Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][C:4]=2[S:5][CH:6]=1.[N+:14]([O-])([OH:16])=[O:15]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:4]=2[S:5][CH:6]=1
Reactant: COc1cc2c(Cl)csc2cc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(Cl)csc2c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophene (0.39 g) was dissolved in ethyl acetate (26 ml). To the solution was gradually added a solution of nitric acid in dichloromethane (2M, 0.9 ml) at room temperature. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water and extracted with ethyl acetate and evaporated to dryness. The product was purified by column chromatography using toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
Reaction SMILES: [C:1]1(=O)[NH:6][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[Cl-:13].[Cl-:14].C1(P(=O)([O-])[O-])C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:13][C:5]1[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[C:1]([Cl:14])[N:6]=1
Reactant: [Cl-]
Reactant: O=C1Cc2ccccc2C(=O)N1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Product: Clc1cc2ccccc2c(Cl)n1

Procedure:
A mixture solution of homophthalimide (10.5 g) and phenylphosphonate dichloride (30 ml) was heated at 110° C. for 2 hr. After the reaction mixture was cooled, water was added thereto, and then the resulting mixture was neutralized with sodium carbonate. The resulting mixture was extracted with ethyl acetate, washed with brine, dried, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride), to give 9.30 g of the title compound as white crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]([OH:18])=O)[CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:41][CH2:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51](=[O:62])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:58]([F:61])([F:60])[F:59])[CH2:47][CH2:46]1)=[O:44]>CN(C=O)C.O>[O:44]=[C:43]([N:45]1[CH2:46][CH2:47][N:48]([C:51](=[O:62])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:58]([F:61])([F:60])[F:59])[CH2:49][CH2:50]1)[CH2:42][NH:41][C:16]([C:13]1[CH:12]=[C:11]([CH3:10])[O:15][N:14]=1)=[O:18]
Reactant: Cc1cc(C(=O)O)no1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)no1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 59.5 %

Procedure:
DIPEA (82.66 mg, 0.09 mL, 0.63 mmol) was added to a stirred solution of 5-methyl-isoxazole-3-carboxylic acid (32.52 mg, 0.25 mmol) in DMF (2 mL). HOBT (34.53 mg, 0.25 mmol) and EDCI (48.9 mg, 0.25 mol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (75 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and 80% EtOAC in hexane as eluent) to afford 53 mg (58.62% yield) of 5-methyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 88.47%. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.88-7.74 (m, 2H), 7.74-7.62 (m, 1H), 7.6-7.5 (s, 1H), 6.75 (s, 1H), 4.22-4.4 (dd, 2H), 3.8-3.64 (m, 2H), 3.64-3.52 (s, 3H), 3.5-3.36 (m, 3H), 3.22-3.0 (m, 3H), 2.48-2.44 (s, 3H).
Reaction SMILES: O1CCCC1.[CH3:6][O:7]/[N:8]=[C:9](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:10][O:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:30][CH2:31][CH3:32])[CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.CO.[OH-].[Na+]>O>[CH3:6][O:7]/[N:8]=[C:9](/[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)\[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:30][CH2:31][CH3:32])[CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:33][CH:34]=1
Reactant: CCCC(CC(=O)OC)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with 3 mL of tetrahydrofuran. To the stirred solvent were added methyl 3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}hexanoate (0.017 g, 0.03 mmol), methanol (0.5 mL) and sodium hydroxide (0.013 g, 0.32 mmol) in water (0.5 mL). After addition, the reaction mixture was stirred at room temperature 30 minutes. The reaction mixture was concentrated to distill off the solvent; the crude was washed with diethyl ether (5 mL). The salt was dissolved in water (1 mL) and the aqueous layer was acidified with saturated citric acid to solution to make pH 6. The aqueous layer was extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by preparative TLC using methanol and chloroform as eluents. The product was obtained as white semi solid (0.012 g, yield: 24.73%). MS (ESI, 120 ev): m/z=462.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:14][CH:13]([CH2:15][OH:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:16][CH2:15][CH:13]1[NH:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:14]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1CC(CO)N1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC(CO)N1

