Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[C:8]([Si:12]([O:15][C@@H:16]1[C@H:25]2[C@@:20]([CH3:30])([C@@H:21]([C@H:26]([CH3:29])[CH2:27]I)[CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH2:17]1)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1.O1CCCC1.[Zn]>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][CH2:6][CH2:29][C@H:26]([C@@H:21]1[C@:20]2([CH3:30])[C@H:25]([C@@H:16]([O:15][Si:12]([C:8]([CH3:10])([CH3:9])[CH3:11])([CH3:14])[CH3:13])[CH2:17][CH2:18][CH2:19]2)[CH2:24][CH2:23][CH2:22]1)[CH3:27])[CH3:2]
Reactant: C[C@H](CI)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: C=CC(=O)OCC
Agent: [Zn]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCC[C@@H](C)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To 342.5 mg (5.24 mMol) of Zn powder are added 1.57 ml of tetrahydrofuran/pyridine 2/1. The reaction mixture is stirred under Argon, 247.2 mg (1.04 mMol) of NiCl2.6H2O and then 472.2 mg (4.72 mMol) of ethylacrylate are added. The reaction mixture is heated at 65° for 30 minutes, cooled to room temperature and 947 mg (2.10 mMol) of (1S,4aR,5R,8aR)-tert-Butyl[5-[(S)-2-iodo-1-methyl-ethyl]-4a-methyl-decahydronaphtalen-1-yloxy]-dimethylsilane dissolved in 1.57 ml of tetrahydrofuran pyridine 1/2 are added and the reaction mixture kept overnight at room temperature. Filtration through Speedex and washing of the filter cake with ethylacetate is followed by evaporation in vacuo to 1/3 of the volume. The solution is diluted with ethylacetate and the organic phase is washed 4 times with a disodium ethylene diamine tetraacetate dihydrate (EDTA) solution (8 g of EDTA and 8 g of NaHCO3 in 100 ml water) and twice with brine. The organic phase is dried over Na2SO4, filtered and evaporated in vacuo. The residue is chromatographed over 100 g of silicagel with hexane/ethylacetate 98/2 to yield 269 mg of starting material and 390 mg (44%) of (R)-5-[(1R,4aR,5S,8aR)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphtalen-1-yl)-hexanoic acid ethyl ester as an amorphous product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH:18][CH2:19][C:20](=O)[CH3:21]>O>[CH3:21][C:20]1([CH2:19][OH:18])[NH:12][C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: CC(=O)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(CO)Nc2cccc3cccc(c23)N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 79.1 g of 1,8-diaminonaphthalene, 57.4 g of 96% strength sulphuric acid and 700 ml of water is initially introduced into the reaction vessel at 50° C., and 57.8 g of hydroxy acetone are metered in over a period of 10 minutes. The mixture is then subsequently stirred at 50° C. for 2 hours and cooled to 0° C., and the product is isolated by filtration and dried at 70° C. in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:32])[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=2)([OH:24])[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:33])[CH:13]=1)C(OCC)=O)[CH3:2].[Na+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:32])[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=2)([OH:24])[C:20]([F:21])([F:23])[F:22])=[C:14]([Cl:33])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Temperature: 140 °C

Procedure:
To a mixture of 2-{3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzyl}-malonic acid diethyl ester (214 mg) and NaCl (29 mg) in DMSO (4 mL) was added a small amount of water (0.011 mL). The mixture was then heated to 140° C. for 7 days. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless, viscous oil (127 mg). MS (m/e)=450.1 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[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][CH2:22][CH3:23].[C:49]([O-])(=[O:51])C.[Na+]>CN(C)C=O>[CH2:31]([N:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[CH:49]=[O:51])[CH2:6][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][CH2:22][CH3:23])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccccc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccccc1C=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Phosphorus oxychloride (15.3 g, 0.1 mole) was added dropwise with stirring, at 5° C., under nitrogen, to N,N-dimethylformamide (DMF, 50 mL). The resulting orange solution was stirred for 2 hours, then 42 g (0.08 mole) of N,N-dioctadecylaniline was added all at once. The reaction mixture was heated in a water bath to 90° C., and stirring was continued for 4 hours. The hot solution was poured over 200 g of crushed ice and naturalized to pH 6 by a slow addition of solid sodium acetate with vigorous stirring. The greenish-tint crystalline precipitate was filtered by suction, washed with water on the filter and air dried. The light green product was recrystallized from isopropanol to yield 46.5 g (93%) of pale-green crystals mp 65°-66° C.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:11]2([O:15][N:14]=[C:13]([C:16](O)=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=[N:31]C=2C=1.C(N)CC1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[O:15]1[C:11]2([CH2:19][CH2:20][NH:8][CH2:9][CH2:10]2)[CH2:12][C:13]([C:16]([NH2:31])=[O:17])=[N:14]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C(=O)O)=NO2
Agent: NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)C1=NOC2(CCNCC2)C1
Reaction time: 4 h

