Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])(=O)C.[NH4+:15]>C(O)C>[NH2:15]/[C:3](/[CH2:2][Cl:1])=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C=C(\N)CCl

Procedure:
A solution of ethyl 4-chloroacetoacetate (7.02 ml) and ammonium acetate (11.8 g) in absolute ethanol (180 ml) is refluxed for 3 hours. After a night at room temperature the solution is concentrated to dryness by distillation under reduced pressure and the resulting residue is purified by flash chromatography (silica gel, 200 g; eluent CH2Cl2/MeOH/TEA 15/5/02), to give 6.53 g of ethyl (Z)-3-amino-4-chloro-2-butenoate as dark oil which is used without further purifications.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:25][C:26]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:26]=2[F:25])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)c2cccc(C(F)(F)F)c2F)n(C[C@H]2CCCO2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To the mixture of Example 6B (293 mg, 1.129 mmol) and triethylamine (0.472 mL, 3.39 mmol) in CH2Cl2 (5 mL) cooled with an ice-bath was added 2-fluoro-3-(trifluoromethyl)benzoyl chloride (307 mg, 1.355 mmol) in one portion. The mixture was stirred at ambient temperature for 2 h, the solvent removed under reduced pressure and the residue purified by flash chromatography (silica gel, 10-60% EtOAc/hexane) to yield 420 mg (90%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 9H), 1.58-1.97 (m, 4H), 3.55-3.78 (m, 2H), 4.06-4.20 (m, 3H), 6.30 (s, 1H), 7.57 (t, J=7.80 Hz, 1H), 8.01 (q, J=8.02 Hz, 2H), 10.42 (s, 1H); MS (ESI) m/z 414 (M+H)+, 412 (M−H)−.
Reaction SMILES: N1C=CC=CC=1.[C:7]([Br:11])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][CH:45]([CH2:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)CO)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(OCC)C>[C:58]([O:57][C:55]([N:52]1[CH2:51][CH2:50][CH:49]([CH2:48][CH:45]([CH2:7][Br:11])[CH2:44][CH:41]2[CH2:42][CH2:43][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:39][CH2:40]2)[CH2:54][CH2:53]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CO)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CC(CBr)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
After pyridine (0.090 ml; 1.1 mmol), carbon tetrabromide (716 mg; 2.2 mmol) and triphenylphosphine (567 mg; 2.2 mmol) were added to a solution in diethyl ether (5 ml) of 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]ethyl alcohol (476 mg; 1.1 mmol) synthesized by the above process under ice cooling, the ice bath was removed, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 465 mg (yield: 86%) of 1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)-2-(bromomethyl)propane as a colorless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1([CH3:34])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:14]([CH2:23][CH2:24][C:25]([N:27]2[C@H:31]([CH3:32])[CH2:30][O:29][C:28]2=[O:33])=[O:26])[CH2:13][O:12]1.[C:35]([O:39][C:40](=[O:43])[CH:41]=[CH2:42])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:35]([O:39][C:40](=[O:43])[CH2:41][CH2:42][C@@H:24]([C:25]([N:27]1[C@H:31]([CH3:32])[CH2:30][O:29][C:28]1=[O:33])=[O:26])[CH2:23][C@H:14]1[CH2:13][O:12][C:11]([CH3:10])([CH3:34])[N:15]1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H]1COC(=O)N1C(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COC(=O)N1C(=O)[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
At 0° C., 1.0M TiCl4 in CH2Cl2 solution (8.55 mL, 0.7 eq) was added to CH2Cl2 (100 mL) followed by the addition of 1.0M TiCl(Oi—Pr)3 in hexanes solution (4.28 mL, 0.35 eq) and stirred 5 min DIPEA (2.87 mL, 1.35 eq) was added and stirred 15 min. A solution of (S)-tert-butyl 2,2-dimethyl-4-(3-((R)-4-methyl-2-oxooxazolidin-3-yl)-3-oxopropyl)oxazolidine-3-carboxylate (5.28 g, 12.22 mmol) in CH2Cl2 (50 mL) was added. The reaction mixture was stirred 1 hr at 0° C. To the solution, t-butylacrylate (2.22 mL, 1.25 eq) was added and the mixture was left stirred over 48 hr with concomitant warming to rt. The mixture was concentrated, partitioned between EtOAc (300 mL) and 1% HCl solution (100 mL). The organic layer was washed with sat. NaHCO3 solution (60 mL), brine (60 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (120 g column, 0˜35% EtOAc in Hexanes gradient) to afford 4.12 g (60%) (S)-tert-butyl 4-((R)-5-tert-butoxy-2-((R)-4-methyl-2-oxooxazolidine-3-carbonyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a yellowish solid. MS ESI+ve m/z 583 (M+Na).
