Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:8].[Na+].[C:11]([O:14][C@@H:15]1[C@@H:56]([O:57][C:58](=[O:60])[CH3:59])[C@H:55]([O:61][C:62](=[O:64])[CH3:63])[C@@H:54]([C:65]([O:67][CH3:68])=[O:66])[O:53][C@H:16]1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([O:38][C:39](=[O:41])[CH3:40])[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:26](=[O:42])[N:25]2[C:43]2[CH:48]=[CH:47][C:46]([C:49]#[C:50][CH:51]=[O:52])=[CH:45][CH:44]=2)=[CH:20][CH:19]=1)(=[O:13])[CH3:12].CC(=C)C>O1CCOCC1>[C:11]([O:14][C@@H:15]1[C@@H:56]([O:57][C:58](=[O:60])[CH3:59])[C@H:55]([O:61][C:62](=[O:64])[CH3:63])[C@@H:54]([C:65]([O:67][CH3:68])=[O:66])[O:53][C@H:16]1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([O:38][C:39](=[O:41])[CH3:40])[C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:26](=[O:42])[N:25]2[C:43]2[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]([OH:8])=[O:52])=[CH:45][CH:44]=2)=[CH:20][CH:19]=1)(=[O:13])[CH3:12]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC=O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC(=O)O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1.5 h

Procedure:
An aqueous solution (0.1 mL) of sodium dihydrogenphosphate (9.00 mg, 0.065 mmol) and sodium chlorite (5.00 mg, 0.055 mmol) was added to a solution of 10c (37.0 mg, 0.046 mmol) in tert-butyl alchohol (0.4 mL), dioxane (0.2 mL) and isobutylene (˜0.1 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated in vacuo and the crude residue triturated repeatedly with ethyl acetate. The organic washings were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound 10d.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][CH:12]1[NH:16][N:15]=[CH:14][CH2:13]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([N:16]2[CH:12]([CH3:11])[CH2:13][CH:14]=[N:15]2)=[O:9])[CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC1CC=NN1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CC=NN1C(=O)c1cccnc1

Procedure:
Hydrochloride of nicotinic acid chloride (4 g) was suspended in 20 ml of chloroform followed by addition of a mixture of 1.7 g of 5-methyl-2-pyrazoline and 4 g of triethylamine, washing with water and concentration. The product was purified by chromatography on a silica gel column (chloroform/methanol=100/1). Yield; 3.4 g.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=12.C([Li])CCC.[CH2:29]([O:36][C:37]([NH:39][C@@H:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50](Cl)=[O:51])=[CH:47][CH:48]=2)[S:43][CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH2:29]([O:36][C:37]([NH:39][C@@H:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50]([NH:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=34)=[O:51])=[CH:47][CH:48]=2)[S:43][CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(N[C@H]1CCSc2cc(C(=O)Cl)ccc21)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)ccnc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(NC(=O)c3ccc4c(c3)SCC[C@@H]4NC(=O)OCc3ccccc3)ccnc21
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a tetrahydrofuran solution of 4-amino-1-[2-(trimethylsilyl)ethoxymethyl]pyrrolo[2,3-b]pyridine (1.32 g) was added dropwise n-butyllithium (1.59 M, 3.17 ml) and the mixture was stirred at the same temperature for 15 min. To this solution was added dropwise a tetrahydrofuran solution (20 ml) of (S)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid chloride (4.20 mmol) obtained by a similar reaction step as in Starting Material Synthetic Example 9 at 0° C. The reaction mixture was stirred at room temperature for 5 hr. Water (100 ml) was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (hexane-ethyl acetate) to give the objective (S)-4-(benzyloxycarbonylamino)-N-{1-[2-(trimethylsilyl)ethoxymethyl]pyrrolo[2,3-b]pyridin-4-yl}thiochromane-7-carboxamide (1.06 g) as a pale-brown amorphous solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:19]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25]Cl)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25][O:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[CH3:20]
Reactant: CC(C)(C)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CCOC(=O)NCCCl
Product: CCOC(=O)NCCOc1ccc(Oc2ccc(C(C)(C)C)cc2)cc1

