Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([Cl:6])=[O:5].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH2:16]1>>[ClH:6].[ClH:6].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[N:26]=[C:25]([NH:27][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH2:16]1
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Product: Cl
Yield: 46 %

Procedure:
Using a method similar to example 1, using 2,4,6-trifluoro-benzoyl chloride (134 mg, 0.69 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 2 (preparation 11, 100 mg, 0.46 mmol) provides the free amine of the title compound as an oil (80 mg, 46%): MS (ES): m/z=376.2 (M+H)+; 1H NMR (CD3OD): δ 8.25 (t, 1H), 7.67 (d, 1H), 7.74 (d, 1H), 7.12 (t, 2H), 6.81 (m, 1H), 3.62 (m, 1H), 2.96 (s, 6H), 2.73 (m, 4H), 2.45 (m, 1H), 1.95 (m, 1H). Using a salt formation method similar to that in example 1 gives the dihydrochloride salt.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([CH2:6]O)[O:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][CH3:82])/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[S:63])=[C:56](C(=O)C)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCOCC1.[F:89][C:90]([F:102])([F:101])[S:91]([O:94][CH2:95][CH:96]1[CH2:100][O:99][CH2:98][O:97]1)(=[O:93])=[O:92]>C(N(CC)CC)C.N1C=CC=CC=1>[F:102][C:90]([F:89])([F:101])[S:91]([O:94][CH2:95][CH:96]1[CH2:100][O:99][CH2:98][O:97]1)(=[O:93])=[O:92].[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][CH3:82])/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:72]4[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=4)[C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)=[S:63])=[C:56]([CH2:6][CH:4]4[CH2:5][O:1][CH2:2][O:3]4)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCC1COCO1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=S(=O)(OCC1COCO1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1COCCN1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3COCO3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 94 %

Procedure:
1,3-Dioxolan-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27 (a) from 1,3-dioxolan-4-ylmethanol (180 mg), pyridine (0.15 ml) and trifluoromethanesulfonic acid anhydride (537 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2 -tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (500 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27 (b), followed by reacting the resulting reaction product with the 1,3-dioxolan-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27 (b). The reaction solution so obtained was post-treated in the same manner as in Example 27 (b) and the produced compound was recovered and purified similarly to Example 27 (b) to afford the titled compound (494 mg; 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([O:22]CC=C)=[O:21])=[CH:17][CH:18]=2)[C:13]([CH3:26])=[C:12]1[CH3:27])[CH3:5].N1CCOCC1>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[C:13]([CH3:26])=[C:12]1[CH3:27])[CH3:5]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(O[C@@H](C)C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-allyl 1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (1.0 g, 2.37 mmol, 1 equiv), Pd(PPh3)4 (277 mg, 0.24 mmol, 0.1 equiv), and morpholine (2 mL, 23.7 mmol, 10 equiv) in anhydrous THF (30 mL) was stirred at room temperature under argon atmosphere for 16 h. The completion of the reaction was monitored by anal. HPLC. The crude mixture was dissolved in AcOEt (100 mL) and washed with a 0.5N HCl aqueous solution (×2) and brine, then dried over Na2SO4. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->60%) to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:25]1[CH2:24][CH2:23][CH:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(OC5CCNCC5)nc34)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of tert-butyl 4-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate (0.103 g, 0.22 mmol) in DCM (3.0 mL) at 0° C. was added TFA (0.5 mL, 6.73 mmol). The reaction was stirred at 0° C. for 1 h, then at RT for 40 min. The reaction mixture was then concentrated, the residue was dissolved in DCM, washed with a saturated aq. solution of NaHCO3, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO (2.0 mL) and purified by rpHPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 5-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min.), then dried in a Genevac Series II Evaporator to afford 2-(2-(piperidin-4-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (48.7 mg, 0.094 mmol, 32.4% yield) as an amorphous orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (br. s., 1H), 8.67 (br. s., 1H), 8.47 (br. s., 1H), 8.30 (d, J=9.0 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.95 (br. s., 1H), 5.37-5.48 (m, 1H), 3.34-3.50 (m, 4H), 3.18-3.31 (m, 2H), 2.88 (t, J=6.8 Hz, 2H), 2.36 (d, J=14.3 Hz, 2H), 1.87-2.02 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.36 (s, 3F). m/z (ESI, +ve ion) 363.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([OH:17])=O)=[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH2:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN1C(=O)CCC1>[NH2:1][C:2]1[C:14]([C:15]([NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[O:17])=[C:5]2[N:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: COc1ccncc1N
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccncc1NC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (100 mg, 0.4063 mmol), 4-methoxypyridin-3-amine (50.44 mg, 0.4063 mmol) and DIPEA (52.51 mg, 70.77 μL, 0.4063 mmol) were dissolved in dry NMP (812.6 μL) in a microwave tube. TBTU (130.5 mg, 0.4063 mmol) was added in one portion and the resulting mixture was stirred at RT for ˜10 minutes and at 100° C. for ˜2 h under microwave conditions. The reaction mixture was allowed to cool to RT and filtered through a SCX-2 cartridge (5 g). The cartridge was washed with MeOH/DCM and eluted with 2M NH3 in MeOH (3×10 mL). The eluate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (7.5% MeOH in DCM, ˜75 mL) to give the desired Compound I-O-1 as a bright yellow solid (87.9 mg, 61% Yield). LC-MS (M+H)+353.1; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.55 (s, 1H), 9.26 (dd, 1H), 8.24 (dd, 1H), 7.50-7.51 (d, 1H), 7.17-7.18 (d, 1H), 6.99 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:10][C:9]1[C:8]([O:11][CH3:12])=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=1[Cl:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C=O)c(Cl)c1O
Solvent: c1ccncc1
Product: COc1ccc(C=O)c(Cl)c1OC(C)=O
Reaction time: 8 h

