Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C@@H:6]1[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(=O)C.C[O-].[Na+].CO>CO>[C:31]1(=[O:40])[N:30]([C@@H:6]2[C@@H:5]([OH:4])[C@H:20]([OH:21])[C@@H:19]([CH2:25][OH:26])[O:18][C@H:7]2[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1N1C(=O)c2ccccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 6 h
Yield: 99 %

Procedure:
Compound 61a (26.0 g, 46.18 mmol) was treated with NaOMe/MeOH (25 wt. %, 2.7 mL) in MeOH (200 mL) at room temperature. After 6 h, the mixture was neutralized (IRC-50 resin, weak acid) and concentrated to give product 61b (20.0 g, 99%) as semisolids: 1H-NMR (500 MHz, CDCl3), δ 7.78–7.82 (m, 2H), 7.68–7.72 (m, 2H), 5.16 (d, J=8.5 Hz, 1H), 4.63 (d, J=4.5 Hz, 1H), 4.25–4.31 (m, 2H), 4.06 (dt, J=2.0, 8.5 Hz, 1H), 3.88–3.89 (m, 2H), 3.76 (dt, J=10.0, 6.5 Hz, 1H), 3.65–3.71 (m, 1H), 3.59 (s, 3H), 3.48 (t, J=6.5 Hz, 1H), 3.43 (dt, J=9.5, 3.5 Hz, 1H), 3.38 (dt, J=10.0, 6.5 Hz, 1H), 1.90–2.02 (m, 2H), 1.31–1.43 (m, 4H), 1.00–1.09 (m, 2H); 13CNMR (125 MHz, CDCl3), δ 174.0, 168.4, 134.0, 131.6, 123.4, 98.31, 75.53, 71.53, 71.20, 69.43, 61.63, 56.66, 51.38, 33.65, 28.84, 25.18, 24.34; HRMS (M+Na) calcd for C21H27O9NNa 460.1584. found 460.1598.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Yield: 30.2 %

Procedure:
2,3-dihydrobenzofuran (6.0 g, 49.94 mmol) is added over 20 minutes to chlorosulfonic acid (29.09 g, 249.69 mmol) at -20° C. The reaction mixture is quenched by addition of ice followed by water (20 mL). The mixture is then extracted with ethyl acetate. The combined organic estracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give 2,3-dihydrobenzofuran-5-sulfonyl chloride (3.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.S(=O)(=O)(O)O>C(O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCO
Product: O=C1Cc2ccc(Br)cc2N1
Yield: 89.6 %

Procedure:
4-Bromo-2-nitrophenylacetic acid 0.26 g), 0.26 g of zinc powder and 3 mL of 50% sulfuric acid in 5 mL of ethanol was heated at 100° C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2-oxindole 5 g a yellow solid.
Reaction SMILES: C1N([C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)N=NC=1COCC(N)(COCC1N=NN([C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C=1)CO.[F:43][C:44]([F:141])([F:140])[C:45]([F:139])([F:138])[C:46]([F:137])([F:136])[C:47]([F:135])([F:134])[C:48]([F:133])([F:132])[C:49]([F:131])([F:130])[C:50]([F:129])([F:128])[C:51]([F:127])([F:126])[CH2:52][CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][C:101]([F:125])([F:124])[C:102]([F:123])([F:122])[C:103]([F:121])([F:120])[C:104]([F:119])([F:118])[C:105]([F:117])([F:116])[C:106]([F:115])([F:114])[C:107]([F:113])([F:112])[C:108]([F:111])([F:110])[F:109])[C:65]=1[O:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([F:95])([F:94])[C:72]([F:93])([F:92])[C:73]([F:91])([F:90])[C:74]([F:89])([F:88])[C:75]([F:87])([F:86])[C:76]([F:85])([F:84])[C:77]([F:83])([F:82])[C:78]([F:81])([F:80])[F:79])[C:60]([OH:62])=[O:61].[CH:142]1[C:154]2[N:153]([CH2:155][CH2:156][O:157][CH2:158][CH2:159]O)[C:152]3[C:147](=[CH:148][CH:149]=[CH:150][CH:151]=3)[C:146]=2[CH:145]=[CH:144][CH:143]=1>>[CH:151]1[C:152]2[N:153]([CH2:155][CH2:156][O:157][CH2:158][CH2:159][O:61][C:60](=[O:62])[C:59]3[CH:58]=[C:57]([O:56][CH2:55][CH2:54][CH2:53][CH2:52][C:51]([F:126])([F:127])[C:50]([F:128])([F:129])[C:49]([F:130])([F:131])[C:48]([F:132])([F:133])[C:47]([F:134])([F:135])[C:46]([F:136])([F:137])[C:45]([F:138])([F:139])[C:44]([F:140])([F:141])[F:43])[C:65]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([F:94])([F:95])[C:72]([F:93])([F:92])[C:73]([F:91])([F:90])[C:74]([F:89])([F:88])[C:75]([F:87])([F:86])[C:76]([F:85])([F:84])[C:77]([F:83])([F:82])[C:78]([F:81])([F:80])[F:79])=[C:64]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][C:101]([F:124])([F:125])[C:102]([F:122])([F:123])[C:103]([F:120])([F:121])[C:104]([F:118])([F:119])[C:105]([F:117])([F:116])[C:106]([F:115])([F:114])[C:107]([F:113])([F:112])[C:108]([F:111])([F:110])[F:109])[CH:63]=3)[C:154]3[C:146](=[CH:145][CH:144]=[CH:143][CH:142]=3)[C:147]=2[CH:148]=[CH:149][CH:150]=1
Reactant: OCCOCCn1c2ccccc2c2ccccc21
Reactant: O=C(O)c1cc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Agent: NC(CO)(COCc1cn([C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)nn1)COCc1cn([C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)nn1
Product: O=C(OCCOCCn1c2ccccc2c2ccccc21)c1cc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1