Procedure:
179 mg (0.575 mmol) of N-benzyl-4-(hydroxymethyl)azetidine-2-carboxylic acid benzyl ester and 60 mg of 20% Pd(OH)2 /C (containing 31% of water) in 30 ml of methanol are hydrogenated in a Parr shaker under 4 atm of hydrogen for 3.5 h. The catalyst is filtered off through a double paper filter and washed with methanol, the solution evaporated, and the residue chromatographed on silica gel (isopropanol/water/conc. NH3 14:5:1) to yield, after evaporation and drying i.v., 53.6 mg (71%) of 4-(hydroxymethyl)azetidine-2-carboxylic acid as a colorless solid. 1H NMR (D2O): δ 4.71 (t, 1H, J=9), 4.56 (m, 1H), 3.80 (m, 2H), 2.81 (dt, 1H, J=12 (d), 9.5 (t)), 2.43 (dt, 1H, J=12.5 (d), 8.5 (t)). IR (nujol): 3239, 3146, 2589, 2438, 1620, 1565, 1410, 1327, 1302, 1188, 1099, 1038, 999, 885, 828, 758, 725 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:28])[C:10]1[N:14]([CH2:15][CH2:16][CH2:17][OH:18])[C:13]2[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10]1[N:14]([CH2:15][CH2:16][CH2:17][OH:18])[C:13]2[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1)=[O:28]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
A suspension of 3-{2-[(2,4-dichlorophenyl) (hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propan-1-ol (1.18 g, 2.79 mmol) and manganese dioxide (2.43 g, 27.9 mmol) in tetrahydrofuran (14 mL) was stirred for 1.5 h at room temperature. The reaction mixture was filtrated and the filtrate was concentrated in vacuo to afford the desired product as a yellow solid (1.16 g, 2.76 mmol, 99%).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][CH:5]1[OH:14])=[N+:2]=[N-:3].[H-].[Na+].[CH3:17]I>O1CCCC1>[N:1]([CH:4]1[CH2:9][CH2:8][N:7]([S:10]([CH3:13])(=[O:11])=[O:12])[CH2:6][CH:5]1[O:14][CH3:17])=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(S(C)(=O)=O)CCC1N=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
To the stirred solution of the azide (500 mg, 2.27 mmol, Example 304) in tetrahydrofuran (8 mL) at 0° C., sodium hydride (60% in oil dispersion, 180 mg, 4.54 mmol, Aldrich) was added slowly and the mixture was stirred for 30 minutes. Methyl iodide (184 uL, 2.95 mmol, Aldrich) was then added and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried with sodium sulfate. The solvent was removed and the residue was purified by chromatography (15% ethyl acetate/hexanes first and then 35%) to give a yellow oil. 280 mg, 53%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[NH:12][C:11]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH2:22]([O:29][C:30]([N:32]([CH2:34][CH2:35]Cl)[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[K+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:35][CH2:34][N:32]([C:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[CH3:33])[C:11]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3NC(=O)[C@@H]2O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Yield: 80.8 %

Procedure:
A mixture of 5.96 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5.89 g of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride, 1.68 g of potassium hydroxide and 85 ml of dimethylsulfoxide is treated in the same manner as described in Example 1-(1). The crude product thus obtained is purified by silica gel chromatography (solvent, benzene:ethyl acetate=9:1). 7.89 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [CH2:1]([CH:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[CH2:12]1[C:20]2[C:15](=[CH:16][C:17](O)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([O:7][C:6](=[O:8])[CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:9]([O:11][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH2:14]4)=[O:10])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CC(C)CC(C(=O)O)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: CC(C)CC(C(=O)Oc1ccc2c(c1)CCC2)C(=O)Oc1ccc2c(c1)CCC2

