Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28]>ClCCl>[CH3:16][NH:15][C:13](=[O:14])[C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:27](=[O:28])[C:26]([Cl:31])([Cl:30])[Cl:25])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)C(Cl)(Cl)Cl)cc2)ccn1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
The clear solution of 4-(4-aminophenoxy)-N-methylpicolinamide (100 g, 0.411 mol) in dichloromethane (100 ml) was cooled to 0° C. to −5° C. and pyridine (83 ml, 1.02 mol) was added in one lot to the reaction mass. It was then agitated at same temperature for 15 minutes and a solution of trichloroacetyl chloride (60 ml, 0.535 mol) in dichloromethane (500 ml) was added dropwise maintaining temperature of the reaction mass below 0° C. The reaction mass was then stirred for 2-3 hours below 0° C. and quenched with water (500 ml) below 5° C. The organic phase was then separated and aqueous layer was reextracted with dichloromethane. The combined dichloromethane layer was washed with water, dried over sodium sulfate and evaporated under vacuum to obtain (72 g) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([Li])[CH2:21][CH2:22][CH3:23]>O1CCCC1.CCCCCC>[CH3:11][C:7]([N:5]1[CH2:6][C:2]([CH3:1])=[C:3]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4]1=[O:13])([CH3:12])[C:8](=[O:10])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: [Li]CCCC
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)C1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(=O)C(C)(C)N1CC(C)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
5 g (19.3 mmol) of 2-(4-methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl)isobutyric acid was dissolved in 50 ml of tetrahydrofuran, and a solution of 41 g (97 mmol) of 15% n-butyl lithium in n-hexane was dropwise added at 0° C. under a nitrogen stream. After completion of the dropwise addition, the mixture was stirred at room temperature for one day. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was treated by a conventional method, and the crude product thereby obtained was purified by column chromatography to obtain 2.7 g (yield: 47%) of the desired product having a melting point of from 87° to 89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH:41]([CH3:43])[CH3:42])[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:21][C:20]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[O:18])[C:12](OC)=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH:41]([CH3:43])[CH3:42])[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:21][C:20]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[O:18])[CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@H](CCN(Cc1ccc(OC)cc1)C(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(CC[C@@H](CO)NC(=O)c2cc3c(cnn3CC(C)C)cc2Oc2ccc(F)cc2F)C(C)C)cc1
Temperature: 50 °C
Yield: 59 %

Procedure:
(S)-methyl 4-((4-methoxybenzyl)(isopropyl)amino)-2-(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxamido)butanoate (0.035 g, 0.057 mmol) and NaBH4 (0.022 g, 0.57 mmol) were dissolved in THF/MeOH (5 mL, 3:2) and heated to 50° C. for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was chromatographed eluting with 5% MeOH in dichloromethane with 1% triethylamine to provide 0.020 g of gel (59% yield).
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:9][C:10]1([CH3:26])[S:14][C:13]2[C:15]([CH2:24][OH:25])=[C:16]3[S:20][C:19]([CH3:22])([CH3:21])[S:18][C:17]3=[CH:23][C:12]=2[S:11]1.C([Li])CCC.CCCCCC.[CH3:38][Si:39]([CH3:42])([CH3:41])Cl>C(OCC)C>[CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:38][Si:39]([CH3:42])([CH3:41])[C:23]1[C:12]2[S:11][C:10]([CH3:26])([CH3:9])[S:14][C:13]=2[C:15]([CH2:24][OH:25])=[C:16]2[C:17]=1[S:18][C:19]([CH3:21])([CH3:22])[S:20]2
Reactant: C[Si](C)(C)Cl
Reactant: CC1(C)Sc2cc3c(c(CO)c2S1)SC(C)(C)S3
Agent: NC(CO)(CO)CO
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)Sc2c(CO)c3c(c([Si](C)(C)C)c2S1)SC(C)(C)S3
Temperature: 0 °C
Reaction time: 3 h
Yield: 138.5 %

Procedure:
Compound 1d (0.15 g, 0.17 mmol) was dissolved in dry diethyl ether (5 mL) and tetrametyhlethylendiamine (0.26 mL, 1.69 mmol) was added under argon atmosphere. The mixture was cooled at 0° C., n-butyl lithium 2.5 M in hexane (0.68 mL, 1.69 mmol) was added drop wise over 10 min and the mixture was left to reach RT. After stirring for 3 h at RT, the resulting brown solution was added drop wise at 0° C. to a solution of trimethylchlorosilane (0.65 mL, 5.08 mmol) in diethyl ether (2 mL). The solution was stirred at RT for 4 h and the formation of a white solid was observed. The solid was filtered off, washed with diethyl ether and the organic solution was concentrated under vacuum. The crude product was purified by gravimetric chromatography on silica gel eluting with 15:1 hexanes-ethyl acetate to afford the title compound as an orange powder (0.12 g).
