Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=C1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:27][C:21]3[C:26]([C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:7]=[CH:6]2
Reactant: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: CCO
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)[nH]c2ccccc12
Yield: 102.6 %

Procedure:
To a stirred suspension of the 1-(6-methoxy-2-naphthyl)heptan-1-one (81.5 g, 301.44 mmol) in ethanol (2000 mL) under N2 was added phenylhydrazine (35.857 g, 331.58 mmol) and p-toluene sulfonic acid monhydrate (120.41 g, 633.02 mmol). The mixture was refluxed. Warming gave a homogenous solution. (A modification of this Fisher indole reaction to incorporate varied substitution on the indole ring utilizes an N-arylhydrazone in place of the aryl hydrazine-details of hydrazone preparation in a recent JACS, S. Wagaw; B. H. Yang; S. L. Buchwald. JACS, 121, 1999, 10251-10263). After 92 h reflux, heating was stopped and the reaction mixture cooled and rotovap'd to a residue. The residue was partitioned between EtOAc (1700 mL) and 1 N HCl (500 mL). The layers were shaken, separated, and the organic layer washed with 1 N HCl (2×300 mL), sat. aq. NaHCO3 (3×250 mL), H2O (3×250 mL), brine (2×250 mL), dried over Na2SO4, filtered, rotovap'd and dried in vacuo to give a dark viscous oil (106.2 g). The residue was triturated with hexane to give an off-white solid which was collected, rinsed and dried in vacuo to give the product as an off-white solid (95.9 g, 279.21 mmol, 93%) which dec. 93-96° C. 400 mg of the crude indole was recrystallized from hexane to give the product as a white solid (298 mg) with mp 95-97° C.; 1H NMR (DMSO-d6) δ 0.82 (t, J=7.0 Hz, 3H), 1.31 (m, 4H), 1.66 (m, 2H), 2.89 (t, J=7.6 Hz, 2H), 3.90 (s, 3H), 6.98-7.02 (m, 1H), 7.07-7.10 (m, 1H), 7.21 (dd, J=2.4, 8.9 Hz, 1H), 7.34-7.37 (m, 2H), 7.54 (d, J=7.94 Hz, 1H), 7.73 (dd, J=1.5, 8.6 Hz, 1H), 7.88 (d, J=9.00 Hz, 1H), 7.93 (d, J=8.55 Hz, 1H), 8.03 (s, 1H), 11.17 (s, 1H); IR (solid) 3350, 2960, 2920, 2840, 1600, 1200, 740, cm−1; mass spectrum [ESI], m/z 344 (M+H)+;
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH:20]([CH3:22])[CH3:21])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si:24]([CH3:40])([CH3:39])[CH2:25][CH2:26][O:27][CH2:28]N1C2C=NNC(=O)C=2C=C1.[Cl-].[NH4+]>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:40])([CH3:39])[CH3:23])[C:18](=[O:19])[C:13]=2[C:12]([CH:20]([CH3:22])[CH3:21])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]ncc21
Reactant: CC(C)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)c1cn(COCc2ccccc2)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 0 °C
Yield: 62 %

Procedure:
Reaction was carried out in the same manner as in Reference example 18-(a) except for using 0.98 g (3.3 mmol) of 1-benzyloxymethyl-3-isopropyl-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Reference example 21-(e) in place of 1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction mixture was poured into ice-water, neutralized with a saturated aqueous solution of ammonium chloride and extracted with toluene. The organic layer after separation was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=3:2 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.87 g of the title compound as a slightly yellowish oil. (Yield: 62%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH:13]1([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[CH2:15][CH2:14]1>>[CH:13]1([NH:16][C:17]([C:18]2[CH:23]=[C:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][CH:10]=[CH:11][N:12]=4)=[CH:4][CH:3]=3)[C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:34])[CH2:14][CH2:15]1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2ncc[nH]2)cc1