Procedure:
26.0 g of 2-chloro-3-hydroxy-p-anisaldehyde are dissolved in 400 ml of acetic anhydride and 5 ml of pyridine. The solution is stirred at 80° for 8 hours, subsequently evaporated, the residue is partitioned between ice-water and methylene chloride, the organic phase is dried over sodium sulfate, evaporated and the residue is recrystallized from methylene chloride/petroleum ether. There is obtained 2-chloro-3-formyl-6-methoxyphenyl acetate of m.p. 48°-50°.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][C:11]=2[C:10]([NH2:25])=[N:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].ClC[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=O>>[NH2:25][C:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13](=[O:24])[C:12]=2[N:8]([C:6](=[O:5])[CH2:34][CH2:35][N:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:39][CH2:38]2)[N:9]=1
Reactant: O=C(CCCl)N1CCN(c2ccccc2)CC1
Reactant: Cc1ccc(N2CCc3c(N)nn(C(=O)OC(C)(C)C)c3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccccc5)CC4)c3C2=O)cc1

Procedure:
A target compound (77.8 mg, 0.169 mmol, 44.7%) was yielded as liquid in the same manner as Example 1 by reacting 1-N-t-butoxycarbonyl-3-amino-4,5,6,7-tetrahydro-6-N-(p-tolyl)pyrazolo[3,4-c]pyridin-7-one (130 mg, 0.379 mmol) with potassium carbonate (57.6 mg, 0.417 mmol) and 3-chloro-1-(4-phenylpiperazin-1-yl)propan-1-one (100.6 mg, 0.398 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C@@H:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([O:1][C@@H:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCC[C@@H](C)O
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
Methyl 4-hydroxy-3-nitrobenzoate was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-methyl-4-(1-methyheptyloxy)-3-nitrobenzoate (Compound 23, Scheme IV, R1 =(S)-OCH(CH3)C6H13). The product was purified by flash chromatography with hexanes/ethyl acetate (95/5) as eluent affording a yellow liquid, Rf [hexanes/ethyl acetate 95/5]:0.25; 1H-NMR (300 MHz, CDCl3): δ 0.82 (t, 3H, J=7.1 Hz); 1.14-1.50 (m, 8H); 1.34(d, 3H, J=6.1 Hz); 1.60(m, 1H); 1.75(m, 1H); 3.87(s, 3H); 4.57(m, 1H); 7.06(d, 1H, J=8.9 Hz); 8.11(dd, 1H, J=2.2 Hz, J=8.9 Hz); 8.39(d, 1H, J=2.2 Hz); 13C-NMR (300 MHz, CDCl3): δ 13.96, 19.31, 22.47, 25.06, 29.02, 31.60, 36.00, 52.35, 76.80, 114.63, 121.80, 127.17, 134.80, 140.27, 154.91, 165.08; Mass spectrum, m/z(rel.intensity): 309 (M+ 1), 197(32), 166(46), 112(48), 71(63), 57(100), 55(46).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:30])[C@@H:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:4][N:3]=1.[C@:31]12(CS(O)(=O)=O)C(C)(C)[CH:35]([CH2:36][CH2:37]1)[CH2:34][C:32]2=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C.C[N:58]1CCCC1=O>NC1C=CC=CC=1>[CH3:29][N:21]([C@@H:19]([CH3:20])[C:18](=[O:30])[NH:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]([NH:58][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:31]=2)=[N:3][CH:4]=1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CN1CCCC1=O
