Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[Cl-].C[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[C:9]([OH:11])[CH:10]=1>CO>[OH:4][C:5]1[CH:10]=[C:9]2[C:8]([CH2:12][CH2:13][C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[O:11]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CCCc2ccc(O)cc2)c(O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc([C@@H]2CCc3ccc(O)cc3O2)cc1

Procedure:
Brown powder; mp 110-111° C.; [α]D20 −55.0° (c 0.02, MeOH); UV (MeOH) λmax (log ε) 282 (3.25), 223 (3.84), 204 (4.38) nm; CD (MeOH) nm Δε276.5 −11.0; IR (NaCl) γmax 3348, 2927, 1507, 1456 cm−1; 1H NMR (CD3OD, 300 MHz) δ 1.99 (1H, m, H-3), 2.09 (1H, m, H-3), 2.67 (1H, m, H-4), 2.86 (1H, m, H-4), 4.91 (1H, overlapped, H-2), 6.24 (1H, d, J=2.4 Hz, H-8), 6.30 (1H, dd, J=2.4 and 8.2 Hz, H-6), 6.77 (2H, d, J=8.6 Hz, H-3′), 6.85 (1H, d, J=8.2 Hz, H-5), 7.22 (2H, d, J=8.6 Hz, H-2′) EIMS m/z 242 (M+, 100), 149 (18), 136 (23), 123 (62) 120 (89).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[SH:12].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: Sc1ccccn1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Sc1ccccn1
Reaction time: 1 h
Yield: 90 %

