Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN[C:3](NN)=O.ClC1C=[C:15]2[C:11]([C:12](=[O:18])[C:13](=O)[NH:14]2)=[CH:10][C:9]=1I>>[CH3:3][N:14]1[CH2:15][CH2:11][CH2:10][CH2:9][C@H:13]1[CH2:12][OH:18]
Reactant: NNC(=O)NN
Reactant: O=C1Nc2cc(Cl)c(I)cc2C1=O
Product: CN1CCCC[C@H]1CO

Procedure:
Compound (S)-(−)-6 was prepared from carbazide (S)-d and aldehyde C (prepared from 6-chloro-5-iodo-isatin by Method I and Method A) by the procedure described in Example 5. 1H NMR (DMSO-d6) δ 1.10-1.30 (m, 2H), 1.49 (m, 3H), 1.64 (m, 1H), 2.09 (t, 1H), 2.38 (s, 1H), 2.41 (s, 3H), 2.83 (d, 1H), 3.00 (dd, 2H), 3.23 (dd, 2H), 4.13 (s, 3H), 4.18 (q, 1H), 4.31 (q, 1H), 6.90 (s, 1H), 7.30 (s, 1H), 7.85 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.41 (s, 1H), 8.45 (s, 1H). ESI-MS m/z 493.2 (100, M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:32][OH:33]>>[OH:33][NH:32][C:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[NH:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21])=[O:31]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 69 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 220.3 mg (0.5 mmol) of cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid with hydroxylamine provided 156.1 mg of cis-N-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide in 69% yield. MS: 456.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][C@H:28]([CH2:33][OH:34])[CH2:29][CH2:30][S:31][CH3:32]>>[OH:34][CH2:33][CH:28]([NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26])[CH2:29][CH2:30][S:31][CH3:32]
Reactant: CSCC[C@H](N)CO
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CSCCC(CO)NC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and L-(−)-methioninol in a manner similar to that described in Example 11.
Reaction SMILES: C(OC(=O)C[N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH:11]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)(C)(C)C.[C:30]([OH:36])([C:32](F)(F)F)=[O:31]>C(Cl)Cl>[C:30]([O:36][N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH:11]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)(=[O:31])[CH3:32]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)CC1c2ccccc2C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Product: COC(=O)CC1c2ccccc2C(=O)N(OC(C)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl [5-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate 2 (30.5 g, 77.5 mmol) was taken up in 100 ml of CH2Cl2 and, at 0° C., 150 ml of TFA were added, and the mixture was stirred at 0° C. for about 1 h and then at RT. After the reaction was complete, the mixture was evaporated, and mixed with toluene 2× and again evaporated. 33.6 g of a yellowish oil were obtained as crude product; crystallization from acetone afforded 14.8 g of white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:17][CH2:16][CH2:15][Br:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: BrCCCBr
Reactant: Oc1ccc(Cn2cccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCOc1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a mixture of 4-(1-pyrazolyl)methylphenol (5 g), 1,3-dibromopropane (11.59 g) and water (50 ml) was added dropwise an aqueous solution of sodium hydroxide (1.38 g) dissolved in water (10 ml) while stirring under heating at reflux over 30 minutes. The reaction mixture was then heated at reflux under stirring for further 1 hour, and then cooled to room temperature, which was extracted with diethyl ether (300 ml). The organic layer was washed with 5N aqueous sodium hydroxide solution and then water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 3-[4-(1-pyrazolyl)methylphenoxy]propyl bromide (4.76 g) as white crystals. Yield, 56%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]([CH2:15][CH2:16]O)[CH2:12][CH2:13]O>>[F:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:16][CH2:15][NH:11][CH2:12][CH2:13][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: OCCNCCO
Product: Fc1cccc(B2OCCNCCO2)c1
Yield: 79 %