Procedure:
To a solution of 8-(tert-butoxycarbonyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-3-carboxylic acid (300 mg, 1.06 mmol), EDC (242 mg, 1.26 mmol), HOBt (171 mg, 1.26 mmol) in DMF (4 mL) was added phenethylamine (159 μL, 1.26 mmol). After 4 h at room temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (1×5 mL) and brine (1×5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude oil was taken up in CH2Cl2 (4 mL) and treated with TFA (2 mL). The reaction mixture was concentrated and the crude oil purified by reverse-phase chromatography (10-75% MeCN/H2O with 0.05% TFA) to give the N2-phenylethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-3-carboxamide confirmed by MS (ESI+): cal'd [M+H]+ 288.2, obs'd 288.2.
Reaction SMILES: C([O:8][C:9]1[C:33]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[C:11]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:10]=1)C1C=CC=CC=1>[Pd].C1(C)C=CC=CC=1.CO.C(OCC)(=O)C>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:32]=[C:33]([C:34]([CH3:35])([CH3:36])[CH3:37])[C:9]([OH:8])=[CH:10][C:11]=2[C:38]([CH3:40])([CH3:41])[CH3:39])=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(OCc3ccccc3)cc2C(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)cc2C(C)(C)C)ccc1N
Yield: 63.7 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-benzyloxy-2,5-di-t-butylphenoxy)-2-nitrophenyl]-N-methylcarbamate (7.1 g), palladium on carbon (10%, 0.7 g) and toluene/methanol/ethyl acetate=16/16/25 (57 ml) and the reaction mixture was purified to give the title compound (3.56 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][NH2:10].Cl.O.[C:13]([OH:17])(=[O:16])[CH:14]=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][N:10]=[CH:14][C:13]([OH:17])=[O:16]
Reactant: NNc1cc(F)ccc1Br
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)C=NNc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of (2-bromo-5-fluorophenyl)hydrazine (2.15 g, 10.5 mmol) and concentrated HCl (1.2 mL) in water (30 mL) was added glyoxylic acid hydrate (1.06 g, 11.5 mmol). The resulting mixture was stirred at room temperature for 2 h. The precipitate that formed was collected by filtration, washed with water and dried at reduced pressure to afford the title compound as a yellow solid (2.67 g, 98% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 12.57 (1H, s), 10.65 (1H, s), 7.65 (1H, s), 7.56 (1H, dd, J=8.7, 5.9 Hz), 7.31 (1H, dd, J=11.4, 3.0 Hz), 6.73 (1H, td, J=8.5, 3.0 Hz); LCMS (+ESI, M+H+) m/z 261-263.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[NH:22]1[CH:27]=[CH:26][C:25](=O)[N:24]=[CH:23]1>COCCOC>[N:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:24][CH:23]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=c1cc[nH]cn1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccncn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 4(1H)-pyrimidinone, using dry DME as the reaction solvent: MS (ESI) m/z 391 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>C(#N)C>[CH:18]1([C:21]([N:15]2[CH2:16][CH2:17][CH:12]([CH:9]3[C:10]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH2:7][CH2:8]3)[CH2:13][CH2:14]2)=[O:22])[CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)C(C1CCNCC1)CC2
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(c1)C(C1CCN(C(=O)C3CC3)CC1)CC2
Reaction time: 72 h

Procedure:
A mixture of 4-(6-methoxy-indan-1-yl)piperidine (0.46 g, 2 mmol), cyclopropane carbonyl chloride (0.21 g, 2 mmol), and excess powdered potassium carbonate in acetonitrile was stirred for 72 h. The solution was filtered and concentrated in vacuo. The residue chromatographed on silica eluting with 2% methanol in methylene chloride to give, on concentration of the appropriate fractions, the product as an oil (0.5 g, 83%), IR (KBr) 2940, 1636, 1490, 1244, 1034 cm-1 ; H NMR (CDCl3, 300 MHz) δ 7.08 (d, 1H, J=7.9 Hz), 6.70-6.67 (m, 2H), 5.27 (m, 2H), 3.77 (s, 3H), 3.10-3.04 (m, 1H), 2.83-2.67 (m, 4H), 2.13-2.03 (m, 1H), 1.92-1.83 (m, 2H), 1.75-1.67 (m, 2H), 1.52-1.48 (m, 1H), 1.37-1.18 (m, 2H), 0.96-0.91 (m,2H). 0.73-0.67 (m, 2H). Anal. Calc'd for C19H25 NO2 ·0.2CH2Cl2 : C, 73.08%; H, 8.03%; N, 4.39%. Found: C, 72.81%; H, 7.94%; N, 4.44%.
Reaction SMILES: [C:1]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=S)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:19][CH2:20]N(CC)CC.C[N:27](C=O)C>CO.[Pd].Cl[Hg]Cl>[CH2:19]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[NH:27])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: Cl[Hg]Cl
Solvent: CO
Product: CCN(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 79 %