Reaction SMILES: IC.[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1OCc2c(O)cccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1COC2=O
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Iodomethane (1.313 mL, 20.78 mmol) was added to 4-hydroxyisobenzofuran-1(3H)-one (3.12 g, 20.78 mmol) and potassium carbonate (5.74 g, 41.56 mmol) in DMF (50 mL) at 21° C. under air. The resulting solution was stirred overnight. The solvent was removed to give a yellow solid which was then quenched with potassium carbonate (70 ml). The mixture was extracted ethyl acetate (3×75 ml). The combined extracts were evaporated to give the desired material as a yellow solid (3.18 g, 93% yield), which was used without further purification; 1H NMR (400.132 MHz, CDCl3) δ 3.30 (2H, s), 5.37 (2H, s), 7.31-7.42 (2H, m), 7.51-7.61 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: CCCc1ccc2c(Nc3cc(OCc4cccc(F)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (85 mg, 0.41 mmol) was reacted with 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (141 mg, 0.41 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (95 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.36 Hz, 3H) 1.85 (sext, J=7.72 Hz, 2H) 3.00 (dd, J=7.36 Hz, 2H) 5.16 (s, 2H) 6.27 (d, J=7.35 Hz, 1H) 6.66 (d, J=8.83 Hz, 2H) 7.09-7.34 (m, 7H) 7.43 (m, J=6.25 Hz, 1H) 7.83 (d, J=8.83 Hz, 1H) 8.40 (d, J=6.99 Hz, 1H) 9.03 (d, J=8.83 Hz, 1H) 9.80 (s, 1H) 11.04 (br s, 1H) 14.45 (br s, 1H); MS (ESI+) m/z, 512 (M+H−TFA)+; (ESI−) m/z, 510 (M−H−TFA)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[C:20]([F:31])=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[C:26]([O:29][CH3:30])[CH:25]=[CH:24]2>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=3)[N:22]=[CH:21][C:20]=2[F:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Product: COc1ccc2ncc(F)c(N3CCCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
According to procedure F and starting from [1,4]diazepane-1-carboxylic acid benzyl ester (commercial) and 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine, the title compound was isolated as a brown oil (1.62 g, 51%).
Reaction SMILES: [OH:1][CH:2](CC#N)[CH2:3][C:4]#[N:5].CC[O:11][C:12]([CH3:14])=[O:13].Cl>N#N>[OH:1][C@H:2]([CH2:3][C:4]#[N:5])[CH2:14][C:12]([OH:11])=[O:13]
Reactant: CCOC(C)=O
Reactant: N#CCC(O)CC#N
Agent: Cl
Agent: N#N
Product: N#CC[C@@H](O)CC(=O)O
Reaction time: 22 h

Procedure:
3-hydroxyglutaronitrile (1 g, 9 mmol) was suspended in 37.5 mL of N2 (g) sparged, room temperature, 100 mM sodium phosphate buffer at pH 7. To this 240 mM solution of HGN was added 150 mg of cell lysate normalized for protein content. As assessed by PAGE, the nitrilase content was established to be 20% of the total protein. Therefore effectively, 30 mg of nitrilase is used in this reaction. The reaction was agitated at 100 rpm. Reaction progress was monitored by TLC (1:1 EtOAc:Hexanes, Rf=0.32, nitrile; Rf=0.0, acid) and GC. After 22 h, the reaction was filtered through a 10,000 MW cutoff filter and then concentrated in vacuo. The concentrated hydrolysis solution was acidified with 1M HCl and the product was continuously extracted with MTBE (30 mL). The acid product (R)-3-hydroxy-4-cyanobutyric acid was isolated as a yellow oil (1.15 g, 98% yield). 1H NMR (d6-DMSO, 500 MHz) δ12.32 (s, 1H), 5.52 (s, 1H), 4.10 (m, 1H), 2.70 (dd, 1H, J=16.8, 4.1 Hz), 2.61 (dd, 1H, J=16.9, 6.3 Hz), 2.44 (dd, 1H, J=15.4, 5.3 Hz), 2.37 (dd, 1H, J=15.6, 7.8 Hz). 13C NMR (DMSO, 298K, 125 MHz) δ171.9, 118.7, 63.4, 41.2, 25.2 MS calc'd for [C5H7NO3]: 129.0, found: 130.0 [M+H+], (ESI+). ee=95% [HPLC]. Based on the isolated yield a productivity of 40 g g−1 d−1 is calculated.
