Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:30]=[CH:31][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:16]([OH:26])[CH:15]=2)=[N:11][CH:12]=1.[P:38](Cl)(=[O:47])([O:43][CH:44]([CH3:46])[CH3:45])[O:39][CH:40]([CH3:42])[CH3:41]>C1COCC1>[P:38]([O:43][CH:44]([CH3:46])[CH3:45])([O:39][CH:40]([CH3:42])[CH3:41])([O:26][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[N:9]=[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:28]=3)[C:7]([Cl:6])=[CH:12][N:11]=2)[CH:19]=[CH:18][C:17]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:47]
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)ncc2Cl)c1
Reactant: CC(C)OP(=O)(Cl)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(OP(=O)(OC(C)C)OC(C)C)c3)ncc2Cl)c1
Reaction time: 0.08 h
Yield: 35.3 %

Procedure:
n-Butyl lithium (0.14 mL, 2.5 M solution in hexane) was diluted 10-fold in THF (1.4 mL), and the resulting mixture added dropwise to a rapidly stirring solution of N-(3-(5-chloro-2-((3-hydroxy-4-morpholinophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide (100 mg, 0.221 mmol) in THF (5 ml) that was under argon gas and the reaction vessel was immersed in a salt-ice bath (bath temperature about −10° C. to −5° C.). The resulting white suspension was stirred for 5 min, followed by addition of diisopropyl phosphorochloridate (178 mg, 0.885 mmol) to the reaction mixture in a single portion. The suspension became a clear solution within about 5 min, and then reaction mixture was stirred at ambient temperature for about 18 h. Then reaction mixture was evaporated to dryness on a rotary evaporator. The resulting crude residue was purified by silica gel flash chromatography using a mixture of 3% methanol and DCM as eluting solvent to provide the title compound (50 mg, 0.078 mmol, 35.2% yield) as a syrup. 1HNMR (400 MHz, CDCl3): δ 8.52 (bs, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.37 (s, 1H), 7.98 (s, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.38 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=8.0 Hz), 6.45 (m, 2H), 5.68 (t, 1H, J=6.0 Hz), 4.74 (m, 2H), 3.81 (m, 4H), 2.96 (m, 4H). Mass: 616.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[N:13][C:14]([O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:15][CH:16]=1
Reactant: CCOC(=O)CO
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ncc(Br)cn1
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of ethyl 2-hydroxyacetate (0.081 g, 0.775 mmol) in toluene (1.0 mL) was added NaH (60% in mineral oil, 0.037 g, 0.931 mmol) at room temperature. The mixture was stirred for 30 min and a solution of 5-bromo-2-chloropyrimidine (0.100 g, 0.517 mmol) in toluene (0.5 mL) was added. The reaction mixture was stirred at 60° C. for 16 h. The mixture was diluted with EtOAc and slowly quenched with water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (82 mg, 61% yield) as a clear colorless oil. LCMS, [M+H]+=260.9.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:27]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:27])([CH3:13])([CH3:14])[CH3:12]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Sc1nc2ccccc2n1CC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 50 mg, 0.19 mmol), 1-bromomethyl-benzene (38.5 mg, 28.5 μl, 0.2 mmol) and K2CO3 (52 mg, 0.38 mmol) in acetone (3 ml) is stirred at reflux overnight. The suspension is cooled to rt and filtered through Celite. Evaporation of the solvent in vacuo and drying under high vacuum yields quantitatively the title compound as a slightly yellow oil. This material is used in the next step without further purification. tR=7.45 min (LC-1), MS (pos.): m/z 369.21 [M+H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.36 (s, 9H, tBu), 1.73 (d, 3H, Me), 4.94 (m, 2H, CH2CO2), 5.09 (q, 1H, SCHMePH), 7.16-7.20 (m, 2Harom), 7.26-7.36 (m, 3Harom), 7.44-7.50 (m, 3Harom), 7.61 (m, 1Harom).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([O:25][CH3:26])[C:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[C:18]3[Cl:38])([C:7]2[C:8]([CH3:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[OH:6])[CH2:2]1.N1CC(C(C2C(C)=NC(C)=CC=2)(O)C2C=C3C(=CC=2)N=[C:49]([OH:54])[C:48](CC2C=CC(C(F)(F)F)=CC=2)=C3Cl)C1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:38][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:5]([C:7]3[C:8]([CH3:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)([OH:6])[CH:3]3[CH2:4][N:1]([C:49](=[O:54])[CH3:48])[CH2:2]3)[CH:16]=2)[N:21]=[C:20]([O:25][CH3:26])[C:19]=1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=1
