Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2].O=S(Cl)Cl.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18](=[O:20])[NH:50][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:38])([F:40])[F:39])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(C(=O)O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)N1c2cc(OC)c(C(=O)NCCN(C)C)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 1.5 h

Procedure:
A mixture of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,6-dicarboxylic acid 1-ethyl ester (Example 60) (75 mg, 1.26 mmol) and 1.5 ml SOCl2 was heated at reflux for 1.5 h. The cooled solution was evaporated to dryness and the residue dried under high vacuum for 30 min. The residue was diluted with 0.75 ml dichloromethane, and triethylamine (0.021 ml) and N,N-dimethyl ethylenediamine (11 mg, 1.26 mmol) were added sequentially. After 1.5 h, the reaction mixture was concentrated and the residue was chromatographed (5% MeOH-dichloromethane) to afford the desired product (72 mg (86%). MS m/z 663 (M++1); 1H NMR (CDCl3) δ 3.75 (s, 3H), 7.22 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:21][NH:22][O:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10]([N:22]([O:23][CH3:24])[CH3:21])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)O)c1cccc(Br)c1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C

Procedure:
In analogy to example 74, step 4, from 3-(3-bromo-phenyl)-3-o-tolyl-propionic acid and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a white solid, mp 89° C., MS (ESI+): m/z=362.07 ([M+H]+, 1 Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Benzyloxy-3-methoxybenzaldehyde (4.85 g) was added to nitric acid (d=1.42, 20 mL) in a dropwise manner over 1 hour at room temperature, and this mixture was stirred for 1 hour. This reaction mixture was poured into ice water and the precipitated solid was collected by filtration. This solid was washed with water, dried under reduced pressure at 50° C. to give 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde (4.99 g). To this product was added acetic acid (50 mL), followed by adding nitromethane (3.19 g) and ammonium acetate (5.36 g), and this mixture was stirred for 5 hours at 100° C. This reaction mixture was concentrated under reduced pressure. To this residue was added water and the precipitated solid was collected by filtration, and this solid was washed with methanol, dried to give 1-benzyloxy-2-methoxy-5-nitro-4-(2-nitrovinyl)benzene (4.03 g). To this compound were added benzene (96 mL), acetic acid (72 mL) and cyclohexane (24 mL), followed by adding silica gel (18 g) and iron powder (10.2 g), and this mixture was stirred at 100° C. for 1 hour. The insoluble material was removed by filtration, and this filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (1.06 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1.O1CCOCC1.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]1
Reactant: Fc1cc(F)c(C2CCC3(CC2)OCCO3)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC(c2cc(F)c(F)cc2F)CC1

