Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:27][CH:28]1[C:49](=[O:50])[N:30]2[C:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[C:32]([Cl:35])[CH2:33][S:34][C@H:29]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([NH:27][CH:28]2[C:49](=[O:50])[N:30]3[C:31]([C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])=[C:32]([Cl:35])[CH2:33][S:34][C@H:29]23)=[O:23])[N:19]=1)=[O:13]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 80.8 %

Procedure:
Vilsmeier reagent prepared from dimethylformamide (0.22 g.) and phosphorus oxychloride (0.46 g.) was suspended in dry ethyl acetate (20 ml.). 2-(2-Formamido-4-thiazolyl)-2-methoxyiminoacetic acid (anti isomer, 0.62 g.) was added to the suspension under ice-cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes to prepare the activated acid solution. The solution was added all at once to a solution of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (1 g.) and trimethylsilylacetamide (2.58 g.) in ethyl acetate (20 ml.) at -20° C. with stirring, and the mixed solution was stirred at -10° to -20° C. for 1.5 hours. To the resultant solution was added water (20 ml.), and the solution was stirred at -20° C. After separating the ethyl acetate layer, the aqueous layer was extracted with ethyl acetate (20 ml.). The ethyl acetate layer and the extract were combined together, washed with 10% hydrochloric acid (20 ml.) twice, water (20 ml.) once, a 5% aqueous solution of sodium bicarbonate (20 ml.) three times, and an aqueous solution of sodium chloride (20 ml.) once in turn, dried, and then concentrated under reduced pressure. The residue was washed with diethyl ether (50 ml.) to give p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate (anti isomer, 1.27 g.), m.p. 135° to 145° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1Nc1cncc(F)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(Br)c1Nc1cncc(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(2-bromo-6-nitrophenyl)-5-fluoropyridin-3-amine (5.686 g, 18.22 mmol) and tin(II) chloride dihydrate (20.56 g, 91 mmol) in EtOAc (121 mL) was heated under reflux with stirring. After 2.5 h, the mixture was cooled to rt. The cooled mixture was poured into 10M aqueous NaOH solution (150 mL). The mixture was extracted with EtOAC (100 mL×2) washed with water (100 mL×2), brine (100 mL×1), dried over Mg2SO4, filtered, and concentrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide 6-bromo-N1-(5-fluoropyridin-3-yl)benzene-1,2-diamine as brown syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (1H, s), 7.76-7.82 (2H, m), 6.91-6.98 (1H, m), 6.81-6.87 (1H, m), 6.77 (1H, dd, J=8.0, 1.4 Hz), 6.39 (1H, dt, J=11.7, 2.3 Hz), 5.28 (2H, s); LC-MS (ESI) m/z 282.0 [M+H (79Br)]+ and 283.9 [M+H (81Br)]−.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:5]=1.[OH-].[K+].Cl.C(Cl)(Cl)Cl>CO.C(O)C.O>[CH3:28][C:25]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:29])=[O:2])([CH3:26])[CH3:27]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(C)(C)C
Yield: 88.7 %

Procedure:
A solution of 36.2 g of product from Example 31 in 320 ml of methyl alcohol, 125 ml ethyl alcohol, 20 ml of water and 15 g of potassium hydroxide is mechanically stirred at reflux temperature for 4 1/2 hours. The reaction is cooled and 325 ml of 1N hydrochloric acid and 200 ml of chloroform is added. The mixture is heated until homogeneous, the layers are separated and extracted with chloroform. The combined organic layers are washed with 1N hydrochloric acid, dried and concentrated in vacuo. The residue is recrystallized from chloroform/hexane to give 31 g of the product as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:44]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:45])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To a solution of 288 mg (0.74 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of dichloromethane, 0.21 ml (1.48 mmol) of triethylamine and 0.1 ml (0.89 mmol) of benzyloxycarbonyl chloride were added, and the resulting mixture was stirred at room temperature for one day. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic phases were combined, washed with 10% aqueous citric acid solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) to obtain 284 mg of 2-benzyloxycarbonylamino-3-((3-methyl-4-oxo-1-phenyl-1,3,8,-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 73%)
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:36]([N:40]=[C:41]=[O:42])[CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl>[CH2:32]([N:31]([CH2:34][CH3:35])[C:28]1[CH:29]=[CH:30][C:2]([NH:1][C:41]([NH:40][CH2:36][CH2:37][CH2:38][CH3:39])=[O:42])=[C:3]([CH:27]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:13]1)=[O:5])[CH3:33]
Reactant: CCCCN=C=O
Reactant: CCN(CC)c1ccc(N)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc(N(CC)CC)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Step 3): To a solution of 2-amino-5-diethylamino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (593 mg, 1.259 mmol) in CHCl3 (20 ml) was added n-butylisocyanate (374 mg, 3.779 mmol). The solution was refluxed overnight and evaporated. The residue was purified by column chromatography on silica gel to give 5-diethylamino-2-(N'-n-butylureido)-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 366 mg (51%): mp 158°-160° C.;
Reaction SMILES: [H][H].O.[N+:4]([C:7]1[C:8]([O:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:9]([Cl:21])[CH:10]=[C:11]([N+:18]([O-])=O)[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][OH:17])([O-])=O.[ClH:27]>C(O)C.[Fe].C(OCC)(=O)C.C(O)(=O)C>[ClH:21].[ClH:27].[NH2:4][C:7]1[C:8]([O:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:9]([Cl:21])[CH:10]=[C:11]([NH2:18])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c(OCCCO)c([N+](=O)[O-])c1OCCCO
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(OCCCO)c(N)c1OCCCO
Temperature: 95 °C