Procedure:
The title compound (79%, crystals) was prepared from 3-fluorophenylboronic acid and diethanolamin.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(B([CH2:12][CH3:13])CC)C.[Br:14][C:15]1[C:16](I)=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[C:16]([CH2:12][CH3:13])=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:18]2=[N:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(Br)cnc32)cc1
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(Br)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (26 mg), potassium carbonate (130 mg) and triethylborane (1 M solution in hexane) (0.75 ml) were added to a solution of the compound obtained in Step 1 of Example 122 (300 mg) in N,N-dimethylformamide (12 ml). The mixture was stirred under nitrogen atmosphere at 80° C. for 24 hours. The reaction solution was cooled to room temperature and then separated by adding ethyl acetate and distilled water. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (147 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2C3C(=CC=C(I)C=3)N=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]12[CH2:35][O:34][C:31]([C:36]3[O:40][C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][CH:37]=3)([O:32][CH2:33]1)[O:30][CH2:29]2>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:13]3[C:12](=[CH:11][CH:10]=[C:9]([C:39]4[O:40][C:36]([C:31]56[O:30][CH2:29][C:28]([CH3:27])([CH2:33][O:32]5)[CH2:35][O:34]6)=[CH:37][CH:38]=4)[CH:14]=3)[N:15]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C23OCC(C)(CO2)CO3)o1
Reactant: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC12COC(c3ccc(-c4ccc5nc(Nc6ccc(OCc7ccccc7)cc6)ncc5c4)o3)(OC1)OC2
Yield: 131.4 %

Procedure:
(4-Benzyloxy-phenyl)-(6-iodoquinazolin-4-yl)-amine (0.925 g, 2.04 mmol), 5-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-2-[tri(n-butyl)stannyl]furan (2.00 g, 4.1 mmol) and bis(triphenylphosphine)palladium (II) chloride (catalytic) were reacted in dry dioxane (25 ml) according to Procedure B. Purification by silica gel chromatography and eluting with 100% EtOAc gave the title compound as a yellow solid (0.700 g, 1.34mmol, 66%); δH [2H6]DMSO 10.0 (1H,s), 8.75 (1H,s), 8.48 (1H,s), 8.12 (1H,d), 7.79 (1H,d), 7.66 (2H,d), 7.30-7.52 (5H,m), 7.03-7.12 (3H,m), 6.64 (1H,d), 5.14 (2H,s), 4.06 (6H,s), 0.85 (3H,s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]([C:15]#[N:16])=[CH:9][C:8]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1>C1COCC1>[CH3:1][S:2]([O:14][CH2:13][C:12]1[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[C:8]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH:25]3[CH2:27][CH2:26]3)[C:21]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]3[N:19]=2)[C:7]=1[Cl:6])(=[O:4])=[O:3]
Reactant: N#Cc1cc(CO)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 0 °C
Yield: 89.3 %

Procedure:
Added methanesulfonyl chloride (0.153 ml, 1.97 mmol) to an ice-cooled solution of 2-((2-chloro-5-cyano-3-(hydroxymethyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (300 mg, 0.788 mmol) in THF (20 ml). The bath was removed and after 15 min, water was added and the reaction was extracted with EtOAc. The organic extracts were washed with brine and dried with sodium sulfate. The solvent was removed to leave crude 2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl methanesulfonate (323 mg) as a tan solid
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.[NH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:18][CH2:19][CH2:20][CH2:21][S:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: NCCCSc1ccncc1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)s1
Yield: 64.5 %

Procedure:
To a solution of 1.27 g (8.91 mmol) of 5-methyl-2-thiophenecarboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of t-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.68 g of the desired compound (yield: 64.5%, colorless powder).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[CH:7].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CCOCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOCCO)c21

Procedure:
Using Method C above, 3-(2-hydroxyethoxy)-1-propyne (53 mg, 0.53 mmol) (from Example 21 above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-[3-(2-hydroxyethoxy)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: [N:1]([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1N1C=CC(=O)NC1=O)=[N+:2]=[N-:3].C(=[O:27])C1C=CC=CC=1>O.NN.O>[N:1]([C@H:4]([C@@H:8]([C@@H:7]([CH2:10][OH:11])[OH:6])[OH:9])[CH:5]=[O:27])=[N+:2]=[N-:3]
Reactant: O=Cc1ccccc1
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: NN
Solvent: O
Product: [N-]=[N+]=N[C@@H](C=O)[C@H](O)[C@H](O)CO
Temperature: 110 °C
Yield: 64 %

