Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[CH3:16][C:17]1[CH:18]=[C:19]([CH3:30])[N:20]=[C:21]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:22]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:16][C:17]1[CH:18]=[C:19]([CH3:30])[N:20]=[C:21]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:22]=1.[C:1]12([CH2:11][S:12]([O-:15])(=[O:13])=[O:14])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1cc(C)nc(Nc2ccccc2)n1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2
Reaction time: 0.5 h

Procedure:
A solution of camphorsulfonic acid (1.25 g) in ethanol (10 ml) was added slowly to a solution of pyrimethanil (1 g) in toluene (20 ml) and the mixture allowed to stand for 30 minutes at room temperature. The mixture was evaporated under reduced pressure and the residue recrystallised from a mixture of diisopropyl ether and ethyl acetate to give pyrimethanil camphorsulfonate, m.p. 1 66-7° C. (compound 2)
Reaction SMILES: [C:1]([C:3]1[C:8](=O)[NH:7][C:6]([C:10]2[CH:21]=[CH:20][C:13]([C:14]([O:16]C(C)C)=[O:15])=[CH:12][CH:11]=2)=[CH:5][C:4]=1[S:22][CH3:23])#[N:2].P(Cl)(Cl)([Cl:26])=O.CN(C=O)C.Cl>O>[Cl:26][C:8]1[N:7]=[C:6]([C:10]2[CH:21]=[CH:20][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[C:4]([S:22][CH3:23])[C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1cc(-c2ccc(C(=O)OC(C)C)cc2)[nH]c(=O)c1C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(-c2ccc(C(=O)O)cc2)nc(Cl)c1C#N
Temperature: 110 °C
Yield: 97.7 %

Procedure:
A suspension of isopropyl 4-(5-cyano-4-(methylthio)-6-oxo-1,6-dihydropyridin-2-yl)benzoate (1.6 g, 4.87 mmol) in phosphoryl trichloride (14.94 g, 97 mmol) was heated to 110° C. for 60 h, cooled to room temperature and carefully added to cold water (50 mL). The resultant mixture was carefully quenched with saturated. NaHCO3(200 mL), and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to give a mixture of acid and ester. The material was treated with DMF (10 ml) and 6 N HCl (10 ml), heated to 100° C. for 1 h, cooled to room temperature and diluted with water (50 ml) and filtered. The solid was washed with water (10 ml), dried under vacuum to give 4-(6-chloro-5-cyano-4-(methylthio)pyridin-2-yl)benzoic acid (1.45 g. 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (2H, d, J=8.53 Hz), 8.10 (2H, d, J=8.53 Hz), 7.95 (1H, s), 2.87 (3H, s); MS (ES+) m/z: 305 (M+H); LC retention time: 3.45 min (analytical HPLC Method A).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27](OC)=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.[BH4-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][OH:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of methyl 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylate (prepared in an analogous manner to Example 279, 500 mg, 1.23 mmol) in anhydrous THF (50 mL) at 0 C, was added sodium borohydride (95 mg, 2.46 mmol) portion-wise under nitrogen. The resulting solution was sonicated briefly and stirred at 40 C for 1 h. The reaction mixture was then allowed to stir at room temperature for a further 16 h. The reaction was quenched with water (25 mL) and extracted with EtOAc (3×25 mL). Combined organics were dried over magnesium sulfate and evaporated to dryness to afford the crude product as a yellow solid. The solid was triturated with MeOH, filtered and washed further with diethyl ether (100 mL) to afford the title compound as a salmon coloured solid (305 mg, 67%).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]#[N:17])[C:9]1=[O:18].N([O-])=O.[Na+].C(=O)([O-])O.[Na+].[ClH:28]>[Cu]Cl>[Cl:28][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]#[N:17])[C:9]1=[O:18]
Reactant: COc1ccn(-c2ccncc2N)c(=O)c1C#N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=C([O-])O
Agent: O=N[O-]
Product: COc1ccn(-c2ccncc2Cl)c(=O)c1C#N
Reaction time: 2 h