Procedure:
2-[p-(p-tert.butylphenoxy)phenoxy]ethylcarbamic acid ethyl ester as a yellow oil (nD20 =1.5436) is prepared from 4-[4-(1,1-dimethylethyl)phenoxy]phenol and (2-chloroethyl)carbamic acid ethyl ester.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43]>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[NH:34]/[C:3](=[N:2]\[OH:1])/[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH:46]([CH3:48])[CH3:47]
Reactant: N=C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)NO
Reactant: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)COC(=O)N/C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)=N\O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-Hydroxy-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamidine (0.13 g, 0.28 mmol, 1.0 equiv) in 2 Ml DMF was added pyridine (0.023 Ml, 0.31 mmol, 1:1 equiv). The solution was cooled to 0° C., then isobutyl chloroformate (0.04 Ml, 0.31 mmol, 1.1 equiv) was added dropwise via syringe. The reaction was allowed to warm to room temperature and stirred for 2 h. Extractive aqueous workup afforded the title compound which was used in the next step without further purification. (M+H)+571.4.
Reaction SMILES: S=[C:2]([CH2:6][CH2:7][CH2:8][C@H:9]1[C@@H:17]2[C@@H:12]([NH:13][C:14]([NH:16]2)=[O:15])[CH2:11][S:10]1)[C:3](=[O:5])[OH:4].BrC(O)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOCCOC>[OH:5][C:3]([CH2:2][CH2:6][CH2:7][CH2:8][C@H:9]1[C@@H:17]2[C@@H:12]([NH:13][C:14]([NH:16]2)=[O:15])[CH2:11][S:10]1)=[O:4]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCC(=S)C(=O)O)N1
Agent: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Yield: 0.1 %

Procedure:
A diglyme solution (3 ml) containing dl-thioxobiotin (255 mg, 0.981 mol) and bromoethanol (140 μl, 1.98 mmol) was allowed to reflux (150°) for 2.5 hours. The solution was cooled, dilute sodium carbonate (50 ml) was added, and the solution was extracted with hexane (50 ml). The pH of the aqueous phase was adjusted to 1.5 with 6N HCL and extracted with ethyl acetate (4×100 ml). The ethyl acetate extract was dried over magnesium sulfate, filtered and concentrated in vacuo to give 148 mg (62%) of crude biotin, mp 220°-223° C. which was recrystallized from water IR (KBr) 3279, 2899, 1724; NMR (d, DMSO) 0.76-1.95 (6H, m, C--CH2), 2.00-2.40 (2H, t, CH2 --CO), 2.70-2.98 (1H, m, CH2S) 3.00-3.54 (2H, m, CH2S, CHS) 4.00-4.44 (2H, m, CHN), 6.44 (1H, bs, NH), 6.55 (1H, bs, NH), 11.8-12.4 (1H, bs, OH). Analysis calculated for C10H16O3N2S: C, 49.18; H, 6.56; N, 11.48; Found: C, 49.30; H, 6.34; N, 11.37. Mass spectrum: calculated: 244.0880, found: 244.0925.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH:20]1(N)[CH2:22][CH2:21]1.O>ClCCCl>[Cl:1][C:2]1[CH:13]=[C:12]([NH:14][CH:20]2[CH2:22][CH2:21]2)[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CC1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Reactant: NC1CC1
Solvent: ClCCCl
Solvent: O
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(NC2CC2)cc1Cl

Procedure:
2.00 g (5.95 mmol) of 2-chloro-N-cyclopropyl-4,5-dinitrobenzamide (see Synthesis Example 4, Stage 1) were initially charged in 150 ml of 1,2-dichloroethane, 0.85 g (14.88 mmol) of cyclopropylamine was added and the mixture was heated under reflux for three hours. After cooling, water was added and the 2-chloro-N-cyclopropyl-4-(cyclopropylamino)-5-nitrobenzamide was filtered off with suction and dried. Yield 1.16 g (66% of theory)
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:25])[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=O.C[NH:28]N.C(O)(=O)C>C(O)C>[CH3:1][N:2]1[CH:3]=[CH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:25])[CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[N:28]1
Reactant: CN(C)/C=C/C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Reactant: CNN
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1ccc(-c2sccc2NC(=O)Cc2cccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of (E)-N-(2-(3-(dimethylamino)acryloyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (Example 7.3.1., 143 mg, 0.39 mmol) in abs. ethanol (2 mL) was added methyl hydrazine (0.2 mL, 3.80 mmol) and acetic acid (0.5 mL, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under N2(g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H2O. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20:80 ethyl acetate/hexane) yielded N-(2-(1-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (27 mgs, 20%). Method [7] m/z 348.0 (M+H); retention time=5.328. 1H-NMR (CDCl3) δ 7.96 (d, J=5.2 Hz, 2H), 7.94-7.91 (m, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.56-7.53 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.36 (d, J=9.1 Hz, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J=1.9 Hz, 1H), 5.17 (d, J=1.9 Hz, 1H), 4.13 (s, 2H), 3.45 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>CC(C)=O.Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)c1ccsc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccsc1
Yield: 73.5 %