Procedure:
15.6 ml (1.2 equivalents) of propionyl chloride were slowly added at room temperature to a solution of 20 g of 2-pyridinethiol and 25.1 ml (1.2 equivalents) of triethylamine in 200 ml of anhydrous methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate. The organic solution thus obtained was washed twice with a dilute aqueous solution of sodium hydrogencarbonate and then with water. The organic layer was separated and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was subjected to fractional distillation in vacuo, to give 27 g (yield 90%) of the title compound, boiling at 93° C./0.05 mmHg (6.7 Pa).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[CH2:3]1.I[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:9][CH:10]=2)[N:5]([CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[CH2:3]1
Reactant: C#Cc1ccc2c(c1)N(C(C)C)C(=O)CC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(C(C)C)C(=O)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.282 g (1.17 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-iso-propyl-7-ethynyl quinoline (Compound 30) and 0.52 g (1.9 mmol) of ethyl 4-iodobenzoate in 2.5 ml of diethylamine which was degassed under argon for 30 min, was added 0.049 g (0.26 mmol) of copper(I) iodide and then 0.159 g (0.23 mmol) of bis(triphenylphosphine)palladium(II) chloride. The reaction was stirred at room temperature for 4 h. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][C:30]4[N:35]=[CH:34][CH:33]=[CH:32][N:31]=4)(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[NH2:36][OH:37]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([S:22]([CH2:25][CH:26]([NH:36][OH:37])[CH2:27][CH2:28][CH2:29][C:30]4[N:35]=[CH:34][CH:33]=[CH:32][N:31]=4)(=[O:24])=[O:23])[CH2:20][CH2:21]3)=[N:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(C=CCCCc1ncccn1)N1CCN(c2ccc(C#Cc3ccc(F)cc3)cn2)CC1
Reactant: NO
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3ccc(F)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 2-{(4EZ)-5-[(4-{5-[(4-fluorophenyl)ethynyl]pyridin-2-yl}piperazin-1-yl)sulfonyl]pent-4-enyl}pyrimidine (760 mg, 1.55 mmol) in THF (10 mL) was added a solution of hydroxylamine (2 mL, 50% aqueous solution in water). The reaction was stirred for 2 hours at RT before being quenched with saturated aqueous ammonium chloride solution (5 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by bond elut (silica, EtOAc to 10% MeOH in ethyl acetate) to give 2-[5-[(4-{5-[(4-fluorophenyl)ethynyl]pyridin-2-yl}piperazin-1-yl)sulfonyl]-4-(hydroxyamino)pentyl]pyrimidine (518 mg, 0.99 mmol, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([OH:17])=O)([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].C(Cl)[Cl:19].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([Cl:19])=[O:17])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: ClCCl
Reactant: COC(=O)C12CC3CC(CC(C(=O)O)(C3)C1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(C(=O)Cl)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Methoxycarbonyladamantane-1-carboxylic acid (1.0 eq) was suspended in a solution of CH2Cl2 containing a catalytic amount of DMF. This mixture was then cooled to 0° C. and oxalyl chloride (3.0 eq) was added. After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 30 minutes, and then warmed to reflux for 1 hour. During the reflux period, the reaction became homogenous. The reaction mixture was then cooled and concentrated at reduced pressure. The residue was taken-up in diethyl ether and filtered. The filtrate was concentrated at reduced pressure to yield the title intermediate as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C@H](C2C=CC=CC=2)C)[C@@H:5]1[C:17]([NH2:19])=[O:18]>[Pd].O>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][NH:6][C@@H:5]1[C:17]([NH2:19])=[O:18]
Reactant: COC[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Agent: [Pd]
Solvent: O
Product: COC[C@@H]1CCN[C@@H]1C(N)=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.8 but (2S,3R)-3-methoxymethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Step 14.2) was used instead of (2S,3R)-3-methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide. Moreover, 10% Pd on charcoal, wet with 50% H2O (Aldrich 330108) was used instead of the dry catalyst.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH:49]1([CH2:54][CH:55]=[O:56])[CH2:53][CH2:52][CH2:51][CH2:50]1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:55]([OH:56])[CH2:54][CH:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: O=CCC1CCCC1
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (prepared as in Example 1, 2.6 g, 8.3 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (6.7 mL, 10.7 mmol) to a solution of diisopropylamine (1.6 mL, 11.3 mmol) in dry tetrahydrofuran (15 mL) at 0° C.] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with cyclopentyl acetaldehyde (1.2 g, 10.7 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and then quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 15% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-(2-cyclopentyl-1-hydroxy-ethyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester as a colorless oil (730 mg, 21%): 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (m, 2H), 1.53-1.68 (m, 4H), 1.73-2.16 (m, 5H, H), 3.50 (br, 1 H), 3.89 (s, 3H), 5.41 (dd, J=5.0 Hz, 8.1 Hz, 1H), 6.67 (s, 1H), 7.42 (brt, 2H), 7.53 (brt, 1H), 8.14 (br. d., 2H), 8.33 (m, 1H), 8.96 (m, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:15]1(=[O:20])[N:3]([CH2:4][CH2:5][C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: NCCc1nc2ccccc2[nH]1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
2-Aminoethylbenzimidazole dihydrochloride (Bull. Soc. Chim. Fr. 1991, 128, 255-259; 2.34 g, 10 mmol), phthalic anhydride (1.63 g, 11 mmol) and triethylamine (2.79 ml, 20 mmol) in chloroform (25 ml) were heated at reflux overnight, and the mixture was then cooled to room temperature, diluted with ethyl acetate and filtered off. The filtrate was washed with saturated sodium carbonate solution, buffer (pH=7) and saturated sodium chloride solution and dried over sodium sulphate. Chromatography (dichloromethane:methanol 10:1, Rf=0.4) gave 2.08 g of 2-(2-phthalimidylethyl)-benzimidazole (71.4% of theory) as a colourless foam. MS (DCI, NH3)=292 (M+H+). 1H-NMR (DMSO-d6): 3.15 (2H, t); 4.0 (2H, t); 7.05-7.2 (2H, m); 7.4-7.5 (2H, m); 7.8-7.9 (4H, m); 12.4 (1H, br s).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:20]=[CH:19][C:9]([CH2:10][CH2:11][NH:12]C(=O)C(F)(F)F)=[CH:8][CH:7]=2)[NH:4][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[N:1]1[N:2]=[C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][NH2:12])=[CH:19][CH:20]=2)[NH:4][CH:5]=1
Reactant: O=C(NCCc1ccc(-c2nnc[nH]2)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCCc1ccc(-c2nnc[nH]2)cc1