Procedure:
A solution of 211 (100 mg, 0.38 mmol) in methanol was treated with 10% Pd-C (50 mg) and was shaken under 60 psi H2 in a Paar apparatus. The catalyst was filtered (celite) and solvent was evaporated to afford a solid residue which was dissolved in DMF (2.5 mL). To this solution was added bis-Boc-thiourea (113 mg, 0.42 mmol), and Et3N (111 mL, 0.80 mmol). The DMF solution was cooled to 0° C., HgCl2 (114 mg, 0.42 mmol) was added, and the mixture was stirred at 0° C. for 3 h then at rt for 20 h. The crude product was isolated in the same manner as described for Example 201 and was chromatographed on silica gel (1/1-ethyl acetate/hexane) to afford bis-Boc-guanidine 212 (145 mg, 79%) as a colorless glass: 1H NMR (300 MHz, CDCl3) d 1.25 (t, 3H, J=7.6), 1.49 (s, 9H), 1.55 (s, 9H), 2.16 (s, 3H), 2.68 (q, 2H, J=7.6), 3.91 (s, 3H), 7.86 (d, 1H, J=1.5), 8.05 (d, 1H, J=1.5), 8.76 (s, 1H), 10.46 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [CH2:1]([CH:4]([NH2:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O1CCCC1>C(OCC)C>[Br-:9].[CH2:1]([CH:4]([NH2+:8][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: CCCCCCCCCCCCBr
Reactant: C=CCC(N)CC=C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(CC=C)[NH2+]CCCCCCCCCCCC
Product: [Br-]
Temperature: 65 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a 2 L Morton flask was added diallylmethylamine (100 g), 1-bromododecane (249 g), and tetrahydrofuran (750 mL). The mixture was heated to 65° C. for 44 h, and then allowed to cool to room temperature. The solvent was removed by rotary vacuum evaporation to leave two layers. Diethylether (500 mL) was added and the mixture was stirred for 1 hr. The mixture was allowed to settle and the top layer was decanted and discarded. Additional diethylether (500 mL) was added. The mixture was stirred for 24 h, and the top layer was again decanted and discarded. The remaining oil was dried in a vacuum oven at 65° C. for 4 days to yield 67 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:21](I)([CH3:23])[CH3:22]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:14][CH:21]([CH3:23])[CH3:22])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: CC(C)I
Reactant: O=C1NCCc2cc(F)c(O)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(F)cc2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.6 %

