Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a 1 l three-necked flask equipped with a stirring machine, a condenser and a dropping funnel, there were introduced 170.2 g (1.0 mole) of p-aminobenzenesulfonamide and 700 ml of tetrahydrofuran, and the mixture was stirred while cooling it in an ice-water bath. 52.3 g (0.5 mole) of methacrylic acid chloride was dropwise added to the mixture through the dropping funnel over about one hour. After the dropwise addition, the flask was removed from the ice-water bath and the content thereof was stirred at room temperature for 30 minutes and further stirred for additional one hour while heating it to 60° C. in an oil bath. After completion of the reaction, the reaction mixture was poured into 3 l of water while stirring. The stirring was continued for 30 minutes and then the mixture was filtered to give white solid of N-(p-aminosulfonylphenyl) methacrylamide. The white solid thus obtained was purified by recrystallization from ethanol-acetone mixed solvent (yield 39.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:22])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: Nc1ccc2ncccc2c1
Product: CN(C)c1ccc(NC(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
Prepared from 6-aminoquinoline and 4-(dimethylamino)phenyl isocyanate. m/z (ES+) 307 (M+H)+.
Reaction SMILES: C(OC([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][CH3:27])=[C:21]([F:28])[CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:29]([O:31][CH3:32])=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][C:14]3[NH:8][CH2:9][CH2:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[CH:18]=2)=[CH:20][C:21]=1[F:28])[CH3:27]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1F
Yield: 86 %

Procedure:
In a mixture of water:ethanol toluene (1:1:10, v/v, 42.0 ml) were dissolved 4-ethoxy-3-fluorophenyl borate (754 mg) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1305 mg). To the solution was added potassium carbonate (1132 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (158 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, hexane:ethyl acetate=4:1) to give methyl 1-(t-butoxycarbonyl)-7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate as yellow amorphous. The obtained methyl 1-(t-butoxycarbonyl)-7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate was dissolved in ethyl acetate (80 ml). To the solution was added 1N hydrochloric acid (15 ml) at room temperature, and the mixture was stirred at 100° C. for 1 hour and neutralized with 1N sodium hydroxide and saturated sodium hydrogen carbonate solution. To the mixture was added ethyl acetate, and the separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (50 g, hexane:ethyl acetate=9:1→4:1→2:1) to give methyl 7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1007 mg, 86%) as yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[C@@H:7]2[C@H:8]([CH3:11])[CH2:9][CH2:10][C@@H:6]2[C:5](C(OC)=O)=[CH:4][O:3]1.B.[Na].CO.[Cl-].[NH4+]>O1CCCC1>[OH:1][CH2:2][C@@H:7]1[C@@H:8]([CH3:11])[CH2:9][CH2:10][C@@H:6]1[CH2:5][CH2:4][OH:3]
Reactant: COC(=O)C1=COC(O)[C@@H]2[C@H](C)CC[C@H]12
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CC[C@H](CCO)[C@@H]1CO
Temperature: 80 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
Methyl (4aS, 7R, 7aR)-1, 4a, 5, 6, 7, 7a-hexahydro-1-hydroxy-7-methylcyclopenta[c]pyran-4-carboxylate (300 mg, 0.0014 mol) and sodium boron hydride (270 mg, 0.007 mol) were dissolved in 8 mι of tetrahydrofuran, and while the reaction mixture was refluxed at 80° C., 1.5 mι of methanol was added dropwise in the course of 1 hour. The reaction mixture was stirred at the same temperature for 5 hours, and 10 mι of a saturated ammonium chloride solution wad added. The reaction mixture was once concentrated under a reduced pressure, and extraction was made with ethyl acetate (50 mι×2). The organic layers were joined, dried by adding magnesium sulfate, filtered and thereafter concentrated under a reduced pressure. The residual substance was purified by chromatography using silica gel, and the solvent of the fraction obtained from ether:ethyl acetate=1:1 eluent was distilled, and a colorless oily substance was obtained, i.e., 2-[(1R, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]ethan-1-ol (169 mg, yield=63.8%). This 2-[(1R, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]ethan-1-ol had the following physicochemical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:31])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:27]([F:28])([F:30])[F:29]
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (123 mg, 0.280 mmol) and DIPEA (0.490 mL, 2.80 mmol) in DCM (3.0 mL) was added MeI (0.175 mL, 2.80 mmol) dropwise. The reaction mixture was stirred at rt for 3 h. Purification via MDAP then afforded the title compound (40 mg, 29.9% yield). LCMS: rt=3.60 min, [M+H+]=453
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19](O)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12.CN(C=O)C.C(Cl)(=O)C([Cl:38])=O>C1COCC1>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19]([Cl:38])=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(C(=O)O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Cl)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 100 %