Procedure:
8-(2,4,5-Trifluorophenyl)-1,4-dioxaspiro[4.5]decane was added to a solution of 1,4-dioxane (600 mL), water (160 mL) and concentrated sulfuric acid (160 mL) and the resultant mixture was stirred for one h. The solution was then mixed with water (1 L) and extracted with dichloromethane (1 L). The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to yield the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](=[N:14]O)[NH2:13]>C(Cl)Cl.O>[Cl:10][CH2:11][C:12]1[N:14]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][N:13]=1
Reactant: NC(CCl)=NO
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: ClCc1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
Benzoyl chloride (1.60 ml, 13.8 mmol) was added to a suspension of 2-chloro-N′-hydroxyacetimidamide (I44) (1.0 g, 9.21 mmol) in DCM (25 ml), with stirring at room temperature. After 30 minutes, TEA (1.41 ml, 10.1 mmol) was added to the white suspension, and the mixture was stirred for additional 30 minutes. (UPLC-MS complete conversion). The solution was diluted with DCM (20 ml), and water (30 ml) was added. The aqueous phase was extracted three times with DCM (15 ml), and the combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting residue is suspended in toluene (25 ml), and the mixture is heated to reflux for six hours and then at room temperature for two days. The dark solution was evaporated, and the crude product was purified by flash chromatography eluting with petroleum ether/EtOAc=95/5 to obtain 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (803 mg, 44.8% yield) as a off-white solid.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[C:23]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:24]>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])/[C:14]/2=[CH:25]/[C:23]#[N:24])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])/[C:14]/2=[CH:25]\[C:23]#[N:24])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2/C(=C/C#N)C(=O)N2[C@@H](C(=O)O)C1(C)C
Product: C=S1[C@@H]2/C(=C\C#N)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 3.2 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 150 ml of benzene is treated at room temperature with 5 g of cyanomethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (7:3). There are obtained methylene-(2S,5R)-6-[(Z)-cyanomethylene]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as a reddish oil [Rf: 0.38; cyclohexane/ethyl acetate (6:4); NMR (CDCl3) δ (ppm): 1.24 (9H); 1.53 (3H); 1.59 (3H); 4.59 (1H); 5.84 (2H); 5.89 (1H); 5.97 (1H)] and methylene-(2S,5R)-6-[(E)-cyanomethylene]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as a reddish oil [Rf: 0.33; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.24 (9H); 1.51 (3H); 1.6 (3H); 4.64 (1H); 5.59 (1H); 5.84 (3H)].
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.BrCC#C[C@H](OC(=O)C)CCCCC.C([O:32][C@H:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[C:38]#[N:39])(=O)C>>[OH:32][C@H:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[C:38]#[N:39].[OH:32][C@H:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[C:38]([NH2:39])=[O:11]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCCCC[C@H](C#CCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Agent: CCCCC[C@H](C#CCBr)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4(R)-acetoxy-2-nonyne (Example J). The product of Step A is thus ethyl 7-[N-(4(R)-acetoxy-2-nonynyl)cyanamido]-heptanoate. The subsequent steps yield 7-[N-(4-(R)-hydroxy-2-nonynyl)cyanamido]heptanoic acid (B), and 7-[1-(4(R)-hydroxy-2-nonynyl)ureido]heptanoic acid (C). The product of Step C is hydrogenated over a platinum on charcoal catalyst to afford 7-[1-(4(R)-hydroxynonyl)ureido]heptanoic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OC(=O)CCNC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)C>>[C:24]([NH:28][C:29]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10](=[O:23])[NH:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=3)=[CH:12][N:13]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: CC(C)(C)N=C=O
Agent: CCOC(=O)CCNC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)NC(C)(C)C)CC3)nc2)cc1I

Procedure:
4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butylamide was synthesized from N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and tertbutyl isocyanate in a manner similar to the one described in the synthesis of 3-({4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-amino)-propionic acid ethylester above. LCMS calcd for C22H28IN5O2 (m/e) 521, obsd 522 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[C:33]([Cl:38])=[C:32]([Cl:39])[CH:31]=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[CH:31][C:32]([Cl:39])=[C:33]([Cl:38])[C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 24 h
Yield: 68.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 24 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc and yielded 0.16 g of impure product. Then, crystallization from EtOAc/heptane gave 90 mg (37%) of a white solid; mp 208.5-210.0° C.; 1H NMR (300 MHz, DMSO) δ 10.45 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.30 (m, 3H), 7.07 (m, 1H), 5.08 (br s, 2H), 3.63 (m, 4H), 3.40 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 3275, 1693, 1671, 1602, 1554, 1449, 1409, 1365, 1319, 1312, 1302, 1254, 1166, 1113, 762 cm−1; MS (EI) m/z 487 (M+), 346, 345, 105, 94, 92, 76, 65, 62, 56, 52; MS (FAB) m/z 488 (M+H+), 488, 487, 434, 433, 432, 431, 388, 57, 42, 41; HRMS (EI) calcd for C25H27Cl2N3O3 487.1429, found 487.1441; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.41; H, 5.70; N, 8.48.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:15][C:16]1[CH:21]=C(C(C)(C)C)C(O)=[C:18](C(C)(C)C)[CH:17]=1.CC(=C)CCO>O.C1CCCCC1>[CH3:2][C:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH:16]([CH3:21])[CH:17]=[CH:18][O:3]1
Reactant: CC(=O)c1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C(C)CCO
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: O
Product: CC1C=COC(C)(c2ccccc2)C1
Temperature: 94 °C