Procedure:
A total of 32 g of isobutylmalonic acid was boiled under reflux with 60 g of 5-indanol and 60 g of phosphorus pentoxide in 1000 ml of toluene. The solution was decanted from undissolved material and evaporated under reduced pressure. The brownish oily residue was chromatographed on a column of silica gel with benzene as the eluant. After evaporation under reduced pressure, the fractions containing the desired compound yielded 26.0 g of a light oil which crystallizes on standing to yield isobutylmalonic acid di-5-indanyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.CCCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]=[O:30])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2-chloropyridin-4-yl)carbamate (1.14 gm, 5 mmol) in dry THF (20 mL) was cooled to −70° C. under an inert atmosphere and 1.7 M t-butyl lithium/pentane (8 mL, 13.5 mmol) was slowly added. The reaction was stirred for two hours and then dry DMF (1.2 mL, 15.5 mmol) was added. The reaction was allowed to slowly warm to room temperature over a three hour period. The reaction mixture was quenched with 3 N HCl (12 mL) and diluted with diethyl ether. The ether layer was washed with aqueous NaHCO3, dried (over Na2SO4), filtered and evaporated. The residue was triturated with cold diethyl ether to give pure t-butyl (2-chloro-3-formylpyridine-4-yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 15-20% ethyl acetate/hexane to give additional product. 1H-NMR (500 MHz, CDCl3): δ 11.0 (1H, br s), 10.52 (1H, s), 8.38 (1H, d, J=6 Hz), 8.31 (1H, d, J=6 Hz), 1.54 (9H, s); m/e (m+1): 257.2.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]=[CH:10][CH:11]=[CH2:12].[H][H]>C1C=CC=CC=1.C(O)C.[Pd]>[CH2:9]1[CH:5]2[CH:6]([C:1](=[O:8])[CH:2]3[CH:3]([C:4]2=[O:7])[CH2:3][CH2:2][CH2:1][CH2:6]3)[CH2:12][CH2:11][CH2:10]1
Reactant: C=CC=C
Reactant: [H][H]
Reactant: O=C1C=CC(=O)C=C1
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C1C2CCCCC2C(=O)C2CCCCC12

Procedure:
The reaction was conducted using a solution of p-benzoquinone and each of the above-mentioned butadiene derivatives in benzene under heating and refluxing conditions for four hours. The resulting compounds were dissolved in ethanol, in which was suspended a palladium catalyst adsorbed on alumina. Thereafter, hydrogen gas was blown into the solution for 2 hours while keeping the temperature of the solution at 20° C. to obtain dodecahydro-9,10-anthraquinone derivatives.
Reaction SMILES: C([Mg]Cl)(C)C.[O:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[CH:7]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]=[O:30])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]([OH:30])[C:7]2[O:6][C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[N:8]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: c1cc2ocnc2cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(O)c2nc3cnccc3o2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
i-PrMgCl (0.44 mL of a 2 mmol/mL solution in THF, 0.88 mmol) was added dropwise to a stirred solution of oxazolo[4,5-c]pyridine (105 mg, 0.87 mmol) in anhydrous THF (3 mL) at 0° C. After 1 h, a solution of 4-(2-oxo-ethyl)piperidine-1-carboxylic acid tert-butyl ester (198 mg, 0.87 mmol) in anhydrous THF (2 mL) was added, then the mixture was allowed to warm to 20° C. over 16 h, before being quenched with saturated aqueous NH4Cl (10 mL). The layers were separated, then the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash chromatography (EtOAc) of the residue furnished the title compound: m/z (ES+)=348.1 [M+H]+.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=[N:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])C.[CH:12]1[CH:13]=[CH:14][C:15]2N(O)N=N[C:16]=2[CH:17]=1.C[N:23]([CH:25]=[O:26])C>>[CH:17]([O:26][CH:7]([CH3:6])[CH3:8])([CH3:16])[CH3:12].[N:5]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:11][C:2]=2[NH:3][C:4]=1[C:17]1[C:16]2[C:13]3[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:25]([NH-:23])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Product: CC(C)OC(C)C
Product: [NH-]C1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21

Procedure:
Carry out the procedure as in Example 14, starting from 200 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluorene-9(R,S)-amine, obtained in Example 6, and 138 mg of 2-methyl-quinoline-5-carboxylic acid, which can be obtained according to J. Med. Chem. 2002, 4647, in the presence of 128.4 mg of EDCI and 90.5 mg of HOBT in 5.5 ml of DMF for 20 hours. After purification by washing successively with a saturated aqueous solution of sodium hydrogen carbonate then with water and diisopropyl ether, we obtain 70 mg of [4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9-yl]amide of 2-methyl-quinoline-5-carboxylic acid, in the form of a pale yellow powder, with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:25][N:26](C)C)[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=O.[NH2:29]N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:11]2[S:24][C:14]3[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[O:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[N:29][NH:26][CH:25]=1
Reactant: NN
Reactant: CN(C)C=C(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Solvent: CO
Product: Clc1ccccc1-c1c[nH]nc1-c1cc2c(s1)-c1ccccc1OCC2