Procedure:
The synthesis of a mobility donor fluorinated dendron D1 of the present invention is as shown in the Scheme below. D1 is prepared using 3,4,5-tris-(12,12,12,11,11,10,10,9,9,8,8,7,7,6,6,5,5-heptadecafluoro-n-dodecan-1-yloxy)-benzoic acid as a starting material. The intermediate is then reacted with an alcohol of the desired apex moiety, 2-(2-carbazol-9yl-ethoxy)-ethanol, to obtain the compound of the invention.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[C:25]([CH3:38])=[C:26]([CH2:30][NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH:27]=[N:28][CH:29]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[C:25]([CH3:38])=[C:26]([CH2:30][NH:31][S@@:32]([C:34]([CH3:36])([CH3:35])[CH3:37])=[O:33])[CH:27]=[N:28][CH:29]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Reactant: Cc1c(Br)cncc1CN[S@](=O)C(C)(C)C
Product: Cc1c(CN[S@](=O)C(C)(C)C)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2

Procedure:
In analogy to the procedure described for the preparation of example 45, 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22) has been coupled to (R)-2-methyl-propane-2-sulfinic acid (5-bromo-4-methyl-pyridin-3-ylmethyl)-amide (intermediate A-59) to give the title compound as a brown amorphous solid. MS: 404.5 (M+H+).
Reaction SMILES: BrN1[C:6](=[O:7])CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>CN(C=O)C.CO>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][O:7][CH3:6])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: COCc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.26 g) was added to a solution of the product from Example 27 step b) (0.5 g) in DMF (5 ml) and methanol (2 ml), and the solution stirred for 1 h. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid which was filtered and dried to yield the title compound as a white solid (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][C:12]([OH:14])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:11][C:12]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:14]
Reactant: COc1cccc(OC)c1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.58 h
Yield: 59.2 %

Procedure:
N,N'-Carbonyldiimidazole (0.52 g) is added to a solution of 2-(2,6-dimethoxyphenyl)acetic acid (0.63 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 35 minutes at +5° C. The mixture is stirred for 35 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.05 g) and triethylamine (0.44 cc) in dichloromethane (25 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (16 cc) and isopropyl ether (15 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-dimethoxyphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (0.89 g) melting at 224° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:12][CH:13]([F:14])[F:15]
Reactant: COC(=O)c1cnc(OC(F)F)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cnc(OC(F)F)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of methyl 5-chloro-6-(difluoromethoxy)nicotinate (4.080 g; 17.17 mmol) in anh. toluene (110 ml) was treated dropwise with a solution of 1 M DIBAH in toluene (60.30 ml; 60.30 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 3 h. The obtained mixture was treated successively with water (55 ml), 1 M aq. NaOH (11 ml), and aq. sat. NaHCO3 (100 ml). The separated aq. layer was further extracted with Et2O (2×100 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording (5-chloro-6-(difluoromethoxy)pyridin-3-yl)methanol as an orange oil. LC-MS (conditions A): tR=0.62 min.; [M+H]+: 210.25 g/mol.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[O:39]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[O:39]1[CH:43]=[CH:42][C:41]([CH2:44][O:13][C:14]2[CH:38]=[CH:37][C:17]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]3)=[CH:16][CH:15]=2)=[CH:40]1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: OCc1ccoc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccoc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A toluene solution (1.04 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (699 mg), 3-furanmethanol (0.172 ml), triphenylphosphine (577 mg) and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred at room temperature overnight, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(3-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (385 mg, yield: 45%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8]C.Br>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(O)c(Br)c1