Reactant: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Product: CCCNc1nc(Nc2ccccc2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl (1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (L1, 57 mg) and (1S)-(+)-10-camphorsulfonic acid (150 mg) in N-methylpyrrolidone (1 mL), aniline (60 μL) was added at room temperature, and the mixture was stirred at 60° C. for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 50 to 25% hexane in ethyl acetate) to obtain oily (S)-tert-butyl methyl(1-oxo-1-((5-(2-(phenylamino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)propan-2-yl)carbamate (L2, 52 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8](=[O:10])[CH3:9])[CH2:7][CH2:6]1)=[O:4].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: OCCO
Reactant: COC(=O)C1(C(C)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C1(C2(C)OCCO2)CC1

Procedure:
18.7 g of 4 is dissolved in 500 ml of benzene, 30 ml of ethylene glycol and 1 g of p-toluenesulfonic acid are added and heated under nitrogen in a water separator for 12 hours. After cooling, sodium bicarbonate solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation, whereby 23 g of title compound 5 accumulates as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O>CS(C)=O.C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=CC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
A mixture of 1-hydroxy-1,2-benziodooxol-3(1H)-one-1-oxide (IBX) (8.73 g, 3.12 mmol) in DMSO (30 mL) and THF (15 mL) was stirred at room temperature over a period of 20 minutes. In one portion [1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-methanol (4.69 g, 15.6 mmol) was added and the solution heated to 50° C. Water was added to the reaction until a white precipitate formed. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was partitioned with ethyl acetate and water. The organic phase was dried (sodium sulfate) and concentrated in vacuo to give 4.32 g of the product as a tan solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([O:24]C(C)(C)C)=O)[C@H:19]([C:29]([O:31]C)=[O:30])[CH2:18]1)(=[O:16])=[O:15].[Cl:33][C:34]1[CH:35]=[C:36]([F:46])[C:37]([C:40]2(C(O)=O)[CH2:42][CH2:41]2)=[N:38][CH:39]=1>>[Cl:33][C:34]1[CH:35]=[C:36]([F:46])[C:37]([C:40]2([C:22]([N:20]3[CH2:21][C@H:17]([S:14]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:7][C:2]=4[Cl:1])(=[O:16])=[O:15])[CH2:18][C@H:19]3[C:29]([OH:31])=[O:30])=[O:24])[CH2:41][CH2:42]2)=[N:38][CH:39]=1
Reactant: O=C(O)C1(c2ncc(Cl)cc2F)CC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2Cl)CN1C(=O)OC(C)(C)C
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1

Procedure:
The title compound was prepared in analogy to General Procedure C, steps C4-C6, using (2S,4R)-1-tert-butyl 2-methyl 4-(2-chloro-4-(2,2,2-trifluoroethoxy)phenylsulfonyl)pyrrolidine-1,2-dicarboxylate in step C4, and 1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid in step C5. MS (m/e)=584.9 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([Cl:22])[C:11]=1[C:12]([OH:14])=[O:13].CN(C)C1C=CC=CC=1>CCOCC>[Cl:22][C:15]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: Cc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reaction time: 2.67 h