Procedure:
To a mixture of 3′-amino-4-methoxy-2-oxo-2H-[1,4′-bipyridine]-3-carbonitrile obtained in Step B (1.00 g) and 1N hydrochloric acid (20 mL) was slowly added an aqueous solution (3 mL) of sodium nitrite (0.31 g) at 0° C., and the mixture was stirred for 2 hr. This reaction mixture was added to a mixture of copper(I) chloride (0.30 g) and 1N hydrochloric acid (5 mL) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with a mixed solvent of tetrahydrofuran/ethyl acetate=1/1. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.40 g).
Reaction SMILES: O[CH:2]([C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]([C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]2)[C:3]([OH:5])=[O:4].P(O)(O)O.[I-].[K+].O>C(O)(=O)C>[C:16]([N:11]1[C:12]2[C:8](=[C:7]([CH3:19])[C:6]([CH2:2][C:3]([OH:5])=[O:4])=[C:14]([CH3:15])[CH:13]=2)[CH2:9][CH2:10]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCc2c1cc(C)c(C(O)C(=O)O)c2C
Agent: OP(O)O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCc2c1cc(C)c(CC(=O)O)c2C
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of hydroxy(1-acetyl-4,6-dimethylindolin-5-yl)acetic acid obtained in Example 1 (280 g) in acetic acid (1120 ml) were added phosphorous acid (130 g) and potassium iodide (17.6 g), and the resulting mixture was stirred for 2 hours at 100–107° C. After cooling to 50° C., water (1120 ml) was added, and crystals precipitated were separated by filtration and dried to afford (1-acetyl-4,6-dimethylindolin-5-yl)acetic acid (223 g, yield: 85%).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:9][CH2:8]1)=[O:6].[Li+].[OH-]>C1COCC1.O>[CH:19]1([C:10]2([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH:4]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:3]([OH:33])=[O:2])[CH2:8][CH2:9]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)C(Cc1ccc(F)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cc1ccc(F)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-cylcohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-(4-fluorobenzyl)-3-oxo-propionic acid methyl ester, 57, (456 mg, 1 mmol) in THF/H2O (2:1) at RT is added LiOH (1.5 equiv.). The reaction is stirred at RT until the starting material is consumed. The solvent is removed in vacuo, and the residue is purified by reverse phase HPLC to provide the desired product.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].I[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)(=[O:29])=[O:28])=[CH:22]2>>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([S:27]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:7]2[CH2:6][C@@H:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@@H:4]3[CH2:8]2)(=[O:29])=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cnc2c(I)cccc2c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cccc4cc(S(=O)(=O)c5cccc(C(F)(F)F)c5)cnc34)C[C@@H]2C1
Yield: 60 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 8-iodo-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline. 107 mg (60%) of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:5])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH2:7]([O:6][C:2]([CH:3]1[CH2:4][O:31]1)([CH3:1])[CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C=CC(C)(C)OCCCCCCCCCCCCCCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(C)(C)C1CO1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A mixture of 36.5g of 1-[(1,1-dimethyl-2-propenyl)oxy]hexadecane, 23.92 g of m-chloroperbenzoic acid and 225 ml of methylene chloride was stirred overnight. A 7 g portion of m-chloroperbenzoic acid was added, then the mixture was stored in a chill room for 56 hours. This mixture was filtered. The filtrate was washed with dilute aqueous sodium bisulfite, then saturated aqueous sodium bicarbonate, dried and the solvent removed, giving 36 g of the desired compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([NH2:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]#[N:13])[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(N)=O)nc(NC(C)C)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C#N)nc(NC(C)C)n1
Reaction time: 4 h
Yield: 249.2 %