Procedure:
A solution of N-(4-(4H-1,2,4-triazol-3-yl)phenethyl)-2,2,2-trifluoroacetamide (83 mg, 0.292 mmol) and NaOH (29 mg, 0.73 mmol) in a mixed solvent (THF/MeOH/H2O=2 mL/5 mL/1 mL) was stirred at RT for 2 h. The solvent was evaporated to dryness and the residue was submitted to flash chomatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:20 to 100:50) to give 2-(4-(4H-1,2,4-triazol-3-yl)phenyl)-ethanamine as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([S:34][CH3:35])=[CH:32][CH:33]=2)=[C:20]([C:36]([F:39])([F:37])[F:38])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CSc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CSc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 96-3 (587 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (490 mg) as a white powder.
Reaction SMILES: [OH:1][CH:2]([C@@H:5]1[CH2:10][C@H:9]([N:11]([C:16]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)[CH2:3][CH3:4].[ClH:40]>C(O)C>[ClH:40].[ClH:40].[OH:1][CH:2]([C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:16]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)=[O:17])[CH2:10]1)[CH2:3][CH3:4]
Reactant: CCC(O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCC(O)[C@H]1CNC[C@@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-(1-hydroxypropyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (200 mg) in ethanol (1 ml) was added 12M hydrochloric acid (0.30 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol, and ethanol was evaporated under reduced pressure. This operation was repeated twice to give the object product (140 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([O:15][CH2:18][CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(benzyloxycarbonylamino)-2-methyl-propanoic acid (which may be prepared as described in Description 32) (5000 mg, 21.08 mmol) in toluene (50 mL) was added ethanol (5 mL) and p-toluenesulfonic acid (400.89 mg, 2.11 mmol). The solution was stirred at 80° C. overnight. The reaction mixture was evaporated and the residues dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate. The aqueous phase was back extracted into EtOAc. The combined organics were dried over magnesium sulphate, filtered and evaporated to yield the title compound (D33) as a light yellow oil (4.667 g);
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: OC1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 98.2 %

Procedure:
A mixture of 4-fluoro-2-(methyloxy)-1-nitrobenzene (7.52 g, 44 mmol), 4-hydroxypiperidine (4.45 g, 44 mmol) and potassium carbonate in 100 mL DMSO was stirred for 72 h. The reaction was diluted with water and extracted twice with Ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinol (10.9 g, 99% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J=9.2 Hz, 1H), 6.54 (d, J=9.6 Hz, 1H), 6.46 (s, 1H), 4.73 (d, J=4.4 Hz, 1H), 3.86 (s, 3H), 3.80-3.69 (m, 3H), 3.18-3.12 (m, 2H), 1.79-1.76 (m, 2H), 1.42-1.34 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[N:7][CH:8]=1.[Cu][C:11]#[N:12].C(Cl)(Cl)Cl>N1C=CC=CC=1.[OH-].[NH4+].[Cl-].[NH4+]>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[CH:6]=[N:7][CH:8]=1
Reactant: OCc1cncc(Br)c1
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#Cc1cncc(CO)c1
Temperature: 165 °C
Reaction time: 2 h
Yield: 357.5 %

Procedure:
A stirred mixture of 5-hydroxymethyl-3-bromopyridine (8.50 g, 45.2 mmol) and copper (I) cyanide (10.1 g, 11.3 mmol) in pyridine (50 mL) was heated in a sealed pressure reaction vessel at 165° C. for 20 hours. After cooling to 23° C., the mixture was diluted with concentrated ammonium hydroxide (15 mL) and saturated aqueous ammonium chloride (60 mL), after stirring for 2 hours, the mixture was treated with chloroform (50 mL) and allowed to set for 72 hours. The aqueous layer was then extracted with chloroform. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2 inch column, 4:1 EtOAc:hexane as eluant) followed by crystallization from diethyl ether to afford 5-hydroxymethyl-3-pyridinecarbonitrile (5.42 g, 40.4 mmol, 89% yield): Rf 0.49 (EtOAc); 1H NMR (CDCl3, 200 MHz)δ8.80 (m, 2H), 8.03 (s, 1H), 4.83 (s, 2H).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C([O:15][C:16](=[O:54])[CH:17]([C:35]1[S:36][C:37]([CH2:40][N:41]2[C:45]([C:46]([O:48]C)=[O:47])=[C:44]([C:50]([O:52]C)=[O:51])[N:43]=[N:42]2)=[CH:38][CH:39]=1)[NH:18][C:19](=[O:34])[CH:20]([CH2:29][S:30]C(=O)C)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>O.CO>[C:50]([C:44]1[N:43]=[N:42][N:41]([CH2:40][C:37]2[S:36][C:35]([CH:17]([C:16]([OH:54])=[O:15])[NH:18][C:19](=[O:34])[CH:20]([CH2:29][SH:30])[CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:39][CH:38]=2)[C:45]=1[C:46]([OH:48])=[O:47])([OH:52])=[O:51]
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cn2nnc(C(=O)OC)c2C(=O)OC)s1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: O=C(O)c1nnn(Cc2ccc(C(NC(=O)C(CS)CCc3ccccc3)C(=O)O)s2)c1C(=O)O
Yield: 27.4 %