Reaction SMILES: C=CCCC(O)=O.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:15]([NH2:19])[C:16](=[CH2:18])[CH3:17]>>[C:8]1(=[N:19][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=C(C)CN
Reactant: O=C1CCCCC1
Agent: C=CCCC(=O)O
Product: CC(C)=CN=C1CCCCC1

Procedure:
The procedure described in Example 1(a) is repeated, except that 302.5 g (2 mols) of N-cyclohexylidene-(2-methylpropenylamine) and 250 g (4.62 mols) of 1,3-butadiene are used. Distillation yields 382 g (1.48 mols) of 3,3-dimethyl-12,12-pentamethylene-1-aza-1,5,9-cyclododecatriene; boiling point 96° C./4 Pa; nD20 =1.5116. The N-cyclohexylidene-(2-methylpropenylamine) was prepared from cyclohexanone and methallylamine, with subsequent isomerisation of the reaction product with potassium tert.-butylate; boiling point 96° C./1,700 Pa; nD20 =1.5160.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.Br[C:25]1[CH:30]=[N:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:35][O:34][CH2:33][CH2:32][O:31][C:28]1[N:29]=[CH:30][C:25]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[N:26][CH:27]=1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COCCOc1cnc(Br)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
A mixture of 5-3 (0.50 g, 1.54 mmol), 2-bromo-5-(2-methoxyethoxy)pyrazine (22-2, 0.540 g, 2.32 mmol), copper iodide (15.0 mg, 0.080 mmol), and potassium carbonate (0.64 g, 4.63 mmol) in 3.1 mL of DMF was heated at 100° C. for 6.0 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (EtOAc:hexanes=5:1 as eluant) to give N-(4-(4-{(5-(2-methoxyethoxy)pyrazin-2-yl)oxy}-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (22, 0.19 g) as brown solids: 1H NMR (500 MHz, CDCl3) δ 8.77 (d, J=4.5 Hz, 2 H), 7.91 (d, J=1.0 Hz, 1 H), 7.88 (d, J=1.0 Hz, 1 H), 7.73 (d, J=5.5 Hz, 2 H), 6.79 (s, 1 H), 6.63 (s, 2 H), 4.46 (t, J=4.5 Hz, 2 H), 3.75 (t, J=4.5 Hz, 2 H), 3.43 (s, 3 H), 1.98 (s, 6 H). ESI-MS: m/z 478.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][N:23]3[C@H:28]4[CH2:29][CH2:30][C@@H:24]3[CH2:25][CH:26]([N:31]3[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=[C:32]3[CH3:40])[CH2:27]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:41][CH:42]([Cl:46])[C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>>[Cl:41][CH:42]([Cl:46])[C:43]([NH:20][C@H:16]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:21][CH2:22][N:23]2[C@H:24]3[CH2:30][CH2:29][C@@H:28]2[CH2:27][CH:26]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:25]3)[CH2:9][CH2:10]1)=[O:15])[CH:17]([CH3:18])[CH3:19])=[O:44]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)C(Cl)Cl)C(C)C)CC1

Procedure:
2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}carbamate (0.614 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S) 3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide (0.031 g, 53%) as an oil. ES-LCMS m/z 656 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][CH2:28][CH2:27][C:26]=2[CH:30]=1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:35]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:29][CH2:28][CH2:27][C:26]=4[CH:30]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 16 h
Yield: 100 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 5e (6.3 g, 14.44 mmol) was dissolved in 60 mL pyridine, followed by addition of 4-dimethylamino pyridine (353 mg, 2.89 mmol) and tert-butyl-dimethyl-chloro-silane (2.61 g, 17.32 mmol) in turn. The reaction mixture was stirred for 16 hours and concentrated under reduced pressure. The resulting residue was dissolved in 200 mL ethyl acetate and partitioned. The organic extract was washed with water (50 mL) and saturated sodium chloride solution (50 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 5f (7.96 g, pale yellow solid), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24].O>CN(C)C=O>[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)#[N:24]