Procedure:
To a suspension of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid amide (1.24 g, 6.4 mmol) in DCM (20 mL), pyridine (2.53 mL, 25.6 mmol) is added followed by TFFA (2.7 mL, 19.2 mmol). The reaction mixture is stirred for 4 h, and then is quenched with water. The mixture is extracted with DCM. The org. phase is washed with sat. aq. NaHCO3 and dried over MgSO4, filtered and evaporated. Purification by CC on silica gel (eluting with Heptane/EtOAc 4:1) affords the 2-isopropylamino-6-methyl-pyrimidine-4-carbonitrile as a yellow oil (2.81 g); LC-MS: tR=0.89; [M+H]+=177.04.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:32]([O:34]C)=[O:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:24]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:32]([OH:34])=[O:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
In methanol (10 ml) and THF (10 ml) was dissolved methyl 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.16 g) as yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[CH2:6][NH:7][SH:8](=[O:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:19]2[CH2:22][CH:21](O)[CH2:20]2)=[CH:14][CH:13]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:18]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=2)[N:19]2[CH2:22][CH:21]([N:7]([CH2:6][C:2]3[S:1][CH:5]=[N:4][N:3]=3)[SH:8](=[O:10])=[O:9])[CH2:20]2)=[CH:25][CH:26]=1
Reactant: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: O=[SH](=O)NCc1nncs1
Product: O=[SH](=O)N(Cc1nncs1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Yield: 15.3 %

Procedure:
N-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1,2,3,4-thiadiazol-2-yl)methylsulfonamide may be prepared by carrying out the procedure as described in Example 13 (method 2), from 0.10 g of N-(1,3,4-thiadiazol-2-yl)methylsulfonamide and 0.215 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol. After chromatography on a silica gel column (particle size 0.06-0.04 mm, height 25 cm, diameter 1 cm), eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane 20/80 and then 40/60 by volume mixture and collecting 60-cm3 fractions, fractions 26 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from dissopropyl ether, filtration and drying, 40 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1,3,4-thiadiazol-2-yl)methylsulfonamide are obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 3.01 (s:3H); 3.09 (split t, J=7 and 1.5 Hz:2H); 3.70 (split t, J=7 and 1.5 Hz:2H); 4.28 (s:1H); 4.76 (mt:1H); from 7.20 to 7.35 (mt:8H); 9.01 (s:1H)].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][N+:8]=1[O-].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)ncc1Cl
Yield: 105.5 %

Procedure:
To a solution of phosphorus oxychloride (6.40 μL, 73.21 mmol) in chloroform (61.2 mL) was added 2,5-dichloro-4-nitropyridine 1-oxide (3.06 g, 14.64 mmol), and the mixture was stirred under reflux overnight. The reaction solution was poured into ice, adjusted by saturated aqueous sodium hydrogen carbonate solution to pH7 to 8, and extracted with chloroform three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure to give a crude 2,5-dichloro-4-nitropyridine (2.98 g, quant.) as a yellow oil. (2) To a solution of vinylmagnesium bromide (54.04 mmol) in tetrahydrofuran (104 mL) was added a solution of the above crude compound (2.98 g, 15.44 mmol) in tetrahydrofuran (100 mL) at 0° C. over 40 minutes, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50) to give 4,7-dichloro-1H-pyrrolo[3,2-c]pyridine (0.74 g, 27%) as a pale yellow powder.
Reaction SMILES: C([O:8][C:9](=[O:60])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:59])[C@H:16]([CH2:44][CH2:45][CH2:46][CH2:47][NH:48]C(OCC1C=CC=CC=1)=O)[NH:17][C@H:18]([C:39]([O:41]CC)=[O:40])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26](C(OCC2C=CC=CC=2)=O)[CH2:25][CH2:24]1)C1C=CC=CC=1>CO.[Pd]>[C:39]([C@@H:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:60])=[O:8])=[O:59])[CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)([OH:41])=[O:40]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCC[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
The Nα -[1(S)-ethoxycarbonyl-5-(1-benzyloxycarbonyl-4-piperidyl)pentyl]-Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester obtained by Example VIII a) (1.1 g) is dissolved in methanol, and palladium black is added for catalytic reduction. After completion of reaction for 5 hours, the methanol is evaporated in vacuo. The residue is added into 10 ml of 1N-NaOH and dissolved. This solution is left standing at room temperature for 1 hour, and thereafter is treated with cation ion-exchange resin DOWEX 50W-X2. The impurities are removed with 2% pyridine. Then, the eluted fractions by aqueous 4% ammonia are subjected to freeze drying to obtain 300 mg of hygroscopic white powder (Rf=0.08, expansive solvent, B).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:12]([O-])=O.[NH4+]>C(O)=O.[Pd]>[Br:1][C:2]1[C:3]2[N:9]=[CH:12][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1[N+](=O)[O-]
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: O=CO
Product: Brc1cccc2[nH]cnc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 30.5 %