Procedure:
2.54 g of 2'-azido-2'-deoxyuridine was dissolved in 250 ml of a 15% hydrazine hydrate solution and heated in an oil bath while stirring for a period of one hour to 65° C. Upon expiration of this time, the thin-layer chromatogram of the solvent System A indicated the total disappearance of the starting material. The solution was evaporated in a vacuum and yielded an orange-colored resin which was dissolved in 100 ml of water. 10 ml of benzaldehyde was added and the mixture heated during constant stirring for a period of 8 minutes in a boiling water bath. The solution was then rapidly cooled to below room temperature and a glutinous precipitate was filtered off, consisting mainly of benzaldehydeazine. The filtrate was then extracted with three times 100 ml of ether. The aqueous solution was evaporated and the residue was dissolved in a minimal amount of methanol. The solution was then applied to a silica gel column (2.3 × 32 cm) prepared with chloroform. The column was eluted with 100 ml fractions of chloroform (200 ml), 700 ml of a 5% solution of methanol in chloroform and with 600 ml of a 10% solution of methanol in chloroform. The desired product was found in the fractions 9 to 13 and was identified by examining each fraction by means of thin-layer chromatography, by the solvent System A, and sprayed on plates with a solution of aniline phosphate (17 ml of n-butanol, 6 ml of water, 0.36 ml of aniline and 0.28 ml of 85% phosphoric acid), and, finally, heated for a period of ten minutes in a drier at 110° C. The 2-azido-2-deoxyribose emerged as a reddish-brown stain with an Rf value of 0.5. The fractions containing the product were combined and evaporated to a colorless resin (1.053 g, yield = 64%), which did not crystallize.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10]N1C(=O)CCC1=O>>[Br:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2[nH]ccc2c1
Product: Brc1c[nH]c2ccccc12

Procedure:
In step 3 indole compound k undergoes bromination by treatment with N-bromosuccinimide or other bromime source (not shown) to yield 3-bromo indole compound l. Bromoindole l is then subject to oxidation in step 4 to provide dihydroindolone compound m. Compound m is a compound of formula I in accordance with the invention.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7](O)[C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([Cl:15])[CH:14]=1)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([Cl:15])[CH:14]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-7-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, 113.2 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-7-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (15 g, 32.6%) as a white solid: LC/MS m/e calcd for C19H19BrClNO2 (M+H)+: 409.73, observed: 407.9 & 409.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>CCO>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH:1][C:2]2[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOC(=O)c1cc(CC)sc1N
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and 5-bromo-2-fluoronitrobenzene, m.p. 76°-78° C. EtOH).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13](Cl)[N:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH2:17]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([NH:17][CH3:16])[N:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)nc(C(C)(C)C)c1
Reactant: CN
Product: CNc1cc(C(=O)O)cc(C(C)(C)C)n1
Temperature: 130 °C