Procedure:
Into a one-liter three neck flask equipped with stirrer, condenser, Barrett Trap, thermometer, addition funnel and heating mantle is placed 288 gms (2.4 moles) of acetophenone, 150 ml of cyclohexane, 1 g of concentrated sulfuric acid and 1 g of Ionol®. The resulting mixture is heated to reflux temperature (94° C). Then 208 gms (2.4 moles) of 3-methyl-3-buten-1-ol is added, dropwise from the addition funnel, to the reaction mass with stirring while maintaining the reaction mass at reflux. Water of reaction formed is azeotroped over into the Barrett Trap. The reaction mass is heated for a period of 10 hours, during which time 24 ml water collected. At the end of the 10 hour period, the reaction is cooled to room temperature and 2 gms of a 50% sodium hydroxide solution are added. The reaction mass is then rushed over using a 2 inches splash column after adding thereto 10 gms Primol® and 0.1 gms Ionol®. Fractions collected and fractionation data for this rush over is as follows:
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([O:26][SiH](C)C)[C:23](O)=O)(C)(C)C.Cl.C[OH:32]>C1COCC1.O>[C:1]1([CH2:23][C:22](=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: C[SiH](C)OC(CCCCCCCCCCC(C)(C)C)C(=O)O
Reactant: CO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCCCCCCCCO)Cc1ccccc1
Reaction time: 5 h
Yield: 68 %

Procedure:
A phenyllithium solution (10 ml, 27 mmol) was added dropwise over 30 min. to a rapidly stirred solution of 12-tertbutyldimethylsiloxydodecanoic acid (3.16 g, 9.6 mmol) in THF (60 ml) at 0° C. with the formation of a white precipitate. The reaction mixture was then warmed to 23° (precipitate dissolved) and stirred for 5 hours. The reaction mixture was added dropwise in three aliquots to three (0° C.) hydrolyzing solutions prepared from 20 ml 1M HCl, 4 ml CH3OH, and 16 ml H2O. The product was extracted into ethyl acetate (2×100 ml) and washed with saturated aqueous NaHCO3 followed by saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. To the crude silyl phenyl ketone (4.29 g) which was dissolved in THF (10 ml) was added tetrabutylammonium fluoride, (1M in THF, 22 ml). After this solution was stirred for 45 min. it was diluted with ethyl acetate (75 ml) and washed with 1 M HCl (100 ml), saturated aqueous NaHCO3 (100 ml) dried over Na2SO4, filtered, and concentrated in vacuo. This crude product was crystallized from ethyl acetate/hexane to yield 1.89 g of 1-phenyl-12-hydroxydodecanone in 68% yield from hydroxydodecanoic acid: mp 68° C.; 1H NMR (CDCl3) delta 7.95-7.35, (m, 5H), 3.62 (t, 2H), 2.95 (t, 2H), 1.28 (br s, 18H).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:17])=[O:4]>CCOC(C)=O.CCO.[Pd]>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:17])=[O:4].[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH3:17])=[O:4]
Reactant: CNC(=O)n1c(C)cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)N1c2ccc(N)cc2CC1C
Product: CNC(=O)n1c(C)cc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %
Yield: 24 %

Procedure:
To a stirred solution of 2-methyl-5-nitro-indole-1-carboxylic acid methylamide (0.65 g, 2.78 mmol) in 20 mL EtOAc and 4 mL EtOH was added Pd on C (0.3 g, 10% w/w). The mixture was stirred under H2 balloon at room temperature for one hour and filtered through a pad of silica gel. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography eluting with 1-3% MeOH in CH2Cl2 to give 140 mg 5-amino-2-methyl-indole-1-carboxylic acid methylamide (24% yield) together with 150 mg 5-amino-2-methyl-2,3-dihydro-indole-1-carboxylic acid methylamide (26% yield). 1H NMR (300 MHz, CD3OD) δ 7.56 (d, 1H, J=6.2 Hz), 6.65 (s, 1H), 6.58 (d, 1H, J=6.1 Hz), 4.41 (m, 1H), 3.23-3.39 (m, 1H), 2.85 (s, 3H), 2.54 (d, 1H, J=15.5 Hz), 1.20 (d, 3H, J=6 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]1[S:17][C:18]([CH3:26])=[CH:19][C:20]=1/[CH:21]=[CH:22]/[C:23]([Cl:25])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:25].[CH3:15][C:16]1[S:17][C:18]([CH3:26])=[CH:19][C:20]=1/[CH:21]=[CH:22]/[C:23]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: Cc1cc(/C=C/C(=O)Cl)c(C)s1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cc(/C=C/c2nc3ccccc3n2-c2ccccn2)c(C)s1