Reactant: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(C(O)(c2ccc3nc(O)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)C2CNC2)c(C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CN(C(C)=O)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 40 °C

Procedure:
To a flask containing crude azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol and 6-(azetidin-3-yl(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)-4-chloro-3-(4-(trifluoromethyl)benzyl)-quinolin-2-ol (630 mg, 1.16 mmol, Example 126) was added DCM (20 mL) which gave a suspension at room temperature. Triethylamine (1 mL, 6.9 mmol) was added, followed by acetic anhydride (0.30 mL, 3 mmol) and the initial suspension became homogeneous after about 2 minutes. The mixture was heated to 40° C. for 4 hours then quenched with brine and extracted with DCM (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The residue was purified by FCC (5% MeOH-EtOAc increasing to 10% MeOH) to provide the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (dd, J=4.1, 2.0 Hz, 2H), 7.81-7.71 (m, 4H), 7.53 (d, J=8.2 Hz, 4H), 7.46-7.37 (m, 6H), 7.25-7.17 (m, 2H), 4.45-4.33 (m, 5H), 4.30-4.07 (m, 4H), 4.04 (d, J=1.3 Hz, 5H), 4.01-3.97 (m, 1H), 3.85 (t, J=8.6 Hz, 1H), 3.77-3.59 (m, 3H), 2.49 (d, J=1.6 Hz, 6H), 2.18 (s, 6H), 1.83 (d, J=13.7 Hz, 6H); MS (ESI): mass calcd. Chemical Formula: C31H29ClF3N3O3, Exact Mass: 583.2. m/z found 583.9 [M+H]+. 1-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidin-1-yl)ethanone was purified by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 75% CO2, 25% i-PrOH (0.3% iPrNH2)) to give two enantiomers. The first eluting enantiomer was Example 87b and the second eluting enantiomer was Example 87c.
Reaction SMILES: [CH3:1][S:2][C:3](=O)[NH:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)[C:6]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>CC#N>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:7]3[CH:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=23)[CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CSC(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-thiocarbamic acid S-methyl ester (200 mg, 0.0005 mol) in MeCN (10 mL) and DMF (0.12 mL, 0.0015 mol) was added POCl3 (0.14 mL, 0.0015 mol); the resulting mixture was stirred at 55° C. overnight. The mixture was quenched with 2N NH3/iPrOH, then diluted with EtOAc, washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex.: EtOAc=80:20→70:30) to give a yellow solid. 1H-NMR (CDCl3) confirmed a mixture of the desired product and starting material in ca. 1:1 ratio, which was taken on to next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Cl:23][C:24]1[C:29]([O:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:26][N:25]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask charged with 3,5-dibromophenol (1.16 g, 4.61 mmol) and potassium carbonate (1.27 g, 9.22 mmol) was added N-methylpyrrolidinone (10 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (0.920 g, 4.61 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 30 minutes, the reaction mixture was allowed to cool to room temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 120 gram column, eluting with 0-75% CH2Cl2 in hexanes to afford the title compound. 1H NMR (CDCl3) δ 8.53 (d, J=5.0 Hz, 1H), 7.62 (d, J=5.0 Hz, 1H), 7.44-7.42 (m, 1H), 6.92-6.88 (m, 2H). LRMS (M+1)=431.5.