Reaction SMILES: [C:1]([OH:7])(=O)/[CH:2]=[CH:3]/[CH2:4][CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1>O1CCCC1.C(OCC)(=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:1](=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH3:5])=[CH:26][CH:25]=1
Reactant: CC/C=C/C(=O)O
Reactant: NCCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC/C=C/C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
A solution of trans-2-pentenoic acid (7.62 g, 76.2 mmol) in tetrahydrofuran (350 mL) was stirred at −15° C. and treated with N-methylmorpholine (8.37 mL, 76.2 mmol). After 10 minutes, isobutyl chloroformate (9.87 mL, 76.2 mmol) was added. After 10 minutes, a precipitate had formed. A solution of 2-(4-fluorophenyl)ethylamine (10.6 g, 76.2 mmol) in tetrahydrofuran (50 mL) was added slowly, and the mixture was stirred at room temperature, and the residue was dissolved in ethyl acetate. The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane to provide white crystals (11.69 g, 69%). 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 7.01 (t, J=9 Hz, 2H), 6.88 (dt, J=15, 7 Hz, 1H), 5.72 (dt, J=15, 2 Hz, 1H), 5.61 (bs, 1H), 3.56 (m, 2H), 2.83 (t, J=7 Hz, 2H), 2.20 (m, 2H), 1.05 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 221.9 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:20]=[C:19]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:24]=[CH:23][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(-c3ccccc3)c2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(-c4ccccc4)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-biphenyl-3-yl-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.16 min; [M+H]+=466.33.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][N:9]1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][NH:11][C:10]1=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][N:9]1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][N:11]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:10]1=[O:18]
Reactant: Brc1cccnc1
Reactant: COC(=O)C1CNC(=O)N1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1CN(c2cccnc2)C(=O)N1C
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of 3-bromopyridine (316 mg, 2. mmol) and methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in 1,4-dioxane (10 ml) was treated with cesium carbonate (977 mg, 3 mmol), Xantphos™ (87 mg, 0.15 mmol) (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, e.g. available from Aldrich, CAS no. 161265-03-8) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and the mixture was heated under reflux under argon for 22 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (273 mg, 58%). LC/MS [M+H]+=236. (ii) A solution of methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (0.27 g, 1.15 mmol) in tetrahydrofuran (3 ml) at 0° C. was treated with a solution of lithium hydroxide (0.030 g, 1.26 mmol) in water (2 ml) and the mixture was stirred at 0° C. for 90 minutes. Hydrochloric acid (2M) was added to adjust the pH of the reaction mixture to pH 2 and the solvent was evaporated. The residue was dried over phosphorus pentoxide to give crude 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylic acid which was used in the next step. LC/MS [M+H]+=222.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([OH:15])[CH:14]=1>CCO>[Cl:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[OH:15]
Reactant: Brc1ccccn1
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: CCO
Product: Oc1cc(Nc2ccccn2)ccc1Cl
Temperature: 90 °C
Yield: 24 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-bromopyridine (0.13 mL, 1.4 mmol) and 5-amino-2-chlorophenol (100 mg, 0.7 mmol) in 10% aqueous EtOH (2 mL) was heated at 90° C. for 18 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 24% yield (36 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:11]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6])(=[O:41])=[O:40])=[CH:37][CH:38]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(OC)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.14 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 1.488 g of 4-methoxybenzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 3-(4-methoxy-benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a resin.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH2:10].[Cu][C:12]#[N:13].Cl>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[C:3]([CH:9]=[CH2:10])[CH:4]=1
Reactant: C=Cc1cc(F)ccc1Br
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: C=Cc1cc(F)ccc1C#N
Temperature: 200 °C
Yield: 60.5 %

Procedure:
4.0 g 1-Bromo-4-fluoro-2-vinyl-benzene and 1.87 g copper (I) cyanide were dissolved in 16 ml dimethylformamide and heated under microwave irradiation at 200° C. for 25 minutes. The cooled reaction mixture was poured into 200 ml 1 M HCl and extracted five times with portions of 60 ml ethyl acetate. The combined organic layers were washed with 100 ml 1 N HCl, dried over MgSO4, then the solvent was removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=6:1 to obtain 1.77 g 4-Fluoro-2-vinyl-benzonitrile as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=2)[CH2:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=2)[CH2:3]1
Reactant: CC(=O)Nc1ccc(OC2CCCN(C)C2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCCC(Oc2ccc(N)c([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[4-(1-methyl(3-piperidyloxy))-2-nitrophenyl]acetamide was dissolved in 1:1 MeOH : 6N NaOH (aq) solution (0.03 M). After stirring at room temperature for 2 hours, MeOH was removed in vacuo. The remaining solution was extracted with EtOAc (3×). The combined organic extracts were then dried over Na2SO4 and concentrated in vacuo to give 4-(1-methyl(3-piperidyloxy))-2-nitrophenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N+:32]([O-])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:36][N:37](C)C(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:36]#[N:37])[CH:30]=4)=[CH:25][CH:24]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CN(C)C(=O)Cl
Reactant: O=C(c1ccc(-c2cc[n+]([O-])cc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In dichloromethane (100 ml), 4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide (1.67 g) was dissolved, followed by the addition of trimethylsilycynanide (0.42 ml) and dimethylcarbamoyl chloride (0.30 ml). The resulting mixture was stirred at room temperature for 24 hours. An aqueous solution of sodium bicarbonate and dichloromethane were added to the reaction mixture to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (1% methanol—dichloromethane), whereby the title compound (1.44 g, 84%) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1([CH2:24][OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:24]([O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OCc1ccccc1
Product: c1ccc(COc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenyl methanol to give (1-benzyloxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21][CH3:22])=[CH:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2]>CCOCC>[CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH:15]=[C:14]([O:21][CH3:22])[CH2:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@]1(O)CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C
Solvent: CCOCC
Product: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21C
Yield: 69.6 %

Procedure:
Add dl-17α-ethyl-3-methoxyestra-1,3,5(10)-trien-17-ol (2 g) in ether (55 ml) to distilled liquid ammonia (180 ml), and add lithium (1 g) to the stirred solution. After 45 minutes add ethanol (15 ml) and ether (15 ml) dropwise followed by ammonium chloride and water. Extract with ether, wash, dry, evaporate, and recrystallize the residue from ether to obtain dl-17α-ethyl-3-methoxyestra-2,5(10)-dien-17-ol (1.4 g), m.p. 131°-134°.