Procedure:
To a pre-cooled solution of acid 214 (1.25 g, 3.02 mmol, scheme 52) in THF (12.07 mL) was added DMF (0.023 mL, 0.302 mmol) and oxalyl chloride (0.660 mL, 7.54 mmol) and the resultant solution was stirred at 0° C. for 30 min. The solvent was evaporated, the residue was triturated with ether and dried under high vacuum to give title compound 219 (1.306 g, 3.02 mmol, 100% yield) as a beige solid. MS: 429.2 (MH+, COOMe), 433.1 (COCl, MH+).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:8]1([CH3:31])[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[CH2:30][CH2:29][CH2:28][NH:27][C:17]3=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([N:27]1[C:17]2=[N:18][C:19]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH3:31])=[CH:9][CH:10]=3)[N:15]=[C:16]2[CH2:30][CH2:29][CH2:28]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCCC3)cc1
Reactant: C=CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: C=CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hex-5-enal (step 1) (solution in DCM, 25 mmol) was treated with 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate B) (3.94 g, 12.5 mmol). After stirring at room temp under nitrogen for 30 mins, sodium triacetoxyborohydride (3.18 g, 15.00 mmol) was added and stirring continued at room temperature overnight. Water (100 ml) was added to the reaction mixture. Once effervescence had ceased the organic portion was separated and dried by passing through a phase separating column. The solvent was removed under reduced pressure and the resulting brown oil was purified by flash column chromatography on silica eluting with 0-100% EtOAc in iso-hexane on a 80 g silca cartridge. The combined fractions were allowed to stand at room temperature for 2 days. The resulting suspension was collected by filtration and dried in a vacuum oven. The crude material was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: [CH2:1]([N:3]1[CH:6](SC2C=CC(C)=CC=2)[CH2:5][C:4]1=[O:15])[CH3:2].[C:16]([OH:19])(=[O:18])[CH3:17]>CCOCC.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([N:3]1[CH:6]([O:18][C:16](=[O:19])[CH3:17])[CH2:5][C:4]1=[O:15])[CH3:2]
Reactant: CCN1C(=O)CC1Sc1ccc(C)cc1
Reactant: CC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOCC
Product: CCN1C(=O)CC1OC(C)=O
Temperature: 110 °C
Yield: 77.6 %

Procedure:
A mixture of 351 mg (1 mmol) of (1'R, 3S, 4R)-3-(1'-tert-butyldimethylsililoxy)ethyl-4-p-methylphenylthio-2-azetidinone and 100 mg (0.5 mmol) of copper (II) acetate monohydrate in 2 ml of acetic acid was heated at 110° C. for 5 minutes with stirring. The reaction mixture was diluted with ether and the insoluble materials were filtered off. The filtrate was washed with saturated sodium bicarbonate solution and then water, dried, and concentrated to produce 223 mg (yield: 77.6%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([OH:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=O.C(Cl)Cl>O.CCCCCC.CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Reaction time: 16 h
Yield: 93 %