Procedure:
250 g of powdered iron which had been reduced with hydrogen were added to 700 ml of water containing 10 ml of acetic acid which had been previously heated to 95° C., and 0.34 mole (119 g) of 3,5-dinitro-2,4-bis(γ-hydroxypropoxy)chlorobenzene was added gradually with stirring. Upon completion of the additions, the reaction mixture was maintained for 10 additional minutes at 95° C. After cooling, 1 liter of ethyl acetate was added. The reaction mixture was filtered off in order to remove the iron slurries. The ethyl acetate phase, which was separated from the aqueous phase, was, after washing with water, and drying over sodium sulphate, evaporated off to dryness. The solids content obtained in this manner was taken up with a hydrochloric acid solution in absolute ethanol. The expected product precipitated. After thorough draining followed by drying, analysis of the product obtained gave the following results:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[NH:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1.C=O.[C:32](O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[N:25]([CH3:32])[CH:24]([CH3:29])[CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CC(C)NC(C)C3)cc2-c2ccccc2)cn1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nc(C(=O)N3CC(C)N(C)C(C)C3)cc2-c2ccccc2)cn1
Reaction time: 1.5 h

Procedure:
4-[1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-2,6-dimethylpiperazine (29.7 mg) obtained in Example 22 was dissolved in ethanol (2.0 mL). To the solution, 35% aqueous formalin solution (0.0325 mL), acetic acid (0.0217 mL), and sodium cyanoborohydride (9.2 mg) were added at room temperature, followed by stirring for 1.5 hours. The reaction mixture was partitioned between aqueous sodium hydrogencarbonate and chloroform at 0° C. The aqueous layer was further extracted with chloroform. The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was brought to dryness, to thereby give the title compound (40 mg, quantitative amount).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]([NH2:40])([CH3:39])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH:37]([CH3:39])[CH3:38])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)N
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)NCc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with isopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (160 mg, 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([NH2:45])[CH:44]=1)[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:43]3[CH:44]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 31 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.43 g, 0.84 mmol) and (5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (0.30 g, 0.84 mmol) in trifluoroethanol (5 mL) was added p-toluene sulfonic acid (0.32 g, 1.7 mmol), and the vial was sealed and heated to 85° C. overnight. The reaction was then cooled to rt and excess NH3 in MeOH (10% in DCM) was added. The solution was transferred to a roundbottom flask and silica was added. The solvent was removed on a rotovap and the product purified on a 40 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (0.23 g, 0.26 mmol, 30% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.29 (d, J=6.2 Hz, 1H), 8.36 (s, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.03 (s, 1H), 7.73-7.70 (m, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.56 (s, 1H), 7.42-7.31 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (t, J=8.2 Hz, 2H), 6.90 (t, J=6.6 Hz, 1H), 6.78 (s, 1H), 6.57 (d, J=5.3 Hz, 1H), 4.23 (q, J=7.3 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.31-3.26 (m, 2H), 3.03 (s, 3H), 2.84-2.78 (m, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.63-2.46 (m, 6H), 1.40 (t, J=6.8 Hz, 3H), 1.22 (t, J=6.9 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H). MS (ESI) m/z=824 [M+H]+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4]O.[CH2:7]=CC=C.[H-].C([Al+]CC(C)C)C(C)C.[CH:21](O)(O)[CH2:22][CH2:23][CH3:24].[Nd].C(Br)C=C>[Nd].CCCCCC>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:7].[CH2:21]=[CH:22][CH:23]=[CH2:24]
Reactant: CCCC(O)O
Reactant: OCCCCO
Agent: C=CC=C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CC(=C)C
Temperature: 20 °C
Yield: 87 %