Procedure:
3-Bromo-4-methoxyphenylacetic acid (1.3 g, 5.6 mmol) was heated in a solution of hydrogen bromide (3 mL) and acetic acid (3 mL) at 100° C. overnight. The mixture was then partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:19][C:20]([C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:25]=[C:24]([NH:36][C:37]([C:39]3[N:43]([CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)[N:42]=[C:41]([N+:53]([O-:55])=[O:54])[CH:40]=3)=[O:38])[CH:23]=2)=[O:21])[CH:6]=1)=[O:4].[OH-].[Li+]>CO.C1COCC1.O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]([NH:19][C:20]([C:22]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[N:25]=[C:24]([NH:36][C:37]([C:39]4[N:43]([CH2:44][C:45]5[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=5)[N:42]=[C:41]([N+:53]([O-:55])=[O:54])[CH:40]=4)=[O:38])[CH:23]=3)=[O:21])=[N:8]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3Cc3ccc(OC)cc3)nn2Cc2ccc(OC)cc2)nn1Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2nc(NC(=O)c3cc(NC(=O)c4cc([N+](=O)[O-])nn4Cc4ccc(OC)cc4)nn3Cc3ccc(OC)cc3)cc2C(=O)O)cc1

Procedure:
A 1.00 g (1.33 mmol, 1.00 equiv) amount of 1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxylic acid methyl ester [O2N-Pz(PMB)-Pz(PMB)-Pz(PMB)-OMe] and 81 mg of lithium hydroxide (3.38 mmol, 2.54 equiv) were stirred in a mixture of methanol/THF/water (5:5:1) for 18 h. The crude product is prepared according to general procedure A to yield the compound as a colorless solid. Yield: 0.92 g (1.25 mmol, 94%).
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[C:11](N1[C@@H](C(C)C)COC1=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[C:11]([OH:12])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)C1CCCCC1)Cc1ccccc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)C[C@@H](Cc1ccccc1)C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.4 %