Procedure:
To a mixture of 1-(4-(4-chlorophenyl)-2-hydroxybutyl)-imidazole (9.0 kg, 35.9 mol) and trimethylamine-sulfur trioxide complex, 2.25 equivalents (11.25 kg, 80.9 mol), was added triethylamine (45 L, 32.7 kg, 323 mol), dimethyl sulfoxide (40.5 L, 44.5 kg, 570 mol), and methylene chloride (18 L). The resulting mixture was heated to 36°-38° C. and stirred for a minimum of 16 hours. Reaction completion was monitored by thin layer chromatography (10% methanol/methylene chloride+2% NH4OH). Upon completion of reaction, the reaction mixture was cooled to 20°-22° C. The temperature was maintained below 27° C. while 40.5 liters of water were added over a period of 15 to 30 minutes. Hexane (54 L) was then slowly added over a period of 15 to 30 minutes at 20°-25° C. Water (81 L) was then added to the mixture over a period of 30-60 minutes while the temperature was maintained at 20°-25° C. The resulting mixture was allowed to stand at 20°-22° C. for 1 to 2 hours. The mixture was filtered and the filter cake washed twice with water and then twice with hexane and dried under vacuum at 48°-51° C. to afford 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one, 8.30 kg (93% yield).
Reaction SMILES: Cl.[F:2][C:3]1([F:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[C:14](=[O:37])[CH:13]=3)=[CH:11][C:5]=2[O:4]1>C(O)C.O>[F:38][C:3]1([F:2])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][OH:25])=[O:23])[C:14](=[O:37])[CH:13]=3)=[CH:11][C:5]=2[O:4]1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc3c(c2)OC(F)(F)O3)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccc3c(c2)OC(F)(F)O3)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Aqueous HCl (1.42 mL, 1.42 mmol) was added to a solution of (2R)-4-[4-(2,2-Difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (259 mg, 0.474 mmol) in ethanol (5 mL) and water (2 mL) and the reaction was stirred overnight at rt. The solid was collected via filtration, washed with water (5×3 mL) and dried under reduced pressure to afford the title compound (143 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6) d ppm 1.58 (s, 3 H) 2.07-2.24 (m, 1 H) 2.36-2.49 (m, 1 H) 3.11 (s, 3 H) 3.68-3.86 (m, 1 H) 3.98-4.13 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.36-7.49 (m, 1 H) 7.55 (d, J=8.39 Hz, 1 H) 7.68 (s, 1 H) 8.06 (d, J=6.63 Hz, 1 H) 9.24 (br. s., 1 H) 11.08 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:27]4[CH2:26][CH2:25][C:24]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([C:22]#[N:23])[CH2:29][CH2:28]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: N#CC1(c2ccccc2)CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-cyano-4-phenylpiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=<100%, [M+H]+=472.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][N:12]=[N+]=[N-])[O:10][C:6]=2[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[F:21]>CO.[Pt]>[F:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][NH2:12])[O:10][C:6]=2[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][C:3]=1[F:21]
Reactant: [N-]=[N+]=NCC1Cc2c(F)c(F)cc(-c3ccccc3)c2O1
Agent: [Pt]
Solvent: CO
Product: NCC1Cc2c(F)c(F)cc(-c3ccccc3)c2O1
Yield: 109.9 %

Procedure:
Treatment of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide (0.60 g, 2.09 mmol) in methanol (40 mL) with sulfided platinum on carbon (0.15 g, 5 wt. %) generally according to the procedure described for Example 1 provided 0.60 g (96%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a pink solid, hydrochloride salt. mp >240° C.; Anal. calcd. for C15H13F2NOHCl 0.5H2O: C, 58.74; H, 4.93; N, 4.57. Found: C, 58.6; H, 4.56; N, 4.33.
Reaction SMILES: [NH2:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1)=[N:3][NH:4][C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=O>C(O)C>[CH3:24][C:20]1[N:19]=[C:18]([C:2]2[N:1]=[C:5]([CH:7]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]3)[NH:4][N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(C(N)=NNC(=O)C2CN(C(=O)OC(C)(C)C)C2)n1
Solvent: CCO
Product: Cc1cccc(-c2n[nH]c(C3CN(C(=O)OC(C)(C)C)C3)n2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
16.4 g (49.3 mmol) tert-Butyl 3-({2-[amino(6-methylpyridine-2-yl)methylene]hydrazino}carbonyl)azetidine-1-carboxylate are heated under a nitrogen atmosphere to the melting point (220° C.) and kept there for 90 minutes. Ethanol is cautiously added to the reaction mixture during the cooling down phase (at around 135° C.). The reaction mixture is stirred over night at room temperature and the ethanol is evaporated. Due to an incomplete reaction the residue is heated once more to 220° C. for one hour and the work up is repeated yielding 12.91 g (74.58%) of the desired crude product (the byproduct is the cyclised compound which has lost the Boc group).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4][C@@H:3]1[CH2:22][NH:23]C(=O)OCC1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[NH2:23][CH2:22][C@@H:3]1[C@H:2]([OH:1])[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4]1
Reactant: COc1ccc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CN)[C@H](O)C3)c2c1
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of phenylmethyl [((3S,4S)-4-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1(2H)-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]carbamate (1 g, 2.21 mmol) was added 20% Pd(OH)2/C, degassed and placed under 1 atm of H2 for 2 h. The reaction mixture was filtered through Celite and concentrated to obtain the title compound as a yellow oil (622 mg, 89%).
Reaction SMILES: [Si]([N:8]1[C:22]2[C:23]3[C:10]([CH2:11][C@@H:12]4[C:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)=[CH:16][C@H:15]([NH:24][C:25](=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:14][N:13]4[CH3:32])=[C:9]1[CH3:33])(C(C)(C)C)(C)C>CO.O1CCCC1.[Cl-].[Na+]>[CH3:33][C:9]1[NH:8][C:22]2[C:23]3[C:10]=1[CH2:11][C@@H:12]1[C:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)=[CH:16][C@H:15]([NH:24][C:25](=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:14][N:13]1[CH3:32]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3c(c(C)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Yield: 68.4 %