Procedure:
In this experiment, an isoprene-butadiene copolymer was synthesized using an alcohol modified neodymium catalyst system modified with 1,4-butanediol. In this procedure, a one gallon (3.78 liter) reactor was charged with 1,093 grams of hexane containing 81.9 grams of butadiene and 663 grams of 1.2 molar diisobutylaluminum hydride (DIBAH) in hexane (i.e., 25% weight percent DIBAH). To this solution was then added 6.78 grams of 1,4-butanediol with stirring and with temperatures maintained at 20° C. The suspension of the butanediol gradually dissolved upon reacting with the DIBAH. After one hour of stirring, 105.4 grams of a 10.3% neodymium solution (neodymium neodecanoate), diluted with 165 grams of hexane, was added to the reactor. The solution was stirred for another thirty minutes after which time 19.1 grams of allyl bromide was added. The cooling was stopped and the mixture allowed to warm up to ambient (and above) temperature. After the exotherm subsided, the catalyst solution was aged by heating at 65° C. for ninety minutes. The catalyst prepared had a [butanediol-DIBAH]-ND-allyl bromide-butadiene molar component ratio of [1-16]-1-2-20, respectively, and a concentration of 0.025 molarity with respect to the neodymium. The aged catalyst was then cooled and stored in a dry container under nitrogen.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH3:24])[CH2:11][CH2:10]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 1: 1-(2,3-dichlorophenyl)piperazine (1.0 g, 3.74 mmol), acetonitrile (40 ml), potassium carbonate (1.55 g, 11.2 mmol) and 1-iodopropane (0.293 ml, 3.74 mmol). Yield: 0.23 g (20%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 220-221° C. MS m/z (relative intensity, 70 eV) 274 (M+, 15), 272 (M+, 22), 245 (63), 243 (bp), 174 (22), 172 (27).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:5]=1[C:12]#[C:13][CH2:14][N:15]1[CH2:20][CH2:19][C@@H:18]([CH2:21][CH2:22][C:23](=[N:36]O)[C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)[C@@H:17]([C:38]([O:40][CH3:41])=[O:39])[CH2:16]1>CO.[Mo]=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:5]=1[C:12]#[C:13][CH2:14][N:15]1[CH2:20][CH2:19][C@@H:18]([CH2:21][CH2:22][CH:23]([NH2:36])[C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)[C@@H:17]([C:38]([O:40][CH3:41])=[O:39])[CH2:16]1
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=NO)c1ccnc2ccc(OC)cc12
Agent: O=[Mo]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(N)c1ccnc2ccc(OC)cc12
Reaction time: 5 h
Yield: 45.1 %

Procedure:
1.44 g of sodium borohydride and 0.77 g of molybdenum oxide are added with stirring and under an inert atmosphere, at a temperature in the region of −5° C., to a solution of 2.05 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-hydroxyimino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 100 cm3 of methanol. After 5 hours at a temperature in the region of 20° C., the mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; mass 30 g), elution being carried out with a dichloromethane/methanol/triethylamine (89/10/1 by volume) mixture. Fractions 3 to 5 (containing the purified product) are combined and then concentrated to dryness under the above conditions. 0.9 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate is obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH2:11][CH2:12][CH3:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O>CS(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([O:10][CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCCOc1cc(I)ccc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CCCOc1cc(I)ccc1C=O

Procedure:
The procedure is the same as that described above, using 5.5 g, that is 18.8 mmol, of (4-iodo-2-propoxyphenyl)methanol, 1.8 ml of oxalyl chloride and 3 ml of DMSO. After evaporation of the solvents, 5.5 g (100%) of the expected compound are recovered in the form of a yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.I[C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>O.[Cu]>[CH3:23][O:22][C:20]1[CH:21]=[C:13]([S:11][C:8]2[CH:9]=[CH:10][C:5]([S:4][CH3:3])=[CH:6][CH:7]=2)[C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)O)c(I)c1
Reactant: CSc1ccc(S)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)O)c(Sc2ccc(SC)cc2)c1
Reaction time: 0.25 h

Procedure:
A solution of 170 g. of potassium hydroxide in 1.6 liters of water is treated under a nitrogen atmosphere at 50° C. with 102 g. of 4-methylthio-thiophenol. The resulting mixture is stirred for an additional 15 minutes. The mixture is then treated with 2.4 g. of copper powder and 180 g. of 2-iodo-4-methoxy-benzoic acid and heated under reflux for 7 hours. The mixture is filtered while hot, acidified with concentrated hydrochloric acid, cooled and filtered. The residue is washed with water, dried under reduced pressure, and there is obtained 4-methoxy-6-[(4-methylthio-phenyl)-thio]-benzoic acid having a melting point of 202°-203° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH3:29][C:30]1([CH3:42])[CH2:34][C:33]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=2[O:31]1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][C:30]1([CH3:42])[CH2:34][C:33]2[CH:35]=[C:36]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH:37]=[CH:38][C:32]=2[O:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc3c(c2)CC(C)(C)O3)c2ncnn12
Reaction time: 48 h
Yield: 102.7 %

Procedure:
To a suspension (20 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.6 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.62 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.59 g), and the mixture was stirred for 48 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 100%).