Procedure:
A mixture of 10.7 g of p-toluidine, 11.8 g of 2,6-dichloro-3-nitrobenzoic acid and 25 ml of N,N-dimethylaniline was stirred at 135° for 160 minutes. The mixture was diluted with ether and extracted with 1N aqueous sodium hydroxide. Acidification of the aqueous solution, extraction with chloroform, and evaporation of the extract provided 6-chloro-2-[(4-methylphenyl)amino]-3-nitrobenzoic acid as orange prisms, mp 192°-197° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:35])[CH:12]([C:14]2[CH:15]=[C:16]([C:31]([O:33]C)=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1.CO.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:35])[CH:12]([C:14]2[CH:15]=[C:16]([C:31]([OH:33])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc(C(C)N(C)c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
2N NaOH (6.54 mL, 13.1 mmol), was added dropwise to a stirred suspension of methyl 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3 g, 6.54 mmol), in THF (30 mL)/MeOH (30 mL). The resulting solution was stirred at RT overnight. The reaction mixture was diluted with water, the pH was adjusted to 3 with a 2M aq. sol. HCl. The solvents were removed and the white precipitate was collected by filtration, washed with water and dried then washed with ethyl acetate and ether to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (2.5 g, 86%) which was used without further purification. Mass Spectrum: M+H+ 445.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:4]=1[O:5][CH2:6][CH2:7][N:8]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:4]=1[O:5][CH2:6][CH2:7][NH2:8]
Reactant: COc1cc(F)c(F)cc1OCCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1OCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of 2-(2-methoxy-4,5-difluoro-phenoxy)-ethylazide (0.69 g, 3.46 mmol) and triphenylphosphine (1.27 g, 4.84 mmol) in tetrahydrofuran (15 ml) containing water (0.08 ml) was stirred at room temperature overnight. The solvent was removed under vacuum. Chromatography with ethyl acetate removed triphenylphosphine oxide, followed elution with ethyl acetate-methanol-ammonium hydroxide 8.5:1.5:0.5, afforded 0.53 g of product as a white solid: mp 44-46° C.; MS EI m/e 203 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.Cl[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22]>>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: COC(=O)c1cc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2o1
Yield: 87 %

Procedure:
In the same manner as in Reference Example 4, methyl 5-hydroxybenzofuran-2-carboxylate was reacted with 4-chloromethyl-5-methyl-2-phenyloxazole to yield methyl 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)bezofuran-2-carboxylate (yield 87%), which was then recrystallized from acetone-ethyl acetate to yield colorless prisms having a melting point of 177° to 178° C.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[C:12]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])(=[O:9])=[O:8])[CH2:6][CH2:5]1)C=C.C[N+]1([O-])CC[O:33]CC1.CCO[C:40]([CH3:42])=[O:41]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[F:19][C:13]1[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([NH:10][S:7]([C:4]2([CH2:1][CH:40]([OH:41])[CH2:42][OH:33])[CH2:6][CH2:5]2)(=[O:9])=[O:8])[C:16]([CH3:17])=[CH:15][C:14]=1[F:18]
Reactant: CCOC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCC1(S(=O)(=O)Nc2c(C)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methylphenyl)cyclopropane-1-sulfonamide (150 mg, 0.29 mmol) and 4-methylmorpholine N-oxide (33 mg, 0.29 mmol) was dissolved in THF (5 mL). Osmium tetroxide was added at room temperature (0.029 mmol, 0.18 mL, 4% in H2O) and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, the organic phase was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified over silica gel chromatography (eluants: EtOAc/MeOH) to obtain the titled product (0.110 g, 68%). 1H-NMR (300 MHz, CDCl3): δ 7.07 (m, 1H), 6.97 (br m, 2H), 6.84 (m, 2H), 6.60 (br m, 2H), 3.98 (br r, 1H), 3.58 (m, 1H), 3.43 (m, 1H), 3.20 (d, J=3.9 Hz, 1H), 2.42 (s, 3H), 2.31 (dd, J=9.9 & 15.6 Hz, 1H), 2.01 (br t, 1H), 2.31 (dd, J=9.9& 15.6 Hz, 1H), 1.66 (dd, J=2.1 & 15.9 Hz, 1H), 1.52 (m, 1H), 1.40 (m, 1H), 0.91 (m, 2H).