Procedure:
Under argon, 183 mg (0.39 mmol) of 3-[1-(tert-butyldimethylsilyl)-9,10-didehydro-2,6-dimethyl-8α-ergolinyl]-1,1-diethylurea is dissolved in 5 ml of methanol with addition of 2 ml of tetrahydrofuran and stirred with 1 ml of 14N potassium hydroxide solution at room temperature for 17 hours. To work up the mixture, it is diluted with saturated sodium chloride solution and extracted with methylene chloride. The methylene chloride extracts are washed with saturated sodium chloride solution and water and dried over sodium sulfate. The crude product of 128 mg is chromatographed and crystallized as the tartrate, thus obtaining 94 mg (67% of theory) of 3-(9,10-didehydro-2,6-dimethyl-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:3]1=[O:23].Br[C:25]1[CH:26]=[C:27]([CH:41]=[CH:42][C:43]=1[CH:44]([F:46])[F:45])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)=[O:29]>>[F:46][CH:44]([F:45])[C:43]1[CH:25]=[CH:26][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)=[O:29])=[CH:41][C:42]=1[C:6]1[CH:5]=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:3](=[O:23])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(N2CCOCC2)c1=O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(C(F)F)c(Br)c1
Product: Cn1cc(-c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc2C(F)F)cc(N2CCOCC2)c1=O
Yield: 8 %

Procedure:
Step 3: Method 2 was followed using 1-methyl-3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one and 3-bromo-4-(difluoromethyl)-N-(3-(trifluoromethyl)phenyl)benzamide to give 4-(difluoromethyl)-3-(1-methyl-5-morpholino-6-oxo-1,6-dihydropyridin-3-yl)-N-(3-(trifluoromethyl)phenyl)benzamid in 8% yield. LC/MS (m/z)=508.1 (MH+), Rt=0.98 min. 1H NMR (400 MHz, <cd3od>) δ ppm 3.12-3.21 (m, 4H), 3.64 (s, 3H), 3.80-3.90 (m, 4H), 6.96 (d, J=1.96 Hz, 2H), 7.41 (d, J=1.96 Hz, 2H), 7.52-7.62 (m, 1H), 7.84-7.92 (m, 1H), 7.97 (br. s., 2H), 8.05-8.12 (m, 1H), 8.14-8.20 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2([C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=4)=[CH:21][CH:20]=3)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN1CCC(C(=O)Nc2cc(Cl)cc(Cl)c2)(c2ccc(I)cc2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(C(=O)Nc2cc(Cl)cc(Cl)c2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Temperature: 25 °C
Yield: 400 %

Procedure:
To a flask containing 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid (3,5-dichloro-phenyl)-amide (175 mg, 0.35 mmol) was added Pd(PPh3)4 (13 mg, 0.035 mmol, 10 mol %), 3-cyanophenylboronic acid (78 mg, 0.53 mmol, 1.5 eq.) and Na2CO3 (0.53 g, 5 mmol). The mixture was suspended in toluene (5 mL), EtOH (2.5 mL) and H2O (2.5 mL) and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by HPLC to give 4-(3′-cyano-biphenyl-4-yl)-1-methyl-piperidine-4-carboxylic acid (3,5-dichloro-phenyl)-amide as a white solid (0.066 g, 1.4 mmol, 14%). 1H NMR (300 MHz, CDCl3): δ 7.95 (M, 1H), 7.91 (M, 1H), 7.62 to 7.76 (m, 6H), 7.51 (d, 2H), 7.19 (br, 1H), 7.15 (t, 1H), 2.71 (m, 6H), 2.42 (s, 3H), 2.30 (m, 2H). MS (ESI): 464.2/466.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.B.CO>O1CCCC1>[C:7]1([N:6]([CH2:4][CH2:3][CH2:2][Br:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCBr)N(c1ccccc1)c1ccccc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: BrCCCN(c1ccccc1)c1ccccc1
Temperature: 21 °C

Procedure:
A solution of 304 g. (1.00 moles) of 3-bromo-N,N-diphenyl propionamide in 800 ml. of tetrahydrofuran is stirred and maintained at -3° C. to -1° C. while adding 1.1 l. of a 1 molar solution of borane in tetrahydrofuran over a period of 15 minutes. The reaction is allowed to gradually warm to 21° C. over a period of about 1.75 hours and refluxed for a period of about 10 minutes. The reaction mixture is then treated dropwise with 50 ml. of methanol. After gas evolution ceases, solvent is removed under vacuum. The oily residue is dissolved in cyclohexane, washed with 20% caustic solution and then with water, dried and passed through a column of about 400 g. of silica gel, eluting with cyclohexane, to give 3-[N,N-diphenylamino]-1-bromopropane.