Procedure:
To a solution of (E)-3-(2,5-dimethylthiophene-3-yl)acrylic acid (328 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-fluorobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-fluorophenyl ketone as a colorless powder. APCI-Mass m/Z 604/606 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.79 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (d, J=3.9 Hz, 2H), 4.27-4.33 (m, 1H), 5.29 (t, J=9.8 Hz, 1H), 5.54 (t, J=9.6 Hz, 1H), 5.72 (t, J=9.4 Hz, 1H), 6.33 (d, J=9.0 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.35-7.42 (m, 3H), 7.80 (d, J=8.3 Hz, 1H), 7.89 (dd, J=8.4, 5.7 Hz, 2H), 8.16 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.[CH3:30][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH3:30])[C:5]1[N:6]=[CH:7][N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (1.01 g, 2.63 mmol) in THF (25 ml) was cooled to -78° C. Lithium hexamethyldisilazide (2.76 ml of a 1M solution in THF, 2.76 mmol) was added dropwise and the reaction stirred 30 min at -78° C. Methyl iodide (0.164 ml, 2.76 mmol) was added and the reaction stirred a furthur 1 hr at -78° C. and then at -20° C. for 4 hrs. The reaction was quenched with water (10 ml) and saturated NaHCO3 solutuon (10 ml) and extracted with EtOAc. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 2 to 3% MeOH in CH2Cl2, gradient elotion) afforded the product.
Reaction SMILES: CC(OC(=O)[N:7]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Br:51])=[CH:47][C:46]=1[F:52])[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:13]=1)(C)C.[ClH:54].O1CCOCC1.CCOCC>C(O)(C)C>[ClH:54].[ClH:54].[ClH:54].[NH2:29][CH2:28][C:24]1[CH:23]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([C:12]3[CH:11]=[N:10][CH:9]=[C:8]([NH:7][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([Br:51])=[CH:47][C:46]=4[F:52])[CH:13]=3)=[O:15])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(N(Cc4ccc(Br)cc4F)C(=O)OC(C)(C)C)c3)CC2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(C)O
Product: NCc1cccc(C2CCN(C(=O)c3cncc(NCc4ccc(Br)cc4F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(4-Bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl ester (0.0806 g, 0.1010 mmol) was treated with 4 M HCl in 1,4-dioxane (2.0 mL, 8.0 mmol) and stirred at ambient temperature. After 25 minutes the reaction mixture was diluted with isopropyl alcohol (0.5 mL) and stirring was continued for an additional 2.5 hours. Dripping the reaction solution into ether (40 mL) with vigorous stirring afforded a white precipitate which was collected by filtration, washed with fresh ether (3.0 mL), and dried to afford 1-[4-(3-aminomethyl-phenyl)-piperidin-1-yl]-1-[5-(4-bromo-2-fluoro-benzylamino)-pyridin-3-yl]-methanone trihydrochloride (0.0563 g): 1H NMR (300 MHz, DMSO-d6) δ 8.39 (br s, 2H), 8.16 (d, J=2.7 Hz, 1H), 8.08 (s, 1H), 7.16-7.70 (m, 8H), 4.49-4.64 (br m, 1H), 4.46 (s, 2H), 4.05-4.30 (m, 1H), 4.00 (AB q, J=5.7 Hz, 2H), 3.01-3.25 (m, 1H), 2.77-2.95 (m, 2H), 1.75-1.92 (m, 1H), 1.45-1.75 (br m, 3H); 19F NMR (282 MHz, DMSO-d6) δ-114.1; MS (ESI) m/z 497 (M+H).