Reaction SMILES: [OH:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[CH:4].C([Li])CCC.[Br:14]Br.CCOCC>C1COCC1.O>[Br:14][C:4]#[C:3][C:2]([OH:1])([CH2:7][CH3:8])[CH2:5][CH3:6]
Reactant: BrBr
Reactant: C#CC(O)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)(C#CBr)CC
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-hydroxy-3-ethyl-1-pentyne (20 mmol) in dry THF (40 ml) at room temperature was added n-butyl-lithium (42 mmol, 1.6M in hexanes) during 10 minutes. After stirring for 30 minutes, the solution was cooled to −40° C. and a solution of bromine (1.13 ml, 3.52 g, 22 mmol) in dry THF (20 ml), also cooled to −40° C., was added, during 20 minutes, followed by re-heating to 25° C., during about 1 hour. Standard work-up after addition of ether and water (chromatography: 0% to 10% ether in petroleum ether) gave the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@H:16]([NH:26][CH3:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=O)=[O:38])([CH3:35])([CH3:34])[CH3:33].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>C(Cl)Cl.CCOC(C)=O>[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42]([N:26]([CH3:27])[C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)=[O:44])=[O:38])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CN[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)C(=O)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl(7R)-14-cyclohexyl-7-(methylamino)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 1, Step 5) and N-(tert-butoxycarbonyl)-β-alanine (1.2 eq) in DCM (0.15 M) was treated with HATU (1.3 eq.) and DIPEA (3 eq.) and the resulting mixture was stirred for 90 min at RT. The reaction was diluted with EtOAc and the combined organic layers were washed with 1N HCl (aq), sat aq NaHCO3 then brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 590 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:2]1.I[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([CH2:18][CH2:19][OH:20])[CH2:2]3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1
Reactant: c1cc2[nH]ncc2cc1OC1CCCNC1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCCC(Oc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
A mixture of the 5-(piperidin-3-yloxy)-1H-indazole (43 mg, 0.20 mmol) obtained in Example 377, 2-iodoethanol (84 mg, 0.49 mmol), potassium carbonate (70 mg, 0.50 mmol) and N,N-dimethylformamide (1 ml) was stirred at room temperature for 24 hours. The precipitate was removed by filtration and the solvent was distilled off as an azeotrope with toluene. The residue oil was purified by a silica gel column chromatography (eluent: ethyl acetate/triethylamine/ethanol=20/1/1) to obtain 2-[3-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol (17 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13]CC(C)=C.C(OCC)(=O)C.N1[C:33]2[C:28](=[CH:29]C=CC=2)[CH:27]=CC=1>>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([OH:13])[C:5]=1[CH2:29][C:28]([CH3:33])=[CH2:27]
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1OC
Reactant: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: C=C(C)Cc1c(C(=O)OC)ccc(OC)c1O
Temperature: 185 °C

Procedure:
20 g of methyl 4-methoxy-3-(2-methyl-2-propenyloxy)benzoate are dissolved in 60 ml of quinoline and the mixture is heated at 180-190° C. for 2 h. After cooling, it is treated with ethyl acetate and the quinoline is extracted using 2N HCl. The organic phase is washed a further 2 times with water and concentrated. The oily residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 15.6 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)([O-:12])=[O:11].[O:22]=[C:23](N1CCCC1)[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])O.[Na+]>CO>[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:23](=[O:22])[C:24]([O:26][CH3:27])=[O:25])=[CH:16][NH:17]2)([O-:12])=[O:11]
Reactant: COC(=O)C(=O)N1CCCC1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: O=C([O-])O
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C

Procedure:
9.4 mL (68 mmol) diphosphoryl chloride were slowly added dropwise to 10 g (62 mmol) 4-nitroindole and 11 g (68 mmol) methyl oxo-pyrrolidin-1-yl-acetate with stirring and while cooling with ice. The reaction mixture was heated to RT and stirred for 3 h at RT. Then first of all 10 mL MeOH were added dropwise at 0° C. and then saturated sodium hydrogen carbonate solution was added dropwise at 0° C. After repeated extraction with DCM the organic phase was dried and evaporated down to 100 mL. This residue was left to stand at RT and the precipitate formed was suction filtered, washed and dried in the air.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[CH:16]=[N:15][C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[CH:8]=1)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:14]1[CH:13]=[CH:12][N:11]=[C:10]2[N:15]=[CH:16][C:7]([CH2:6][CH2:5][CH:4]=[O:3])=[CH:8][C:9]=12