Procedure:
Procedure of Example 4B was followed with 3-thiophenesulfonamide (1.1 g, 6.81 mmole), acetone (10 ml), 1N NaOH (6.8 ml), 4-chlorophenyl isocyanate (1.05 g, 6.8 mmole) in acetone (10 ml), 1N HCl (8 ml) to give the N-[[(4-chlorophenyl)amino]carbonyl]-3-thiophenesulfonamide (1.44 g, 4 5 mmole).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@@H:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[C:20]2=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@@H:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=[O:26])[C:20]2=[O:29])=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cccn([C@@H](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)OC(C)(C)C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)n1cccc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-3-[2-tert-Butoxycarbonyl-2-(3-methoxycarbonyl-2-oxo-2H-pyridin-1-yl)-ethyl]-indole-1-carboxylic acid tert-butyl ester (2.3 g, 4.7 mmol) in dioxane (60 ml) was added a lithium hydroxide (115 mg, 4.7 mmol) in water (30 ml). The mixture was stirred overnight at room temperature. The mixture was diluted with water, acidified to pH-3 with 1M HCl and extracted with ethylacetate. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated to afford the crude product as a white solid was used in the next stage without further purification (1.9 g, 85%); 1H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 1.74 (9H, s), 3.50 (2H, m), 5.65 (1H, br s), 6.08 (1H, t), 7.2-7.5 (5H, m), 8.15 (2H, m);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(O[N:48]1[N:56]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O.NN>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([NH:48][NH2:56])=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)NN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid (Example 78) (120 mg, 0.23 mmol), HATU (95 mg, 0.25 mmol) and N,N-diisopropylethylamine (59 mg, 0.46 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of hydrazine monohydrate (0.125 ml, 2.6 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 10˜12% of methanol in chloroform to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(4-hydrazino-4-oxobutyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 60 mg, 49%.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.Cl.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:15])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.0 g (3.22 mmol) Boc-D-Phe(4-NO2)—OH (Iris Biotech) and 0.84 g (3.22 mmol) H-Phe(4-NO2)—OMe.HCl (Aldrich) were suspended in 25 ml of DMF and stirred on the ice bath. After addition of 1.66 g (3.22 mmol) of PyBOP and 1.67 ml (9.66 mmol) of DIPEA (pH 7-8), the mixture was stirred at 0° C. for 2.5 h. The solvent was removed in vacuo and the yellow oil was taken up in 5% KHSO4 soln./EtOAc. The organic phase was washed 3× with 5% KHSO4 soln., 1× with sat. NaCl soln., 3× with sat. NaHCO3 soln. and 3× with sat. NaCl soln. The organic phase was dried with MgSO4, filtered, and the solvent was removed in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Yield: 573.5 %

Procedure:
A mixture of the acid (8.56 g, 33.4 mmole) of Step E and p-toluenesulfonic acid monohydrate (1.05 g, 5.6 mmole) in methanol (70 mL) is refluxed for 2.5 hours (TLC, methanol-toluene 1:9). The methanol is evaporated and the residue is dissolved in ethyl acetate and washed with brine. After drying (MgSO4) the solvent is removed to yield a tan solid (8.68 g, 96.2%, m.p. 111°-113° C.). The crude product is used as such in the next step.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(Cl)Cl>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[N:3]1
Reactant: NCCCCO
Reactant: Clc1noc2ccccc12
Solvent: ClCCl
Product: OCCCCNc1noc2ccccc12
Temperature: 80 °C
Reaction time: 96 h
Yield: 93.3 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (0.08 mol), 4-amino-1-butanol (0.24 mol) and KI (1 g) was stirred for 4 days at 80° C. The reaction mixture was cooled, dissolved in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 15.4 g (93%) of 4-(1,2-benzisoxazol-3-ylamino)-1-butanol (interm. 1). b) Thionyl chloride (0.048 mol) was cooled to 0° C. A solution of intermediate (1) (0.048 mol) in CHCl3 (20 ml) was added dropwise and the reaction mixture was stirred overnight at RT. The solvent was evaporated. The residue was washed with water. The reaction mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 10.4 g of ON—(4-chloro-butyl)-1,2-benzisoxazol-3-amine (interm. 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[C:6]([C:8]([O:13][CH3:14])([CH:10]([OH:12])[CH3:11])[CH3:9])[CH:7]=1.[CH3:27]I>>[CH3:27][O:12][CH:10]([CH3:11])[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=1)([O:13][CH3:14])[CH3:9]
Reactant: CI
Reactant: COC(C)(c1cc(F)cc(OCc2ccc3ccccc3c2)c1)C(C)O
Product: COC(C)C(C)(OC)c1cc(F)cc(OCc2ccc3ccccc3c2)c1
Yield: 60 %

