Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)CO.C[Si](O[Si](C)(C)C)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C(Cl)CCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:19][CH2:20][CH2:21][O:22]4)[CH2:17][CH2:16]3)[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Al+3]
Agent: [O-2]
Solvent: OCCO
Solvent: ClCCCl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: Fc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)cc1F
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mixture of 7.8 g of crude 1-(3,4-difluorophenyl)-4-(1,4-dioxa-8-spiro[4.5]decyl) cyclohexanol, 1.05 ml of ethylene glycol, 1.05 g of Amberlyst® 15 (strongly acid ion exchange resin, Fluka AG) and 80 ml of ethylene chloride was refluxed through neutral aluminum oxide for 3 hours. Subsequently, the mixture was cooled to room temperature and washed twice with water. The aqueous phases were extracted twice with methylene chloride. The organic phases where dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 96:4) gave 4,9 g of 8-[4-(3,4-difluorophenyl)-3-cyclohexenyl]-1,4-dioxaspiro [4.5]decane as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[C:24]1([CH:30]2[O:35][CH2:34][CH2:33][NH:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:23]=[C:21]([N:32]1[CH2:33][CH2:34][O:35][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:31]1)[CH2:20][N:3]1[CH2:4][CH2:5][CH2:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
To 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.103 g, 0.334 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.155 g, 0.408 mmol) and 2-phenylmorpholine (0.074 g, 0.371 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.097 mL, 0.556 mmol), and the reaction mixture was stirred at room temperature. After stirring overnight, the reaction was directly loaded onto a silica gel column (Analogix®, SF15-12), and the product was eluted with a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes with a flow rate of 30 mL/minute. The product eluted with a more polar impurity. The product was rechromatographed over silica gel (Analogix®, SF15-12), and the title compound was eluted with a gradient of 0.4% to 7.5% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.18-7.40 (m, 15H), 4.37-4.68 (m, 3H), 3.98-4.17 (m, 2H), 3.32-3.85 (m, 6H), 2.64-2.70 (m, 2H), 1.82-1.88 (m, 2H); MS (ESI+) m/z 455 (M+H)+.
Reaction SMILES: N[C:2]1C=CC2N=CSC=2C=1.[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=O)[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>O>[CH3:2][NH:36][S:33]([C:27]1[CH:26]=[CH:25][C:30]([NH:31][N:32]=[C:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]4[C:22]=3[S:11][CH:12]=[N:13]4)[NH:18][C:19]2=[O:24])=[CH:29][CH:28]=1)(=[O:34])=[O:35]
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
6H-1-Thia-3,6-diaza-as-indacene-7,8-ione was prepared from 6-aminobenzothiazole according to Procedure A: 1H NMR (DMSO-d6): δ 7.10 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 9.35 (s, 1H), 11.19 (s, 1H); ESI−MS m/z 204 (M)−. The title compound was prepared from 6H-1-thia-3,6-diaza-as-indacene-7,8-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>260° C.; 1H NMR (DMSO-d6): δ 2.39 (d, J=5.1 Hz, 3H), 7.12 (d, J=8.4 Hz, 1H), 7.32 (q, J=5.1 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.6 Hz, 1H), 9.30 (s, 1H), 11.26 (s, 1H), 12.69 (s, 1H); APCI−MS m/z 387 (M)−. Anal. Calcd for C16H13N5O3S2.0.33 H2O: C, 48.85; H, 3.50; N, 17.80; S, 16.30. Found: C, 48.89; H, 3.40; N, 17.67; S, 16.23.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([NH2:8])=[O:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>S(=O)(=O)(O)O.CCCCCC>[C:9]1([CH2:15][C:16]([NH:8][C:6](=[O:7])[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)SCC(N)=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)SCC(=O)NC(=O)Cc1ccccc1
Reaction time: 8 h

Procedure:
A reaction mixture comprising 6.65 g. (0.05 mole) of 2-(acetylthio)acetamide, 10 ml. of 2-phenylacetyl chloride, and 1 drop of sulfuric acid was heated in a steam bath for 0.5 hour, and then allowed to stand overnight at room temperature, after which it solidified. There was then added 50 ml. of ether and 20 ml. of hexane, followed by stirring for 10 minutes and then filtering. A yield of 8.5 g. of a tan solid was obtained, which was then chromatographed on 100 g. of silica gel, eluting with 5% ether in dichloromethane, followed by concentration to dryness. The solid was suspended in 60 ml. of ethanol and stirred in an ice bath for 1 hour. The product of white crystals, m.p. 153°-155° C., was obtained in a 5.6 g. yield.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:23][CH2:24][N:25]([S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH2:26][CH2:27]4)=[O:21])[CH:14]=3)=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28]
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F)N1CCNCC1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 16, P1 in DMF (0.3 M), was added ethanesulfonyl chloride (1 eq) and DIPEA (1 eq). The resulting mixture was stirred for 1 hour at RT. The product was isolated by purification at preparative-HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 10.91 (1H, m, J=5.6 Hz), 7.38-7.18 (3H, m), 7.14 (1H, s), 6.57 (1H, m, J=5.8 Hz), 4.37 (2H, m), 3.87-3.54 (4H, m), 3.31-3.18 (4H, m), 3.05 (2H, q, J=7.41 Hz), 1.21 (3H, t, J=7.20 Hz). MS (ES) C21H21Cl2FN4O4S requires: 514/516, found: 515/517 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:4][CH2:3]1.[C:19]([N:27]=[C:28]=S)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:28]2[NH:27][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccccc2N)CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Product: CN1CCN(CCCn2c(NC(=O)c3ccccc3)nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
To a solution of N-[3-(4-methyl-1-piperazinyl)propyl]-o-phenylenediamine (1.24 g., 0.005 mole) in ethanol (50 ml.) was added 0.82 g. (0.005 mole) benzoyl isothiocyanate in one portion. After stirring overnight at room temperature, the solution was evaporated in vacuo to a red oil, which was chromatographed on a silica gel column yielding on crystallization from ethyl acetate 390 mg. of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-benzamido-benzimidazole (yield 20.6%), m.p. 147°-148° C. The material isolated by this synthesis was identical in all respects to an authentic sample.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][C:10]([NH:18][C:19]([C:21]1[N:22]=[C:23]([S:29][CH3:30])[S:24][C:25]=1[C:26]([OH:28])=[O:27])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11]>CN(C=O)C>[CH3:11][C:10]([NH:18][C:19]([C:21]1[N:22]=[C:23]([S:29][CH3:30])[S:24][C:25]=1[C:26]([O:28][CH3:1])=[O:27])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CSc1nc(C(=O)NC(C)(C)c2ccccc2)c(C(=O)O)s1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1sc(SC)nc1C(=O)NC(C)(C)c1ccccc1
Temperature: 85 °C

Procedure:
Potassium carbonate (0.37 g) and iodomethane (0.17 ml) were added to a solution of 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylic acid (Intermediate 14; 0.9 g) in DMF (20 ml) and heated in a sealed tube at an external temperature of 85° C. for 30 min. The reaction mixture was concentrated to remove DMF and partitioned with EtOAc and water. The combined organic extracts were washed with water, dried with MgSO4, and concentrated to an orange solid (0.63 g). NMR: 1.60-1.65 (m, 6H), 2.76 (s, 3H), 3.78-3.83 (m, 3H), 7.22 (d, J=7.16 Hz, 1H), 7.33 (t, J=7.63 Hz, 2H), 7.46 (d, J=7.35 Hz, 2H), 8.75 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)([CH3:5])[CH3:4].CN(C)C=O.S(C1C=CC(C)=CC=1)(O[CH2:20][C@@H:21]1[CH2:35][C@H:34]2[C@@H:24]([CH2:25][C:26]3[C:36]4[C:29](=[CH:30][CH:31]=[CH:32][C:33]2=4)[NH:28][CH:27]=3)[N:23]([CH3:37])[CH2:22]1)(=O)=O>CO.C(O)(C)C>[CH:3]([C:6]1[N:7]([CH2:20][C@@H:21]2[CH2:35][C@H:34]3[C@@H:24]([CH2:25][C:26]4[C:36]5[C:29](=[CH:30][CH:31]=[CH:32][C:33]3=5)[NH:28][CH:27]=4)[N:23]([CH3:37])[CH2:22]2)[CH:8]=[CH:9][N:10]=1)([CH3:5])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: CC(C)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)c1nccn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
0.9 g of 50% sodium hydride in an oil was added to a mixture of 4.0 g of 2-isopropylimidazole and 40 ml of dimethylformamide, and the mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were filtered, washed with water and purified by silica gel column chromatography (eluted with acetone). The crystals thus obtained were dissolved in methanol, and isopropyl alcohol was added thereto. The mixture was concentrated and allowed to cool to obtain 0.6 g of the titled compound as colorless needles having a melting point of 283°-288° C. (with decomposition).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]([OH:17])=O)(O)=[O:2].[NH4+:18].[OH-]>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][C:8]=1[O:10][CH3:11])[C:1](=[O:2])[NH:18][C:15](=[O:17])[CH2:14]2