Procedure:
A solution of sodium sulphide nonahydrate (1.09 g) in water (6 ml) was added to a stirred solution of 2-[5-{4,5-di(methoxycarbonyl)triazol-1-ylmethyl}thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 71) (400 mg) in methanol (6 ml). The mixture partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was crystallised by trituration with ether and ethyl acetate, and the solid filtered off and washed with ether then dried under vacuum to give the title compound (92 mg). vmax (nujol) 3294, 1732, 1643 cm-1. m/z (M-H-).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.Cl.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1nn(C)cc1[N+](=O)[O-]

Procedure:
The product was obtained according to the method described in example 1, step 1 starting from 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid and methylamine hydrochloride as light yellow solid (250 mg, 64%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:31]=[CH:30]/[C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:36][CH:35]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Temperature: 120 °C
Yield: 79.1 %

Procedure:
A microwave vial was charged with 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (5 g, 15.30 mmol), (E)-4-(trifluoromethyl)styrylboronic acid (4.96 g, 22.95 mmol), potassium carbonate (7.40 g, 53.6 mmol) and tetrakis(triphenyl phosphine)palladium(0) (0.530 g, 0.459 mmol). The reaction was evacuated and purged with nitrogen before dioxane (3.40 ml) was added and the whole was heated under vacuum. Water (1.7 ml) was then added and the reaction mixture heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and then brine and the combined organics were dried (MgSO4) and concentrated in vacuo to give the desired compound as an orange solid (5.6 g, 79%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=O>ClC(Cl)C.C(Cl)(Cl)(Cl)Cl>[F:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]#[N:25]
Reactant: NC(=O)c1cccnc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: N#Cc1cccnc1F
Temperature: 25 °C
Yield: 64.8 %

Procedure:
Add resin bound triphenylphosphine (4.0 g, 12.0 mmol) to a solution of 2-fluoro-nicotinamide (0.6 g, 4.3 mmol) in dichloroethane (20.0 mL) and carbon tetrachloride (20.0 mL). Reflux for 18 hours, cool to RT, filter, and concentrate the filtrate under vacuum. Purify by flash column on silica gel eluting with 10-60% EtOAc in hexanes to give the title compound (0.34 g, 64%). MS (ES) 123.1 (M+1)+. 1H NMR (400 MHz, CHCl3) δ 8.46 (m, 1H), 8.09 (m, 1H), 7.37 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.C([O:21][P:22]([CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:26])[O:23]CC)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[P:22]([CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:30][CH2:29][CH2:28][CH2:27][P:22]([OH:21])([OH:23])=[O:26])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)([OH:26])([OH:23])=[O:21]
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Reactant: CCOP(=O)(CCCCBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(OCCCCP(=O)(O)O)cc2C(=O)c2ccc(OCCCCP(=O)(O)O)cc21
Reaction time: 8 h

Procedure:
2,6-dihydroxyanthraquinone (1.19 g, 4.98 mmol) and diethyl(4-bromobutyl)phosphonate (3.0 g, 10 mmol) were heated at 60 ° C. in 5 ml DMF in the presence of 0.8 g of K2CO3 for 72 hours. The solution was extracted with CH2Cl2. The CH2Cl2 solution was dried, leaving a yellow solid. The ester was purified by column chromatography. The bisphosphonate ester was converted to the acid by overnight stirring with 4-fold excess of bromotrimethylsilane in dry dichloromethane followed by addition of water. The bisphosphonic acid derivative was washed with CH2Cl2, filtered and collected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:12]C(=O)N[C:9]2=[O:14])[CH:7]=1.[OH-].[Na+].NC(C1C=C(Br)C=CC=1F)(C)[C:21](O)=[O:22].S(Cl)(Cl)=O>CO>[CH3:21][O:22][C:9](=[O:14])[C:8]([NH2:12])([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:16])[CH3:15]
Reactant: CC1(c2cc(Br)ccc2F)NC(=O)NC1=O
Reactant: CC(N)(C(=O)O)c1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)(N)c1cc(Br)ccc1F

Procedure:
The hydrolysis of the (RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione with 6 N sodium hydroxide solution and esterification of the resulting (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid with methanol and thionylchloride yielded the (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid methylester as a light yellow oil. The purity of the product allowed using it in the next step without further purification. Mass (calculated) C10H11BrFNO2 [276.107]; (found) [M+H]+=276 and [M+2+H]+=278.