Procedure:
To a mixture of 3-bromo-2-nitrobenzenamine (4.7 g, 21.66 mmol) in formic acid (98%, 50 mL) was added 10% Pd/C and ammonium formate (13.6 g, 216.6 mmol) and the reaction mixture was stirred under nitrogen at 120° C. for 24 h. The catalyst was filtered, the filtrate was concentrated, the residue was dissolved in water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 1.3 g (30%) of crude 4-bromo-1H-benzo[d]imidazole (52) as dark brown solid: MS (ESI) m/z=197.1 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=CCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.63 mL (4.6 mmol) of triethylamine was added and dissolved in a suspension of 0.73 g (4.2 mmol) of ascorbic acid in acetonitrile (9 mL). After the above crude product of (4,8,12-trimethyltridec-3-enyl)tosylate was added at room temperature, the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O.C(OCC)C>[C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([O:13][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(=O)O)cc1Nc1ccccc1
Reactant: Oc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Oc2ccccc2)cc1Nc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
N,N′-Carbonyldiimidazole (0.41 g, 2.5 mmol) was added to a stirred solution of 3-(phenylamino)-4-methoxybenzoic acid (0.6 g, 2.5 mmol) in dimethylformamide (15 mL) under an inert atmosphere. After 30 minutes, the solution was heated to 50° C. for 1 hour, then phenol (0.24 g, 2.6 mmol) was added followed by diazabicycloundecene (0.40 g, 2.6 mmol) and heating at 50° C. was continued for 20 more hours. The mixture was allowed to cool and was then diluted with diethyl ether (100 mL) and washed successively with 2N HCl, water, 0.5N K2CO3, and saturated brine then dried over MgSO4. The solvent was removed under reduced pressure, and the residue was chromatographed on a column of silica gel in ethyl acetate to afford the product (0.27 g); m.p. 130-131° C. after recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])[CH2:3]1.[NH2:26][NH2:27]>CO>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][C:19]2[C:23]([CH3:24])=[N:26][NH:27][C:20]=2[CH3:21])[CH2:3]1
Reactant: CC(=O)C(C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1)C(C)=O
Reactant: NN
Solvent: CO
Product: Cc1n[nH]c(C)c1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
A mixture of 3 g of 6-methyl-8β-(3-oxo-2-acetyl-butyl)-ergoline, prepared as described in U.S. Pat. No. 4,252,941, 100 ml of methanol and 3 ml of hydrazine was refluxed for 1 hour. After evaporation to dryness in vacuo the residue was crystallized from methanol to give 2.5 g of the title compound, m.p. >300° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[N:6]=1.[C:27]([Cl:31])(=[O:30])[CH2:28][CH3:29].[ClH:32]>O1CCCC1.N1C=CC=CC=1>[ClH:31].[ClH:32].[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:27](=[O:30])[CH2:28][CH3:29])[S:3][CH:4]=2)[CH2:9][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCC(=O)Cl
Reactant: Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1

Procedure:
To a solution of 2-amino-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole (1.1 g) in tetrahydrofuran (10 ml) and pyridine (5 ml) was added dropwise propionyl chloride (0.92 ml) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour. After concentration of the reaction mixture the residue was extracted with ethyl acetate, followed by washing with an aqueous solution of sodium bicarbonate and water and drying over anhydrous magnesium sulfate. Removal of the solvent gave an oil, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from a mixture of methanol and diethyl ether to obtain white crystals (0.8 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-propionamidothiazole dihydrochloride, mp 181°-184° C. (dec.).