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:34]>CN(C)C=O>[CH2:33]([N:35]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:1])[CH3:34]
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCNCCC(=O)OCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(CC)C(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of lysergic acid 5 (934 mg, 3.27 mmol) in 40 ml of dry dimethylformamide (DMF) was treated with 1,1′-carbonydidimidazole (CDI, 795 mg, 4.91 mmol) and stirred under nitrogen at room temperature for 1 hour. The N-ethyl N-(2-carbethoxy)ethyl amine linker 10 (1.90 g, 13.08 mmol) in 10 ml of dry dimethylformamide (DMF) was added dropwise and the reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in 200 ml of chloroform. The chloroform solution was washed twice with 100 ml of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to yield the crude title compound 6 (2.2 g) as an oil. This was used without further purification in the following Example. υmax/cm−1 3121.90, 2987.10, 2848.65, 1735.30, 1676.97, 1202.97 (FT-IR: FIG. 9)
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9]2)([CH3:5])[C:3]#[N:4].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].[OH-].[Na+]>CC(O)C>[NH2:22][CH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C#N)c1ccc2c(c1)CCC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C#N)c1ccc2c(c1)CCC2N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methyl-2-(1-oxoindan-5-yl)-propionitrile (6.00 g, 30.1 mmol) was added to a mixture of ammonium acetate (69.6 g, 903 mmol) in IPA (600 mL) under nitrogen atmosphere at ambient temperature. After stirring 1 hour, sodium cyanoborohydride (6.62 g, 105 mmol) was added to the mixture and refluxed for 2 hours. The reaction solution was cooled to room temperature, added 3N sodium hydroxide (300 mL), extracted with TBME (2×500 mL) and concentrated the organic extracts to an oil. Dissolved in ethyl acetate (500 mL), extracted with 1N hydrochloric acid (3×300 mL), combined the aqueous layers, added 3N sodium hydroxide (400 mL), extracted with ethyl acetate (2×1L), dried with brine and anhydrous sodium sulfate, and concentrated. Obtained 2-(1-aminoindan-5-yl)-2-methylpropionitrile (4.26 g, 71%) as a yellow oil. MS (DCI/NH3) m/z: 201.10 [M+H]+. 1H NMR (DMSO-d6) δ: 1.60 (m, 1H), 1.66 (s, 6H), 1.93 (br, 2H), 2.35 (m, 1H), 2.74 (m, 1H), 2.86 (m, 1H), 4.17 (t, 1H), 7.32 (m, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Temperature: 140 °C
Reaction time: 7 h

Procedure:
To 6.4 g of 3-phenoxy-4-fluorobenzyl bromide was added 7 ml of triethylphosphite, and the mixture was stirred at 140° C. for seven hours. After cooling, 13.1 g of the reaction mixture was purified by column chromatography on silica gel (eluent: benzene) to give 6.3 g of diethyl 3-phenoxy-4-fluorobenzylphosphonate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(OCC)(=O)C.CCCCCCC.C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: N=C(NC(=O)OCc1ccccc1)N1CCC(CO)C1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCC1CCN(C(=N)NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
0.7 g (2.53 mmole) (3RS)-1-(N-benzyloxycarbonylamidino)-3-hydroxymethyl pyrrolidine and 0.70 ml (5.05 mmole) triethylamine was dissolved in 15 ml diethyl ether/CH2Cl2 1/1 and the mixture was cooled to 0° C. 0.25 ml (3.29 mmole) methanesulphonyl chloride in 3 ml diethyl ether was slowly added and the reaction mixture was stirred at 0° C. for three hours.The solvent was evaporated and the residue was dissolved in ethyl acetate and extracted with a 0.3M KHSO4 -solution. The water layer was washed once with CH2Cl2. The water layer was made neutral with 10M NaOH-solution and extracted twice with CH2Cl2. The combined organic layer was dried (Na2 SO4), filtered and evaporated to yield 0.450 g (50%) of the title compound.