Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:33])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1[F:30])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:35]([C:37]1[N:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[F:30][C:21]1[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[CH:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:5]1[NH:4][C:3](=[O:33])[N:35]([C:37]2[N:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[N:36]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: NNc1cccnn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3cccnn3)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
To a solution of 98 mg of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (1d)) in 3 ml of DMF there were added 30.5 mg of 3-hydrazinopyridazine hydrochloride [CAS No. 117043-87-5] and 29 μl of triethylamine, and the mixture was stirred at 85° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF=1:1 mixed solvent. After adding 44 μl of acetic acid and 65 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 5-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyridazin-3-yl-2,4-dihydro-[1,2,4]triazol-3-one (60 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11]>C1C=CC=CC=1>[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[CH3:1][CH:2]1[CH2:6][NH2+:5][C:4](=[O:7])[CH2:3]1
Reactant: CC1CNC(=O)C1
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CC1C[NH2+]C(=O)C1
Product: O=C([O-])C(F)(F)F

Procedure:
To a 100 ml flask containing 9.91 g of 4-methylpyrrolidone (0.1 mol), 30 ml benzene was added and stirred for dissolution. 11.40 g of trifluoroacetic acid (0.1 mol) was added dropwise into the flask over 40 min at room temperature. Then the reaction was stirred for another 6 hours. Desired product was formed after benzene was removed under reduced pressure and dried at 110° C. under 1–5 mmHg for 1 hour. The brown viscous, moisture- and water-stable liquid of 4-methylpyrrolidonium trifluoroacetate was obtained with a yield of 97.7%, which has a glass transition temperature of −85.0° C., a density of 1.33 g/ml, a viscosity of 22 cP, an electrochemical window of 2.4 V, an ionic conductivity of 5.63×10−4 S/cm, and a Hammett acidic scale H0 of 4.82 using methyl yellow as indicator. No melting point was observed.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19](OCC)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][C:26]=1[S:39]([NH2:42])(=[O:41])=[O:40].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:27][C:26]=2[S:39](=[O:40])(=[O:41])[N:42]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)C)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 100 °C

Procedure:
To a solution of the product of Example 39-4 (320 g, 1.01 mol) in toluene (1100 mL) was added product of Example 17A-4 (291 g, 1.01 mol). The solution was heated to 100° C. for 4 h then cooled to RT. The solution was transferred to a pressure bottle and triethylamine (472, 4.66 mol) was added and the solution was heated to 100° C. for 26 h. The solution was concentrated to ⅓ of the original volume and ethyl acetate (2000 mL) was added. The organic layer was washed with 10% KH2PO4 and 10% NaCl then concentrated to a thick oil then chased with CH2Cl2. The crude product of Example 39-5 (assay for 406.5 g, 74.5%) was used directly.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:18][CH3:19])CC)[CH:10]=2)[NH:6][C@@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[O:3]1.[CH3:32][CH2:33]O>Cl[Pd]Cl.C1COCC1>[CH2:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][C@@H:7]([C:2]([OH:3])=[O:1])[NH2:6])[CH2:18][CH2:19][CH2:32][CH3:33]
Reactant: CCC(CC)c1cccc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)c1
Reactant: CCO
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Product: CCCCCc1cccc(C[C@H](N)C(=O)O)c1
Reaction time: 18 h