Reactant: [NH4+]
Reactant: COc1cc(CC(=O)O)c(C(=O)O)cc1OC
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(cc1OC)C(=O)NC(=O)C2

Procedure:
A solution of 8.2 g (34.1 mmol) of 2-carboxy-4,5-dimethoxybenzeneacetic acid (Tetrahedron 1975, 31, 2607) in 17 ml of conc NH4OH is evaporated to dryness. This operation is repeated. The resulting tan solid ammonium salt is suspended in 34 ml of 1,2-dichlorobenzene. The stirred mixture is boiled in an oil bath at 210° while collecting some distillate during 90 m. The cooled mixture is stirred in hexane and H2O, and the resulting solid is collected by filtration. The white solid is stirred in satd NaHCO3 for 15 m, filtered, washed with H2O, and dried to give 3.45 g (46%), mp 234-238°; MS (ES−) m/z 220.1 (M−H)−1.
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:22])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[N:26]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:12][C:11](=[O:22])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(C(=O)CC(=O)C(C)C(=O)c2ccccc2)c1
Reactant: Nc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cccc(-c2cc(=O)c(C)c(-c3ccccc3)n2-c2ccccc2F)c1
Yield: 51.7 %

Procedure:
To 30 ml of xylene were added 2.0 g (0.0068 mole) of 2-methyl-5-(3-methylphenyl)-1-phenyl-1,3,5-pentanetrione, 7.6 g (0.068 mole) of 2-fluoroaniline, 2.0 g (0.012 mole) of para-toluenesulfonic acid and 14.0 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 1 hour. After cooling the reaction mixture, solid matter was filtered off and the filtrate was mixed with 100 ml of chloroform and then washed successively with 50 ml of 10% hydrochloric acid, 50 ml of a 10% aqueous solution of sodium hydroxide and water. The filtrate was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was crystallized from a 1:3 mixed solvent of chloroform and hexane to give 1.3 g of 1-(2-fluorophenyl)-3-methyl-6-(3-methylphenyl)-2-phenyl-4-(1H)-pyridinone having a melting point of 211°-214° C.
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Reactant: CN1CCNCC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C)CC4)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.200 g, 0.469 mmol), N-methyl piperazine (0.062 mL, 0.563 mmol), 1-hydroxy benzotriazole (0.070 g, 0.516 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.099 g, 0.516 mmol) were combined in amine-free N,N-dimethylformamide (1.9 mL), followed by the addition of N,N-diisopropylethyl amine (0.123 mL, 0.704 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% methanol in chloroform to afford 0.224 g of the title compound as an oil. The oil thus obtained was dissolved in diethyl ether and diluted with hexane to afford a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:5]2.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>C(N(CC)CC)C.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][Si:16]([C:14]#[C:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:5]2)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: OCCn1ccc2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(ccn2CCO)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
398 mg (2.1 mmol) CuI and 1.47 g (2.1 mmol) Pd(PPh3)2Cl2 are added to a solution, cooled to 0° C., of 30 g (104 mmol) 2-(5-iodo-indol-1-yl)-ethanol and 18 mL (125 mmol) ethynyl-trimethyl-silane in 480 mL triethylamine and 120 mL THF and stirred for 30 min at 0° C. and 2 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 300 mL EtOAc, the organic phase is washed with 150 mL water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: cyc/EtOAc 4:1 to 2:1).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:11]CO)[CH2:8][CH2:9]O)[CH3:6].C(=O)([O-])O.[Na+].Cl[CH2:20][Cl:21]>>[Cl:3][CH2:9][CH2:8][N:7]([CH2:11][CH2:20][Cl:21])[CH2:5][CH3:6]
Reactant: CCN(CCO)CCO
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CCCl)CCCl
Temperature: 0 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