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Reactant: N#CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-n2ccnc2)n(CCCCC#N)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(1-imidazolyl)-indole (2.0 g) in 12 ml of dimethylformamide is added to a suspension of 0.6 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of dimethylformamide at 0°. The mixture is stirred at 0° for 0.5 hour and is treated with a solution of 1.8 g of 5-bromovaleronitrile in 4 ml of dimethylformamide. This mixture is stirred at room temperature overnight and is poured into 125 ml of water. This is extracted with 2×50 ml of ethyl acetate, the extract is washed with water and dried over magnesium sulfate to give 1-(4-cyanobutyl)-3-methyl-2-(1-imidazolyl)-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:27][O:19][C:18](=[O:20])[CH:17]([C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (250 mg, 0.67 mmol; example 5.1) in dry DCM (7 mL) was added oxalyl chloride (0.14 ml, 1.67 mmol) drop wise at 0° C. followed by 1 drop DMF and the reaction mixture was stirred at that temperature for 30 min. Ice-bath was removed and stirring was continued for 3.5 h at room temperature. DCM and excess oxalyl chloride was then removed under reduced pressure and MeOH (2 ml) was then added to it at 0° C. After being stirring the reaction mixture at rt for 1 h, TLC shows formation of a new spot. MeOH was removed under vacuo and crude material was passed through a bed of silica gel (SiO2, 100-200 mesh, EtOAc:hexane 30:70) to give the title compound as colorless liquid (250 mg, 95.5%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:18]([CH3:19])[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=[C:5]2[N:4]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:19][N:18]1[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:2][O:1][C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1
Reactant: Cn1c(CO)nc2ccc(Sc3ccccc3)nc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Sc3ccccc3)nc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.70.g of 2-hydroxymethyl-3-methyl-5-phenylthio-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 90), 1.20 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.64 ml of tributylphosphine, 0.65 g of 1,1'-(azodicarbonyl)dipiperidine and 25 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.61 g of the title compound, melting at 90°-95° C. (softening).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2].Br[N:14]1[C:18](=O)[CH2:17][CH2:16][C:15]1=O.N1CCCC1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCNC1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc([N+](=O)[O-])ccc1CN1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 4-nitro-2-methoxytoluene (5 g, 30 mmol), N-bromosuccinimide (5.3 g, 30 mmol), azobisisobutyronitrile (AIBN, 10 mg) and CCl4 was refluxed for 60 h. The reaction mixture was cooled to 0° C., filtered through diatomaceous earth and concentrated under vacuum. The resulting oil was redissolved in THF (50 mL) and added portionwise to a cold (0° C.) stirred solution of pyrrolidine (10.65 g, 150 mmol). Afterwards, the cooling bath was removed and the reaction was stirred at ambient temperature for 1 h. It was then concentrated to an oil, diluted with 100 mL saturated aqueous NaHCO3 and 50 mL brine. Following extraction three times with 125 mL EtOAc, the combined organic layer was dried over MgSO4 and concentrated to 6.5 g of an oil. Purification by chromatography (SiO2 ; 30% EtOAc in hexanes) yielded 5.7 g (24 mmol, 80%) of the desired compound as an oil.