THF/EtOH (20/20 mL) was added sodium borohydride (308 mg, 8.14 mmol) portionwise. After 2 h, the reaction was quenched with sat. NH4Cl. The resulting mixture diluted with EtOAc (40 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The resultant residue (2.1 g) was used without further purification. MS (EI): cal'd 251 (MH+), exp 251 (MH+).