Procedure:
Example 8 was prepared using 2-(4-bromophenyl)-1H-imidazole and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (118 mg, 0.550 mmol), tert-butyl (4-aminocyclohexyl)carbamate (140 mg, 0.66 mmol) and triethylamine (0.23 mL, 1.6 mmol) in isopropyl alcohol (5 mL) was heated at 100° C. for 1 h. The mixture was concentrated to give the desired product as a mixture of cis- & trans-isomer mixtures to be used in the next step directly. LCMS calculated for C18H25N4O4S (M+H)+: m/z=393.2. Found: 393.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=CC(=O)O
Reactant: CSc1ccc(/C=C/C(C)=O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 10.5 g (54.6 mmol) of (E)-4-[4-(methylthio)phenyl]but-3-en-2-one and 5.02 g (54.6 mmol) of glyoxylic acid monohydrate in 15 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-6-[4-(methylthio)-phenyl]-4-oxo-2,5-hexadienoic acid of melting point 160°-163°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[S:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16]1COC[CH2:17]1>ICC>[CH2:16]([S:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=2[N:9]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Dissolve 5-Nitro-3H-benzooxazole-2-thione (10.58 g, 53.9 mmol) in anhydrous THF (300 mL). Cool the mixture to 0° C. in an ice bath. Add NaH (4.90 g, 60% dispersion in mineral oil) slowly. Stir the resulting mixture at 0° C. for 10 min. Add iodoethane (20.0 mL, 0.250 mmol) to the stirring mixture. Allow the mixture to warm to room temperature and stir overnight. Adsorb the reaction mixture onto silica gel and subject to flash column chromatography in 2 batches (330 g, 120 g columns, eluting with 10-50% ethyl acetate/n-hexane both times) to yield the desired product (4.93 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, J=2.4 Hz, 1H), 8.23 (dd, J=9.2, 2.6 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 3.37 (q, J=6.8 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([O:15]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O.[CH3:17][O:18][CH:19]([O:24][CH3:25])[CH2:20][CH2:21][CH2:22][NH2:23]>C[O-].C[O-].C([Sn+2]CCCC)CCC>[CH3:17][O:18][CH:19]([O:24][CH3:25])[CH2:20][CH2:21][CH2:22][NH:23][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:23][CH2:22][CH2:21][CH2:20][CH:19]([O:24][CH3:25])[O:18][CH3:17])=[O:15]
Reactant: COC(=O)CCCCCCCCC(=O)OC
Reactant: COC(CCCN)OC
Agent: CCCC[Sn+2]CCCC
Agent: C[O-]
Product: COC(CCCNC(=O)CCCCCCCCC(=O)NCCCC(OC)OC)OC
Yield: 85.3 %

Procedure:
Dimethyl sebacate (25.00 g, 0.1085 mol) was aminated with 30.63 g (0.230 mol) of 4,4-dimethoxybutylamine and 2.50 g (0.00847 mol) of dibutyl tin dimethoxide in 200 g of mixed xylenes according to the procedure used in Example 1. This procedure afforded 40.00 g (0.0925 mol, 85.2% isolated yield) of the desired N,N'-bis(4,4-dimethoxybutyl)sebacamide after recrystallization from mixed xylenes, mp 83.5°-85.5° C.; IR (KBr) 1640 (C=O), 1540, 1190, 1135, 1040 cm-1 ; 1H NMR (CDCl3 ; 300 MHz) δ1.13 (br s, 8H, --CH2 --), 1.35-1.58 (m, 12H, --CH2.00 (t, 4H, J=7.6 Hz, CO--CH2 --), 3.08 (m, 4H, --NH2CH2 --), 3.16 (s 12H, --OCH3), 4.20 (t, 2H, J=5.1 Hz, CH2CH--), 6.38 (t, 2H, J=5.4 Hz, --NH--CH2 --), 13C NMR (CDCl3 ; 75.5 MHz) δ24.3, 25.5, 28.8, 28.9, 29.7, 36.3, 38.8, 52.7, 104.0, 173.0; MS (70 eV) m/z (rel. intensity) 353 (1.90), 305 (9.00), 236 (8.14), 128 (6.94), 100 (8.59), 85 (20.70) 84 (40.52), 75 (100.00); HRMS (FAB) 433.3278 (MH+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[N:27]=[N:26]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:34])[N:27]=[N:26]1
Reactant: N#Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Reactant: O=C(O)CCCc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Cyano-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride (50 mg, 0.137 mmol) and 4-(1H-1,2,3-triazol-4-yl)butanoic acid (25.6 mg, 0.165 mmol) were suspended in EtOAc (5 mL) and triethylamine (0.067 mL, 0.481 mmol) was added. After 5 mins at RT, T3P, 50% in EtOAC (0.164 mL, 0.275 mmol) was added and the mixture allowed to stir at RT for 20 hours. EtOAc (30 ml) was added and the mixture washed with a 10% solution of citric acid and a saturated solution of brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. Purification via silica chromatography eluting with 0-10% MeOH/DCM gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH2:20][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[O:11][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc(Br)c(OCCCC)c1
Reaction time: 8 h
Yield: 66.81 %