24 ml (330 mmol) of thionyl chloride are added dropwise to a solution of 20 g (150 mmol) of 2-[ethyl(2-hydroxyethyl)amino]ethanol in 200 ml of dichloromethane cooled beforehand to 0° C., and then the reaction medium is stirred at ambient temperature for 20 h. After the addition of a saturated aqueous solution of sodium hydrogen carbonate, the product is extracted with dichloromethane. The organic phase obtained is then washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. 19.5 g (76%) of bis(2-chloroethyl)ethylamine are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[C:7](Cl)=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C([Mg:16][Br:17])(C)C>>[F:1][C:2]1[C:7]([Mg:16][Br:17])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Reactant: CC(C)[Mg]Br
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F

Procedure:
The process according to claim 8 wherein the step (a) pentafluorochlorobenzene is reacted with isopropylmagnesium bromide in a mole ratio range from about 1:1 to 2:1 in a dialkyl ether solvent to provide pentafluorophenylmagnesium bromide.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[NH:19])[O:17][CH3:18])=[CH:14][CH:13]=1.Cl.[CH3:23][O:24][C:25](=[O:30])[CH:26](CO)N>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]2[O:17][CH2:18][CH:26]([C:25]([O:24][CH3:23])=[O:30])[N:19]=2)=[CH:20][CH:21]=1
Reactant: COC(=N)c1ccc(F)cc1
Reactant: COC(=O)C(N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
N,N-Diisopropylethylamine (11 mL, 63.3 mmol) was added dropwise to a solution of methyl 4-fluorobenzimidate hydrochloride (10 g, 52.74 mmol) and DL-serine methyl ester HCl salt (9.9 g, 63.63 mmol) in dry CH2Cl2 (200 mL) at 0° C. The reaction mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.5 g, yield 81%) as an orange liquid. 1H NMR (300 MHz, CDCl3) δ 8.02-7.97 (m, 2H), 7.13-7.07 (t, J=8.7 Hz, 2H), 4.98-4.92 (m, 1H), 4.73-4.57 (m, 2H), 3.83 (s, 3H). MS (ESI) m/z: Calculated for C11H10FNO3: 223.06. found: 223.8 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13]2
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc(Br)ccc2c1

Procedure:
Methyl-6-bromo-2-naphtoate (25 g, 94.3 mmol) was reduced with lithiumaluminiumhydride (5.36 g, 141.4 mmol) in tetrahydrofuran (200 ml). The crystalline product was recrystallized from ethanol (96%). Yield 15.84 g (70.8%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@H:22]([O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: CC1=C(CC/C(C)=C/CC(=O)O)C(C)(C)CCC1
Reactant: COC(=O)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](OC(=O)CC=C(C)CCC1=C(C)CCCC1(C)C)c1ccccc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a solution of 10.0 g (40 mmol) (E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid [H. S. Corey, J. R. D. Cormick, W. E. Swensen, J. Am. Chem. Soc. 1964, 86, 1884] in 100 ml MTBE were added at r.t. 6.64 g (40 mmol) (R)-(−)-mandelic acid methyl ester [α]D=−144.9 (c=1.04, MeOH) and 1.0 g DMAP. Then a solution of 8.24 g (40 mmol) DCC in 100 ml MTBE was added and the reaction mixture stirred for 3 h, filtered and the residue washed with MTBE. The combined organic phases were concentrated in vacuo and the residue (17.6 g) was purified by flash chromatography (250 g silicagel, hexane/MTBE 9:1) affording 12.2 g (88%) 4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid (R)-methoxycarbonyl-phenyl-methyl ester (12) in form of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].CI.[C:52](OCC)(=O)C>CN(C)C=O.O>[CH3:1][C:2]1([CH3:47])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:7]=[C:6]([C:19]3[N:20]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28]([CH3:52])[C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(C)=O
Reactant: CC1(C)CCc2c(-c3cc4ccc(NC(=O)OCc5ccccc5)cc4n3COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Under an argon atmosphere, to a solution of benzyl (2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)carbamate (3 g, 4.6 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (219 mg, 5.5 mmol) under ice-cooling, and the mixture was stirred for 10 min. Then, to the reaction mixture was added methyl iodide (0.6 ml, 6.9 mmol), and the mixture was further stirred for 3 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (2.2 g, yield 69%).