Procedure:
To a 300 mL Parr bottle were added 0.41 g of PdCl2, 1.36 g of (2R,3S,5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)morpholine, 50 mL of EtOH, and 30 mL of THF. The mixture was deoxygenated by bubbling nitrogen through for 10 min and was hydrogenated at 45 psi for 18 h. The vessel was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated in vacuo to a volume of 15 mL. The solution was chilled in an ice bath and triturated with addition of 50 mL of hexane. A fine precipitate slowly formed. After storing at 5° C. overnight, the solid was collected by filtration and dried in vacuo to afford 0.65 g (72%) of 3-(3-pentyl-L-phenylalanine.HCl as a white powder, m.p. 170° C. (dec).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:36][C:19]1[C:13]2[C:14](=[CH:15][N:16]=[C:11]([C:4]3[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])[CH:12]=2)[N:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[CH:18]=1
Reactant: CCc1cccc(CC)c1-c1cc2ccn(-c3ccc(C(C)C)cc3)c2cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc2c(Br)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (2.36 g, 6.4 mmol) in DCM (50 mL), NBS (1.25 g, 7.0 mmol) is added and the mixture is stirred at room temperature for 1 h. The mixture is concentrated under reduced pressure, and the product is dissolved in a 5:1 EtOAc/Hexane mixture and filtered over a small pad of silica gel. The solvent is removed under reduced pressure to afford 3-bromo-5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:43])[C:17]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([O:27][C:28](=[O:42])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:23][CH2:22]2)=[O:18])=[O:11])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[NH2:48][CH2:49][C@@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53].C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:55]([Si:52]([CH3:54])([CH3:53])[O:51][C@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[CH2:49][NH:48][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:43])[C:17]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([O:27][C:28](=[O:42])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:25][CH2:26]2)=[O:18])=[O:11])=[CH:7][CH:8]=1)([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CN(CCCCC(=O)Nc1ccc(C=O)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCCC(=O)Nc1ccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-formyl-phenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (2.83 g, 4.84 mmol) and 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one acetic acid salt (1.91 g, 4.84 mmol) in a 1:1 mixture of MeOH:DCM (40.0 mL, 312 mmol) was added sodium triacetoxyborohydride (3.08 g, 14.5 mmol). The reaction mixture was stirred at room temperature for 2 h and then the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. The solid was purified by silica gel flash chromatography (0-30% MeOH in DCM+0.5% NH4OH) to give the title compound (3.60 g, 82% yield) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].BrCC(O[C@H](C1C=CC(OC(F)F)=C(OCC2CC2)C=1)CC1C(Cl)=CN=CC=1Cl)=O.C([O-])([O-])=O.[K+].[K+].[CH3:68][S:69]([NH:72][C:73]1[CH:82]=[CH:81][CH:80]=[CH:79][C:74]=1[C:75]([O:77][CH3:78])=[O:76])(=[O:71])=[O:70]>CN(C=O)C.O>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][N:72]([C:73]1[CH:82]=[CH:81][CH:80]=[CH:79][C:74]=1[C:75]([O:77][CH3:78])=[O:76])[S:69]([CH3:68])(=[O:71])=[O:70]
Reactant: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COC(=O)c1ccccc1NS(C)(=O)=O
Agent: O=C(CBr)O[C@@H](Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
The mixture obtained in step 2, containing (S)-4-(2-(2-bromoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine (100 mg) was dissolved in DMF (2 ml), and K2CO3 (30 mg, 0.22 mmol) and methyl 2-(methylsulfonamido)benzoate (82 mg, 0.36 mmol) were added. The mixture was stirred at RT for 5 hours. The reaction was diluted with water, and the product was extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give 105 mg of the desired product (Yield: 85%, MS/ESI+ 689.5 [MH]+).
Reaction SMILES: [CH2:1]([C:6]1(C(OCC=C)=O)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=CCOC(=O)C1(CCCCC)CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCCCC=C1CCCC1=O
Product: CCCCCC1=CCCC1=O
Temperature: 25 °C

Procedure:
A vessel was charged with 1 mole of allyl 1-pentyl-2-oxocyclopentanecarboxylate of the following formula ##STR7## 20 moles of acetonitrile, 0.05 mole of palladium acetate and 0.05 mole of α,β-ethylenedi(diphenyl)phosphine, and after these materials were rapidly stirred at room temperature, they were heated to the boiling point of the solvent and reacted under reflux for 30 minutes. After the reaction, the reaction mixture was distilled under reduced pressure in a customary manner to give 2-pentyl-2-cyclopenten-1-one and 2-pentylidenecyclopentanone in a yield of 65% and 13%, respectively. These compounds were identified by using IR, NMR and mass spectroscopic techniques.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18](COCC[Si](C)(C)C)[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[NH2:7][CH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCC(N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.1 %