Procedure:
To a flask containing 4-bromo-3-hydroxybenzoic acid (T9.1)(available from Combi-Blocks Inc.)(2.40 g, 11.06 mmol) and Cs2CO3 (8.287 g, 25.44 mmol) in DMF (40 mL), was added 1-bromobutane (2.494 mL, 23.22 mmol), and the mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by CombiFlash® column chromatography (0 to 20% EtOAc/Hexanes) to provide T9.2 (2.4326 g, 66.81% yield).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].CC(C)(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C.P(=O)(O)(O)O.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:4][C:2]([NH:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: C=C(C)C
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)Nc1cccnc1N1CCNCC1
Reaction time: 1 h

Procedure:
Isobutylene (10 ml) is condensed into a solution of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 200 mg) in methylene chloride (10 ml) at -70°. Phosphoric acid (85%, 50 μl) is added and the mixture stirred for 60 minutes. Boron trifluoride etherate (200 μl) is added dropwise and the resulting suspension is stirred 8 hours at reflux and overnight at 20°-25° allowing the isobutylene to evaporate. The suspension is diluted with water and ammonium hydroxide is added until basic to pH paper and then extracted with methylene chloride (3 ×). The combined extracts are dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to a liquid which is flash chromatographed (silica gel, 230-400 mesh), eluting with methanol/chloroform (3/20). The appropriate fractions are pooled and concentrated to give an oil. The NMR, CMR, IR, and MS (m/e) M+234 support the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.C[Si](C)(C)[O:32][C@@H:33]1[C@@H:38]([O:39][Si](C)(C)C)[C@H:37]([O:44][Si](C)(C)C)[C@@H:36]([CH2:49][O:50][Si](C)(C)C)[O:35][C:34]1=O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:34]2[C@H:33]([OH:32])[C@@H:38]([OH:39])[C@H:37]([OH:44])[C@@H:36]([CH2:49][OH:50])[O:35]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclopentyloxy)ethoxy)benzyl)benzene (Intermediate AC) (0.41 g) in anhydrous toluene/THF (v/v=2:1, 10 mL), n-BuLi (1.3 eq) was added dropwise at −78° C. and stirred for 1 h. Then the mixture was transferred to a solution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (1.5 eq) in anhydrous toluene (10 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and the mixture was allowed to warm to room temperature and stirred overnight. Then 20 mL of water was added. The organic phase was separated, and the water phase was extracted with EtOAc. The organic phases were combined, washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified on a flash column (0.8 g, Rf=0.1-0.2, EA:PE=2:1) to collect the crude product. The crude product was dissolved in anhydrous CH3CN (10 mL), Et3SiH (1 mL) was added, the mixture was cooled to −5° C., and BF3.Et2O (0.6 mL) was added dropwise. Then the reaction was allowed to warm to 20° C. and stirred overnight. After the reaction reached completion, it was quenched with saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with EtOAc and washed with water and brine. The product was dried with anhydrous Na2SO4, filtered, concentrated to a solid, and purified by preparative HPLC to obtain compound AD as a white powder upon freeze-drying. 1H NMR (CD3OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.07 (m, 5H), 3.87 (s, 1H), 3.71 (m, 3H), 3.15 (m, 1H), 3.10 (m, 2H), 3.07 (m, 6H), 1.72 (m, 6H), 1.55 (m, 2H); MS ESI (m/z): 494 (M+H)+, calc. 493.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:15][CH2:16]O.O>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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]=[CH2:16])=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: CCO
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: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 2-bromo-5-methyl-pyridine (1.7 g, 10 mmol), 2,4,6-trivinyl-cyclotriboroxanein (1.20 g, 5 mmol) and Na2CO3 (3.73 g, 35.2 mmol) in toluene (15 mL)/EtOH (10 mL)/H2O (5 mL) was added Pd(PPh3)4 (300 mg, 0.25 mmol) under N2. The mixture was stirred at 100° C. overnight. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography column (PE:EA=50:1) to afford 5-methyl-2-vinyl-pyridine (900 mg, 75.6%) as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16].[OH-].[K+].O1CCOCC1>CCOCC>[CH2:5]([O:4][C:2]([O:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CC(=NO)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#CC(=NOC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