Procedure:
To a solution of 8-chloro-6-fluoro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (Cpd O, 131 mg, 0.607 mmol) in DMF (3.0 mL) was added cesium carbonate (0.210 g, 0.645 mmol) and iso-propyl iodide (0.0850 mL, 0.850 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc and washed with water (2×) and brine. The organic layer was concentrated under vacuum and the residue was purified by column chromatography (40-100% EtOAc/heptane) to give the title compound (Cpd P, 62 mg, 40%) as a white solid. MS 258 [M+H].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22]([OH:24])=O)[N:19]([CH3:21])[N:20]=1.[N:25]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([CH2:32][CH2:33][OH:34])[CH2:26][CH2:27]2)=[O:24])[N:19]([CH3:21])[N:20]=1
Reactant: OCCN1CCCNCC1
Reactant: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)N1CCCN(CCO)CC1
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 16D], 5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid (Example 12C]) and 2-(1,4-diazepan-1-yl)ethan-1-ol with DCC and catalytic amount of DMAP gave the title compound in 32% yield as white foam. MS: 445.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:30]1[C:25]([NH2:24])=[C:26]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:6]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Reactant: Nc1ccccc1S(N)(=O)=O
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cccc(S(N)(=O)=O)c3N)cc2Br)ccc1O
Yield: 53.8 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 2-aminobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 11 mg (54%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(S(=O)(=O)c3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and benzenesulfonyl chloride in the same manner as in Example 32.
Reaction SMILES: O1CCN([CH2:7][C:8]2[NH:22][C:21]3[C:23]4[C:9]=2[CH2:10][C@@H:11]2[C@@H:16]([C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]([NH2:24])[CH2:13][N:12]2[CH2:25][CH2:26][CH3:27])CC1.Cl[O:29][C:30](C)(C)C.N.Cl.O1CCC[CH2:37]1>C(N(CC)CC)C>[CH2:25]([N:12]1[C@H:11]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:23]=3[C:9]([CH2:10]2)=[C:8]([CH:7]=[CH2:37])[NH:22]4)[CH2:15][C@H:14]([NH:24][CH:30]=[O:29])[CH2:13]1)[CH2:26][CH3:27]
Reactant: C1CCOC1
Reactant: CC(C)(C)OCl
Reactant: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]21
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Product: C=Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC=O)CN1CCC
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
1.1 g of 2-morpholinomethyl-6-n-propyl-8alpha-ergolinylamine (3 mmol) is formylated as described in example 4, then dissolved in 50 ml of tetrahydrofuran and 1 ml of triethylamine, cooled to -40° C. and mixed with a solution of 0.5 ml of tert-butyl hypochlorite in 10 ml of tetrahydrofuran. After 30 minutes stirring, the batch is poured on ice, made alkaline with ammonia and extracted with dichloromethane. The organic phases are dried and concentrated by evaporation. The residue is dissolved in 40 ml of tetrahydrofuran and added to a Wittig reagent, which was prepared from 6 g of methyl triphenylphosphonium bromide and 2 g of potassium tert-butylate in 70 ml of tetrahydrofuran by stirring 15 minutes at -78° C. It is allowed to react for 1 hour at -78° C., then heated slowly to -40° C. and stirred for 2 hours at -40° C. Then it is mixed with hydrochloric acid solution, extracted with ethyl acetate and the organic phases dried and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane/methanol and crystallized, yield 35%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:28])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccc(F)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2ccc(F)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-Fluorophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 50) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). White solid (53 mg, 75%);
Reaction SMILES: [NH2:1][C@:2](C1C=CC(I)=CC=1Cl)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].Cl[CH2:28][Cl:29]>C(N(CC)CC)C.C(OCC)C.ClCCl.[Cu](I)I>[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:3]([NH:5][C:8]1[CH:7]=[CH:6][C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:3][C:28]=1[Cl:29])=[O:4]
Reactant: ClCCl
Reactant: NC(=O)[C@](N)(Cc1ccccc1)c1ccc(I)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(NC(=O)[C@@H](N)Cc2ccccc2)c(Cl)c1
Yield: 90 %

Procedure:
To a dry flask were added (S)-2-amino-(2-chloro-4-iodo-phenyl)-3-phenyl-propionamide (980 mg, 2.44 mmol), bis-dichlorotriphenylphosphine palladium (19.8 mg, 0.0489 mmol), and copper iodide (9.5 mg, 0.049 mmol). To this mixture was added trimethylsilylacetylene (269.7 mg, 2.69 mmol) in dry triethylamine (1.46 mL). Dry dichloromethane (1 mL) was added after 30 minutes. After 3 hours additional bis-dichlorotriphenylphosphine palladium (40 mg, 0.099 mmol) and copper iodide (20 mg, 0.099 mmol) were added. After 1 hour the reaction mixture was diluted with a 1:1 v/v mixture of diethyl ether/dichloromethane and passed through a bed of silica gel and the silica gel then eluted with a 2:3 v/v mixture of diethyl ether/dichloromethane. The eluant was concentrated in vacuo and the crude residue was purified by chromatography over silica gel gradient eluted with 5 to 30% v/v diethyl ether in hexanes. The pooled fractions containing product were concentrated to give (S)-2-amino-N-(2-chloro-4-trimethylsilanylethynyl-phenyl)-3-phenyl-propionamide as a white solid (820 mg 90% yield).
Reaction SMILES: Cl.[C:2]([C:7]1[C:8](=[O:20])[CH2:9][CH:10]([CH2:14][O:15]C(C)(C)C)[CH2:11][C:12]=1[OH:13])(=[O:6])[CH2:3][CH2:4][CH3:5]>C(O)C>[C:2]([C:7]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][OH:15])[CH2:9][C:8]=1[OH:20])(=[O:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(=O)C1=C(O)CC(COC(C)(C)C)CC1=O
Agent: Cl
Solvent: CCO
Product: CCCC(=O)C1=C(O)CC(CO)CC1=O
Yield: 74.3 %

Procedure:
At 0° to 10° C., 600 ml of concentrated hydrochloric acid was added to a solution of 44.6 g of 2-butyryl-5-tert-butoxymethyl-3-hydroxycyclohex-2-en-1-one in ethanol. After 2 hours the mixture was concentrated, and the residue was taken up in dichloromethane and extracted by shaking with water. After concentration there was obtained 26.2 g of 2-butyryl-3-hydroxy-5-hydroxymethylcyclohex-2-en-1-one as a pale yellow oil (compound no. 3).