Procedure:
In a round-bottomed flask, (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclopentyl)-carbamic acid tert-butyl ester (80 mg, 0.125 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.4 ml, 5.0 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.5 ml, 7.5 mmol) was added. The solution was stirred at room temperature for 2 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 40 mg (74%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclopentyl)-amide as an off-white powder. MS: (M+H)+=410; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.07 (s, 1H), 8.55 (d, J=8.7 Hz, 1H), 8.40 (s, 1H), 8.24 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.40 (d, J=9.1 Hz, 1H), 5.54 (br. s, 2H), 4.34-4.45 (m, 1H), 4.17 (s, 3H), 3.36-3.44 (m, 1H), 2.25-2.37 (m, 1H), 2.03-2.16 (m, 1H), 1.71-1.88 (m, 2H), 1.51-1.62 (m, 1H), 1.32-1.43 (m, 1H). The isolated product was determined to be a single diastereomer of unknown relative stereochemistry by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:57])[CH2:32][CH2:33][C@@H:34]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][C:45]=1[N+:54]([O-:56])=[O:55])[CH2:35][S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:53][S:50]([C:47]4[CH:48]=[CH:49][C:44]([NH:43][C@@H:34]([CH2:35][S:36][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:33][CH2:32][N:31]([CH3:30])[CH3:57])=[C:45]([N+:54]([O-:56])=[O:55])[CH:46]=4)(=[O:51])=[O:52])=[O:26])=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCN(Cc4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1[N+](=O)[O-]

Procedure:
A mixture of EXAMPLE 2C (3.683 g), 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide (3.53 g), EDAC.HCl (3.32 g) and DMAP (2.12 g) in dichloromethane (500 mL) at 25° C. was stirred for 8 hours, washed with saturated NH4Cl (330 mL), and dried (MgSO4), filtered, and concentrated. The concentrate was flash chromatographed on silica gel with 1%, 2%, 5%, 10%, and 15% methanol/NH3-saturated dichloromethane. 1H NMR (DMSO-d6) δ 12.10 (br s, 1H), 11.18 (br s, 1H), 10.40 (br s, 1H), 8.54 (s, 1H), 8.29 (d, 1H), 8.10 (br s, 1H), 7.85 (d, 1H), 7.77 (d, 2H), 7.52 (d, 4H), 7.40-7.36 (m, 2H), 7.35-7.32 (m, 1H), 7.26-7.21 (m, 2H), 7.16-7.09 (m, 3H), 6.93 (d, 2H), 4.34 (br s, 2H), 4.35-4.23 (m, 1H), 3.88 (br s, 2H), 3.42-3.36 (m, 4H), 3.17-3.07 (m, 2H), 2.90-2.78 (m, 2H), 2.50 (s, 6H), 2.20-2.15 (m, 2H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[S:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:11]=1.[Cl-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:1]([S:3][C:7]1[S:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:11]=1)[CH3:2]
Reactant: COc1ccc(-c2nc(Cl)sc2-c2ccc(OC)cc2)cc1
Reactant: CCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Reaction time: 1 h