Reactant: CCOC(CCc1cnc2nccnc2c1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CCCc1cnc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 7-(3,3-diethoxypropyl)-pyrido[2,3-b]pyrazine (522 mg in 20 mL chloroform) at 0° C. was added 20 mL of 50% aqueous trifluoroacetic acid and the mixture allowed to warm slowly to room temperature. After 30 minutes, the mixture was diluted with methylene chloride and the reaction quenched by the cautious addition of saturated sodium bicarbonate. The organics were concentrated in vacuo and purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:1; then methylene chloride:methanol, 95:5) to give the title compound (0.214 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23].N1C=CC=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:18][C:17]=1[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ncc(N)cc1C
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ncc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1C
Yield: 76.3 %

Procedure:
The title compound (2.69 g, 8.32 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (2.41 g, 10.9 mmol), 6-methoxy-5-methylpyridin-3-amine (1.66 g, 12.0 mmol) and pyridine (2.64 mL, 32.7 mmol) in 1,4-dioxane (25 mL) at rt using the methods of (IntA1), step 1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=O)C.CO[NH:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:20][NH:19][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:3]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1C
Reactant: CNOC
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 5-chloro-1-methyl-1H-indole-2-carboxylic acid ethyl ester (1.27 g, 5.3 mmol) in toluene (10 mL) was added O,N-dimethyl-hydroxylamine (9.6 mL of a 1 M solution in toluene, 9.6 mmol). The resulting mixture was heated to reflux overnight after which the reaction was cooled to room temperature and quenched by the addition of 10% aqueous K2CO3 (50 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (2.12 g, 96%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.27 (m, 2H), 6.73 (s, 1H), 6.13 (s, 1H), 4.03 (s, 3H), 3.01 (d, J=4.9 Hz, 3H); MS (ESI) m/e 222 (M+H)+.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([O:17]CC)=[O:16])(=O)C1C=CC=CC=1.[OH-].[Na+].CO.Cl>O1CCCC1>[OH:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCO)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-2-(2-aminothiazol-4-yl)acetate (syn isomer) (8.5 g.), 1 N aqueous sodium hydroxide (35 ml.), methanol (40 ml.) and tetrahydrofuran (40 ml.) was stirred at 35° to 40° C. for 9 hours and at ambient temperature for 12 hours. After adjusting the resultant solution to pH 6.5 with conc. hydrochloric acid, the solution was concentrated to about 2/3 volume of the initial. The concentrate was adjusted to pH 3.5 with conc. hydrochloric acid under ice-cooling, and the precipitates were collected by filtration, washed with water and acetone in turn and then dried over phosphorus pentoxide under reduced pressure to give 2-(2-hydroxyethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (3.3 g.).
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:9])[CH:7]=[CH2:8].C(N(CC)CC)C.[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51](O)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]>C1COCC1>[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51]([O:23][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6](=[O:9])[CH:7]=[CH2:8])=[CH:26][CH:25]=2)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCCCCCCOC(=O)c1cc(O)ccc1O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCOC(=O)c1cc(OC(=O)c2ccc(OCCCCCCOC(=O)C=C)cc2)ccc1O
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of mesyl chloride (3.44 g) in 50 ml of dry THF was added dropwise under argon to a cooled (−25° C.) solution of 4-(6-acryloyloxyhexyloxy)benzoic acid (8.35 g) and triethylamine (6.07 g) in 100 ml of dry THF. After complete addition (15 min), the reaction mixture was stirred for a further 30 min at −25° C., treated with a solution of 2,5-dihydroxybenzoic-6-acryloyloxyhexyl ester in 50 ml of dry THF and further stirred at −25° C. for 4 h. The reaction mixture was then filtered through celite and the solvent was removed by evaporation. The filtrate was purified by flash chromatography using a short silica-gel column and dichloromethane/diethylether (39/1) as eluent to give 10.8 g of 5-[4-(6-acryloyloxyhexyloxy)benzoyloxy]-2-hydroxybenzoic acid 6-acryloyloxyhexyl ester as a slightly beige oil.
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[CH3:11][N:12]([CH3:32])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]([CH:23]=1)[C:20]([OH:22])=O)=[O:14].N1C=CC=C(N)C=1.C(Cl)CCl>CN(C)C=O.O>[CH3:32][N:12]([CH3:11])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]([C:20]([NH:7][C:5]2[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=2)=[O:22])[CH:23]=1)=[O:14]
Reactant: On1nnc2ccccc21
Reactant: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: Nc1cccnc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
HOBT (102 mg, 0.67 mmol) was added in one charge to a stirred solution of 5-[(dimethylamino)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 59; 200 mg, 0.67 mmol), 3-pyridinamine (62.9 mg, 0.67 mmol) and EDC (128 mg, 0.67 mmol) in N,N-dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water (50 ml). The precipitate was collected by filtration. The solid was dissolved in ethyl acetate (100 ml), and the organic phase was washed with NaOH (1 mol/l 25 ml), water (25 ml), saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to yield the title compound as a white solid. 78 mg.