Procedure:
2-(2-Chlorophenyl)-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-3-(dimethylamino)prop-2-en-1-one was treated with hydrazine in methanol to give 283. MS (ESI) 379.1
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[C:15]([PH:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CO>[C:15]([P:19]([CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: ClCc1cccc(-c2ccccn2)n1
Reactant: CC(C)(C)PC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)P(Cc1cccc(-c2ccccn2)n1)C(C)(C)C
Temperature: 50 °C
Yield: 84.9 %

Procedure:
To an oven dried 50 mL pressure vessel equipped with magnetic stirring bar was added 6-chloromethyl-2,2′-bipyridine (BPy-CH2Cl) (2.05 g, 10.00 mmol), di-tert-butyl phosphine (1.75 g, 12.00 mmol), and 30 mL MeOH in a nitrogen glove box. The flask was sealed and heated at 50° C. for 48 hrs with stirring outside the glove box. After cooling, it was reintroduced to the glove box, triethylamine (1.82 g, 18.00 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. The solvents were removed under reduced pressure to obtain a white solid. The residue was washed with ether (3×20 mL) and the ether filtered and was removed under reduced pressure to yield a white solid. It was recrystallized from MeOH at ca. −30° C. to yield 2.67 g (85%) of 6-di-tert-butylphosphinomethyl-2,2′-bipyridine (BPy-tPNN).
Reaction SMILES: [CH:1]([S:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH2:3][CH3:4])[CH3:2].[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:12][C:11]2[C:6]([S:5][CH:1]([CH2:3][CH3:4])[CH3:2])=[N:7][CH:8]=[CH:9][CH:10]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CCC(C)Sc1ncccc1CCl
Product: CCOC(=O)CCc1cc(F)c(OCc2cccnc2SC(C)CC)c(F)c1
Yield: 65 %

Procedure:
2-sec-Butylsulfanyl-3-chloromethyl-pyridine (0.06 g, 0.27 mmol) obtained in Step C of Preparation Example 33 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.074 g, 65%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][OH:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C@@H:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][O:20][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][C@H:25]([O:24][CH2:22][CH3:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C/C(=C\CO)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)OCC
Yield: 74.9 %

Procedure:
The title compound (0.375 g, 75%) was prepared as a colourless gum from (E)-3-(4′-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol (0.280 g, 1.00 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.250 g, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(#N)C>[ClH:9].[Cl:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CN(C)C1CCNC1
Solvent: CC#N
Product: CN(C)C1CCN(C(=O)c2ccc(CCl)cc2)C1
Product: Cl
Temperature: 25 °C

Procedure:
A solution of 3-(dimethylamino)pyrrolidine (2.5 g, 22 mmol) in acetonitrile is added to an ice cold solution of 4-(chloromethyl)benzoyl chloride (5.0 g, 26 mmol) in acetonitrile, stirred while warming to room temperature for 2 hours then concentrated in vacuo. The resultant residue is suspended in ether and filtered to give 1-(4-chloromethylbenzoyl)-3-(N,N-dimethylamino)pyrrolidine hydrochloride as a white solid identified by NMR and MS [267 m/e (M+H)].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29]C)[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1OC
Yield: 26 %

Procedure:
The title compound (10 mg, 26%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-ethoxy-benzaldehyde. MS: 384.5 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+].C(OCC)C.O>CN(C)C=O>[N:20]([C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
(1S,2S)-1-(tert-Butoxycarbonylamino)-2-methane-sulfonyloxycyclohexane (475 mg) was dissolved in N,N-dimethylformamide (6 ml), sodium azide (156 mg) was added, and the mixture was stirred for 2 hours at 60° C. and then for 24 hours at 80° C. After diethyl ether was added to the reaction mixture to conduct water washing twice, the resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane) to obtain the title compound (184 mg) as a colorless solid.