Procedure:
0.217 g of ethyl mercaptan is dissolved under nitrogen in 10 ml of hexamethylphosphoric acid triamide, the solution is cooled to 10° and, while stirring, 170 mg of 50% strength sodium hydride suspension (in mineral oil, de-oiled with hexane) are added in portions. The mixture is then stirred for 15 minutes at room temperature, 1.0 g of 2-chloro-4,5-bis-(p-methoxyphenyl)-thiazole is added and stirring is carried out at room temperature for 1 hour. The mixture is then poured into 300 ml of 10% strength sodium chloride solution, digested until crystallisation occurs and filtered with suction and the residue is then washed twice with water and sucked dry on a suction filter. The crude product is recrystallised from methanol. 2-Ethylthio-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 73°-75° is obtained.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Si:17](C#N)([CH3:19])[CH3:18].[CH2:22]([N:24](CC)CC)C>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]([O:13][Si:17]([CH3:19])([CH3:18])[CH3:16])[C:22]#[N:24])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Product: C[Si](C)(C)OC(C#N)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of 4-phenoxy benzaldehyde (F) (1.00 g, 5.04 mmol) and trimethylsilyl cyanide (0.63 mL, 5.04 mmol) in dichloromethane (20 mL) was added triethylamine (0.07 mL, 0.5 mmol). The reaction mixture was stirred at 0° C. for 3 h and then concentrated to give (4-phenoxyphenyl)-trimethylsilanyloxy-acetonitrile (G) as a clear oil. This protected cyanohydrin (G) was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][C:50]([OH:52])=O)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:50](=[O:52])[CH2:49][CH:46]1[CH2:45][CH2:44][N:43]([C:41]([O:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:42])[CH2:48][CH2:47]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
N-methoxymethanamine hydrochloride (2.61 g, 26.7 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.91 g, 30.8 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (4.72 g, 30.8 mmol), and triethylamine (11.5 mL, 82.2 mmol) were added sequentially to a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (5.00 g, 20.6 mmol) in methylene chloride (150 mL) at 0° C. Stirred at ambient temperature for 4 hours, and partitioned between ethyl acetate and 2N HCl. Washed the organic layer again with 2N HCl, twice with 2N NaOH, brine, dried, and concentrated to afford the title compound (5.93 g, 101% yield) as a clear colorless viscous oil.
Reaction SMILES: [CH:1]12[N:8]([C:9](Cl)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:9]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4]3)=[O:10])=[N:17][CH:18]=1
Reactant: O=C(Cl)N1C2CCCC1CC2
Reactant: NNc1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NNc1ccc(F)cn1)N1C2CCCC1CC2
Reaction time: 120 h
Yield: 46.6 %

Procedure:
To a solution of Intermediate 122a (240 mg, 1.38 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (176 mg, 1.38 mmol) in DCM (10 mL) was added DIPEA (721 μL, 4.15 mmol) and the reaction stirred for 5 days. The reaction was then partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM to give the title compound (170 mg, 47%). LCMS (Method 3): Rt 2.31 min, m/z 265 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[NH:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH2:35][CH3:36]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([CH2:34][CH2:35][CH3:36])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1)OCc1ccccc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 17.5 g (ca. 46 mM) of 8α-benzyloxycarbonylaminoergoline obtained from step (c), 13.5 g potassium carbonate and 6 ml (62 mM) n-propyl iodide in 300 ml dimethylformamide is stirred for 18 hours at room temperature. The mixture is filtered and concentrated in a rotary evaporator. The residue is treated with methylene chloride and shaken with water. The organic phase is dried over sodium sulphate, filtered and concentrated to give the crude heading compound.
Reaction SMILES: S1C=CC=C1.C(O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]3[C:35]([CH3:36])=[CH:34][C:33]([N+:37]([O-])=O)=[CH:32][C:31]=3[CH3:40])=[O:28])[CH:22]([C:41]([NH:43][CH3:44])=[O:42])[CH2:21]2)=[CH:12][CH:11]=1.[H][H]>[Pd].CO>[NH2:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([NH:29][C:27](=[O:28])[CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][CH:16]([C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[CH2:21][CH:22]2[C:41]([NH:43][CH3:44])=[O:42])=[C:31]([CH3:40])[CH:32]=1
Reactant: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: c1ccsc1
Product: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(C)cc(N)cc1C

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 3 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethyl-4-nitrophenyl)-2-[(methylamino)carbonyl]-1-piperazineacetamide and 120 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane, yielding 2.14 parts of N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-2-[(methylamino)carbonyl]-1-piperazineacetamide; mp. 111.7° C. (compound 162).