Procedure:
Using the procedure described in Example 8, (2RS,3SR)-2-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-2-methoxybutan-3-ol was reacted with methyl iodide to give (2RS,3SR)-2-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-2-methoxybut-3-yl methyl ether in 60% yield, m.p. 75°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][Br:9])=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br-:9].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: c1ccncc1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(C(=O)C[n+]2ccccc2)cc1
Product: [Br-]
Yield: 97 %

Procedure:
The title compound was prepared similarly to Example 1 from 4-methoxyphenacyl bromide and pyridine in a yield of 97%.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:22])[NH:9][C@@H:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[C:15]=2[F:21])[CH2:11][CH:12]=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C=C.ClC1C(F)=C([C@H](N[S@@](C(C)(C)C)=[O:42])CC=C)C=CN=1.ClC1C(F)=C([C@@H](N[S@@](C(C)(C)C)=O)CC=C)C=CN=1.Cl.O1CCOCC1>C1COCC1.CO>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C@H:10]([NH:9][C:8](=[O:22])[O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH:12]=[O:42])[CH:19]=[CH:18][N:17]=1
Reactant: C=CC[C@@H](NC(=O)Oc1ccccc1)c1ccnc(Cl)c1F
Reactant: C=CC[C@@H](N[S@](=O)C(C)(C)C)c1ccnc(Cl)c1F
Agent: C=CC[C@H](N[S@](=O)C(C)(C)C)c1ccnc(Cl)c1F
Agent: C=CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: O=CC[C@@H](NC(=O)Oc1ccccc1)c1ccnc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
(R)-Phenyl(1-(2-chloro-3-fluoropyridin-4-yl)but-3-en-1-yl)carbamate: To a solution of Intermediate 24A (1.13 g, 4.30 mmol) in THF (50 mL) at was −78° C. was added allylmagnesium bromide (1 M in ether) (8 mL, 8.00 mmol). The reaction was stirred at −78° C. for 0.5 h and warmed up to rt. The mixture was stirred for 1 h at rt and quenched with saturated NH4Cl. The mixture was extracted with EtOAc (3×). The combined organic layer was concentrated to give a 5:1 mixture of (R)-N-((R)-1-(2-chloro-3-fluoropyridin-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide and (R)—N-((5)-1-(2-chloro-3-fluoropyridin-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (1.56 g, 119%) as an orange oil. The oil was taken up with methanol (10.00 mL) and treated with 4 N HCl in dioxane (3 mL, 99 mmol). The reaction was stirred at rt for 1.5 h and then concentrated to give the desired product (0.55 g, 40%) as an orange oil. MS (ESI) m/z: 321.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO.CO.CCOC(C)=O>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccsc1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccsc2)cc([N+](=O)[O-])c1O
Yield: 24.8 %

Procedure:
A mixture of 1-phenyl-2-(thiophen-3-yl)ethanone (Intermediate 2) (100 mg, 0.50 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (100 mg, 0.47 mmol), and urea (90 mg, 1.4 mmol) in anhydrous EtOH (10 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated and purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 5 as a yellow solid (51 mg, yield 24.8%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.73 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.37 (s, 3H), 7.29 (s, 3H), 7.16 (s, 1H), 6.86 (s, 1H), 6.23 (d, J=4.8 Hz, 1H), 5.21 (s, 1H), 4.10 (q, J=7.2 Hz, 2H); 1.37 (t, J=7.2 Hz, 3H); MS (ESI): m/z 438.1 [M+1]+.