Procedure:
100 mg (2.42 mmole) of lithium hydroxide were added to a solution of 500 mg (1.21 mmole) of 3-[2(R)-benzyl-4-(N-cyclohexyl-N-methylamino)-4-oxobutyryl]-4(S)-isopropyl-2-oxazolidinone (which had been prepared by a similar procedure to those described in Preparations 12-14) in a mixture of 10 ml of tetrahydrofuran and 4 ml of water, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The aqueous layer was adjusted to a pH value of 2 by the addition of an aqueous solution of citric acid and was then extracted with methylene chloride. The latter methylene chloride extract was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure, to afford 130 mg of the title compound as an amorphous product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:23])=[O:4].O[Li].O>O1CCOCC1>[Cl:23][C:6]1[CH:7]=[CH:8][C:9]2[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=3)=[N:11][O:12][C:13]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: CCc1ccc(Nc2noc3c(C(=O)OC)c(Cl)ccc23)cc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccc(Nc2noc3c(C(=O)O)c(Cl)ccc23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of methyl-6-chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylate (211 mg, 638 μmol) in dioxane (10.5 ml) was added a 1N aqueous solution of LiOH hydrate (134 mg, 3190 μmol) and the resulting mixture was heated to 50° C. After 1 hr, the solvent was removed in vacuo, the residue was diluted with H2O and acidified to pH2 with 2N HCl. After diluting with EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (3×). The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated to obtain the title compound as a brown solid, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:22][OH:23]>CCO>[NH2:2][C:1](=[N:22][OH:23])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C#N)cc2C1
Solvent: CCO
Product: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (11.85 g; 41.38 mmol; 1 eq.) was suspended in EtOH (237 mL). Hydroxylamine (6.1 mL; 206.90 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 48 h. The reaction mixture was concentrated under vacuum to give the title compound as a yellow oil. Diisopropyl ether (50 mL) was added. The resulting mixture was sonicated and concentrated under vacuum. This process was repeated 3 times, affording Intermediate 35 as a yellowish solid (13.2 g; quantitative). 1H NMR: (DMSO-d6, 400 MHz) δ 9.51 (br s, 1H), 7.43-7.34 (m, 2H), 7.09-7.06 (d, J=8.17 Hz, 1H), 5.71 (br s, 2H), 3.56 (s, 2H), 2.79-2.64 (m, 6H), 2.47-2.42 (t, J=6.93 Hz, 2H), 1.39 (s, 9H), traces of EtOH by NMR. HPLC/MS: 320.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:23])=[C:20]([F:30])[C:19]([F:31])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[C:20]([F:30])[C:21]=2[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)c(F)c1C(=O)c1cccnc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared by the reaction of 4-t-butylbenzenesulfonyl chloride with (6-Amino-2,3-difluoro-phenyl)-pyridin-3-yl-methanone following the general procedure. MS: m/z 431.1 (M++1).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:18])[NH:12][C@H:13]([CH3:17])[C:14](O)=[O:15])[S:2]1.[S:19]([NH2:23])([NH2:22])(=[O:21])=[O:20].[H-].[Na+]>CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:18])[NH:12][C@H:13]([CH3:17])[C:14]([NH:22][S:19]([NH2:23])(=[O:21])=[O:20])=[O:15])[S:2]1
Reactant: NS(N)(=O)=O
Reactant: C[C@@H](NC(=O)NCCCCC1CCSS1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)NCCCCC1CCSS1)C(=O)NS(N)(=O)=O
Yield: 42.8 %

Procedure:
The reaction was carried out as described in Example 73, but using 0.21 g of 2(R)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionic acid (prepared as described in Example 71), 5 ml of anhydrous dimethylformamide, 0.13 g of N,N'-carbonyldiimidazole, 0.15 g of sulfamide and 0.04 g of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 114 mg of the title compound as a pale yellow powder, melting at 156 to 157° C.
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][C:15]#[N:16].NC(=N)O>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)Cl>[C:6]([O:12][C:11](=[O:13])[C:9]1[CH:8]=[CH:7][C:6]([CH2:14][C:15]#[N:16])=[C:5]([Cl:4])[CH:10]=1)([CH3:14])([CH3:7])[CH3:5]
Reactant: N#CCc1ccc(C(=O)O)cc1Cl
Agent: N=C(N)O
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CC#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
The foregoing compound was dissolved in DMF (3 mL) and cooled to 0° C. NaCN (2 equ) dissolved in 1 mL of water and 2 mL of DMF were added to the solution and the reaction mixture was stirred for 0.5 h. After diluting the mixture with ethyl acetate it was washed with aqueous ammonium sulfate and brine, dried (Na2SO4), filtered and evaporated to give a yellow solid which was directly used in the esterification step. 2-(2-Chloro-4-carboxyphenyl)-acetonitrile (0.391 g, 2 mmol) was treated with 2 equiv of isourea 4 in 35 mL of DCM at reflux over night. After evaporation of DCM, the crude was diluted in EtOAc (50 mL) and filtered. The filtrate was concentrated and purified by flash chromatography in silica gel eluting with 1% EtOAc in petroleum ether to give tert-Butyl-4-(cyanomethyl)-3-chlorobenzoate (0.24 g, 47% yield). 1H NMR (CDCl3, 400 MHz) δ 8.03 (d, J=1.6 Hz, 1 H), 7.93 (dd, J=8.02 Hz, J=1.62 Hz, 1 H), 7.60 (d, J=8.02 Hz, 1 H), 3.89 (s, 2 H), 1.61 (s, 9 H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[C:2]=[S:3].[NH2:11][C@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:30][CH:29]([CH3:31])[C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C@@H:12]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:11][C:2]([NH:1][C:4]3[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[S:3])[CH2:20][CH2:19]2)[CH:22]=1)=[O:32]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: Cc1ccccc1N=C=S
Product: Cc1ccccc1NC(=S)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isothiocyanato-2-methylbenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 529.1 (M+H)+.