Procedure:
1.0 g (4.39 mmol) of methyl 2-tert-butyl-6-chloroisonicotinate [lit.: O. Isler et al., Helvetica Chimica Acta 1955, 38 (4), 1033-1046] and 3.8 ml (43.9 mmol) of a 40% strength aqueous methylamine solution were heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 160° C. for 6 h. After cooling, the volatile components were removed on a rotary evaporator. The residue was taken up in 4 ml of semiconcentrated hydrochloric acid and once more heated in the microwave at 130° C. for 1 h. The product was then isolated directly by preparative HPLC (Method 12). Evaporation of the product fractions and drying of the residue under high vacuum gave 180 mg (92% pure, 18% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31].O[Li].O>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH:29]([CH3:35])[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)C(C)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C(=O)O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (±)-ethyl 2-(7-bromo-1′-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate (63 mg, 0.122 mmol) in anhydrous MeOH (1 mL) was added LiOH.H2O (10 mg, 0.244 mmol) in H2O (0.1 mL). The reaction mixture was stirred at rt overnight. The mixture was concentrated to give crude product, which was purified by preparative TLC to afford 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoic acid. 1H NMR: (400 MHz, CDCl3): δ=1.04 (s, 3H), 1.21 (s, 3H), 1.34-1.43 (m, 2H), 1.60-1.71 (m, 3H), 1.76-2.08 (m, 13H), 2.29-2.40 (m, 1H), 2.51-2.61 (m, 1H), 2.99-3.27 (m, 3H), 3.89 (m, 2H), 4.02-4.14 (m, 2H), 7.01 (m, 1H), 7.21-7.33 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:29]2N=CC=C[C:28]=2N=N1.Cl.N=C=N.C(O)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([O:18][CH2:28][CH3:29])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(C)C(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: On1nnc2cccnc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=N
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc(NC(=O)OC(C)(C)C)cc1)N(C)C(C)C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 25 (1.50 g, 4.66 mmol), THF (45 mL), 1-hydroxy-7-azabenzotriazole (1.27 g, 9.32 mmol) and 1-ethyl-3-[3-dimethyl amino)propyl]-carbodiimide hydrochloride (1.79 g, 9.32 mmol), and the reaction mixture was stirred for 15 min. Ethanol (429 mg, 9.32 mmol) and 4-dimethylamino pyridine (57 mg, 0.47 mmol) were added, and the reaction mixture was stirred at room temperature for a further 16 h. After this time, the reaction was partitioned between water (40 mL) and methylene chloride (50 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×30 mL). The organic extracts were combined and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was dried to a constant weight under vacuum to afford 26 in 73% yield (1.20 g) as a white solid: mp 87-88° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.40 (d, 2H, J=7.5 Hz), 7.28 (d, 2H, J=7.5 Hz), 4.16 (s, 1H), 4.05 (m, 2H), 2.80 (septet, 1H, J=6.5 Hz), 2.02 (s, 3H), 1.47 (s, 9H), 1.11 (t, 3H, J=7.0 Hz), 0.94 (d, 3H, J=6.5 Hz), 0.88 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 351 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([NH2:31])([CH3:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([NH:31][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])([CH3:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(N)CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(Nc2ccccc2[N+](=O)[O-])CCN(Cc2ccccc2)CC1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
3.6 g 1-fluor-2-nitrobenzene and 82.7 g potassiumcarbonate were added to 5.3 g 1-benzyl-4-methyl-piperidin-4-ylamine in 50 mL DMSO and the mixture was stirred at 150° C. 24 h. The reaction was diluted with water and the aqueous layer was extracted with ethylacetate. The organic layer was evaporated and the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1) to give 5.9 g of the desired product.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:22].C(N(CC)CC)C.[C:30]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])([CH3:32])[CH3:31]>CN(C1C=CN=CC=1)C.ClCCl>[Si:34]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[S:7]2)[C@@H:3]([OH:22])[C@@H:2]1[OH:1])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
To a mixture of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate (30 g, 90 mmol), DMAP (550 mg, 4.5 mmol) and triethylamine (18.2 g, 180 mmol) in dichloromethane (200 mL) was added tert-butylchlorodimethylsilane (16.3 g, 108 mmol) at 0° C. The resulting solution was stirred for 4 h at room temperature, and then concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 1% methanol in dichloromethane to give compound 26 as a white solid (20 g, 50%). (ES, m/z): [M+H]+ 449.0; 1H NMR (300 MHz, CDCl3) δ 6.10-6.12 (d, J=6.9 Hz, 1H), 4.15-4.24 (m, 2H), 3.83-3.97 (m, 5H), 3.60 (m, 1H), 2.58-2.66 (m, 2H), 1.55 (s, 9H), 1.18 (m, 3H), 0.91 (s, 9H), 0.09 (s,