A solution of benzyl chloroformate (5.1 g.) in ether (40 ml.) was added to a solution of 2-hydroxyimino-2-phenylacetonitrile (4.4 g.) in a mixture of a 1N potassium hydroxide aqueous solution (30 ml.) and dioxane (10 ml.) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 4 hours at room temperature. The ether layer was separated from the reaction mixture and the aqueous layer was further extracted with ether. Both ether layers were combined, washed with water and dried over magnesium sulfate. The solvent was distilled off and to the residue was added n-hexane. The precipitated crystals were collected by filtration to give 2-benzyloxycarbonyloxyimino-2-phenylacetonitrile (5.2 g.), mp 73° to 75° C.
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)[N:14]([CH3:28])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)#[N:30]>C(Cl)(Cl)Cl>[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]([C:28]#[N:30])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: N#CBr
Solvent: ClC(Cl)Cl
Product: N#CN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
A solution of 29.5 g (79 mM) of 8α-benzyloxycarbonylamino-6-methylergoline obtained from step (a) and 25 g (236 mM) cyanobromide in 600 ml chloroform is stirred for 65 hours at room temperature and finally concentrated on a rotary evaporator to give the heading compound which is dried in a high vacuum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.[CH3:15][N:16]([CH3:31])[CH2:17][CH2:18][N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[CH3:15][N:16]([CH3:31])[CH2:17][CH2:18][N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH:29][C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: O=C(O)c1ccc(-c2cccs2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4cccs4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-thiophen-2-yl-benzoic acid (0.098 g, 0.48 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.10 g, 0.40 mmol) to afford the title compound as a white solid. LC/MS: Retention time=4.37 min; (m/z): calcd for C23H24N4OS2 (M+H)+: 437.6; found: 437.3.
Reaction SMILES: [OH:1][C@H:2]([CH3:19])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:4].[Cl:20][C:21]1[C:26](O)=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O.O1CCCC1>[Cl:20][C:21]1[C:26]([O:1][C@@H:2]([CH3:19])[C:3]([NH:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[O:4])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1
Reactant: Oc1cc(Cl)cnc1Cl
Reactant: C[C@@H](O)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Oc1cc(Cl)cnc1Cl)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a tetrahydrofuran solution (148 ml) of tert-butyl 4-{[(2R)-2-hydroxypropanoyl]amino}piperidine-1-carboxylate (5.13 g), 2,5-dichloropyridin-3-ol (3.40 g) and triphenylphosphine (6.41 g) was added dropwise at room temperature a tetrahydrofuran solution (40 ml) of di-tert-butyl azodicarboxylate (5.63 g) over 10 minutes. The reaction solution was stirred at room temperature for 1 hour, then poured into water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-({(2S)-2-[(2,5-dichloropyridin-3-yl)oxy]propanoyl}amino)piperidine-1-carboxylate (6.40 g).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[Br:14][CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](CBr)NC(=O)OC(C)(C)C
Reaction time: 14 h
Yield: 50.1 %

Procedure:
(R)-tert-Butyl 1-hydroxypropan-2-ylcarbamate (1 g, 5.71 mmol) and carbon tetrabromide (2.84 g, 8.56 mmol) were stirred in CH2Cl2 (20 mL) at −20° C. under argon. A solution of triphenylphosphine (2.40 g, 9.13 mmol) in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to reach rt and stirred for 14 h. H2O (50 mL) was added to the reaction mixture and the aqueous layer was removed and the CH2Cl2 layer was dried over Na2SO4, filtered, and evaporated. The residue was applied to a silica ISCO column and eluted with 5:1 hexanes/EtOAc. Intermediate 5A (0.68 g, 2.86 mmol, 50.0% yield) was isolated as a white solid. LC-MS (ESI) 183.9 (M−tBu+H), RT=1.76 min (Method B).