Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:5]=[CH:4][C:3]2=[CH:6][CH:7]=[CH:8][CH:9]=[CH:10][C:2]=12.C(Cl)(=O)[C:12](Cl)=[O:13].C([O-])(=O)C.[Na+].N>CN(C=O)C>[N:1]1[CH:5]=[CH:4][C:3]2=[CH:6][C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[CH:10][C:2]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2ccnc-2cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc2nccc-2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclohepta[b]pyrrole-5-carboxylic acid nitrile: 800 mg of cyclohepta[b]pyrrole (manufactured according to Helv. Chim. Acta 67, 1647 (1984)) are added in portions, at 0°, to a solution of 1.1 ml of oxalyl chloride in 40 ml of DMF. The whole is subsequently stirred for 30 minutes at room temperature, then 60 ml of saturated sodium acetate solution are added and the pH is adjusted to 9 with concentrated ammonia. The cyclohepta[b]pyrrole-5-carbaldehyde formed is extracted with methylene chloride and purified by flash chromatography with solvent system N6. Rf (N6)=0.46.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH2:27][CH3:28]>C(#N)C>[C:32]1([CH3:35])[CH:33]=[CH:34][C:29]([CH:26]([CH2:27][CH3:28])[C:5]#[N:6])=[CH:30][CH:31]=1
Reactant: C[Si](C)(C)C#N
Reactant: CCC(Br)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCC(C#N)c1ccc(C)cc1
Reaction time: 0.08 h

Procedure:
7.36 g (74.4 mmol) Trimethylsilyl cyanide was added to a solution of 74.4 ml (1.0 M in THF, 74.4 mmol) tetrabutylammonium flouride in 300 ml acetonitrile and the mixture was stirred for 5 minutes. 5.28 g (24.8 mmol) rac-1-(1-Bromo-propyl)-4-methylbenzene were added and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the viscous residue obtained was partitioned between water and dichloromethane. The dichloromethane was separated, then washed with water, dried over MgSO4 and evaporated to dryness. Purification of the residue by column chromatography on silica gel with a gradient of heptane to 9:1 heptane/ethyl acetate afforded rac-2-p-tolyl-butyronitrile as a colourless oil. NMR (CDCl3, ppm): 0.95 (3H, t), 1.77 (2H, m), 2.21 (3H, s), 3.58 (1H, t), 7.07 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH2:25][CH3:26])=[CH:4][C:3]=1[F:18]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O

Procedure:
A 59.7 g portion of the above ester was suspended in 425 ml of dimethylformamide, 76.6 g of potassium carbonate was added and this mixture was stirred in an oil bath at 80°-90° C. An 89 ml portion of ethyl iodide was added, the mixture was stirred at 80°-90° C. for 18 hours and then evaporated. The residue was dissolved in water and then extracted with dichloromethane. The extract was washed with water, dried, filtered through hydrous magnesium silicate and evaporated in vacuo. The solid was recrystallized from ethanol, giving 38 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][CH2:12][C@H:13]([O:18][CH2:19][CH:20]=[N:21][OH:22])[CH2:14][CH:15]=[CH:16][CH3:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>ClCCl>[CH2:4]([O:11][CH2:12][C@@H:13]1[O:18][CH2:19][C:20]2=[N:21][O:22][C@@H:16]([CH3:17])[C@@H:15]2[CH2:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC=CC[C@H](COCc1ccccc1)OCC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1ON=C2CO[C@@H](COCc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 6.6 L) was slowly added to a solution of 2-{[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}-N-hydroxyethanimine (C12) (660 g, 2.51 mol) and triethylamine (19 g, 0.19 mol) in dichloromethane (6.6 L) at 25° C. After completion of the addition, the reaction mixture was stirred at 25° C. for 30 minutes. The organic layer was washed with water (3×3 L), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Eluent: ethyl acetate in petroleum ether) provided (3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C13) as a white solid. Yield: 90 g, 0.34 mol, 14%. The indicated relative stereochemistry of compound C13 was assigned based on nuclear Overhauser enhancement studies, which revealed interactions of the methine proton on carbon 3a with both the protons of the methyl group on carbon 3 and the methine proton on carbon 5. LCMS m/z 261.9 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.24-7.39 (m, 5H), 4.69 (d, J=13.7 Hz, 1H), 4.57 (AB quartet, JAB=12.2 Hz, ΔνAB=13.8 Hz, 2H), 4.13-4.25 (m, 2H), 3.62-3.70 (m, 1H), 3.55 (dd, half of ABX pattern, J=10, 6 Hz, 1H), 3.47 (dd, half of ABX pattern, J=10, 4 Hz, 1H), 2.93 (br ddd, J=11, 11, 7 Hz, 1H), 2.11 (br dd, J=12.6, 6.8 Hz, 1H), 1.45-1.56 (m, 1H), 1.45 (d, J=6.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[C-:23]#[N:24].[K+]>CS(C)=O.O>[CH3:8][C:6]1[N:7]=[C:2]([C:23]#[N:24])[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=1
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(-n2c(C)c(C)c3c(C#N)nc(C)nc32)c(C)c1
Temperature: 130 °C
Yield: 65.3 %

Procedure:
A mixture of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine (10.000 g, 31.90 mmol) and potassium cyanide (20.75 g, 319 mmol) in 100 ml dimethylsulfoxide was heated at 130° C. oil bath over weekend. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 9.61 g (99%) of brown soild. The solid was recrystallized from i-propanol to give 6.34 g (65%) of the title compound as light golden crystals, mp 188-190° C. 1H NMR (CDCl3) δ 1.8(s, 6H), 2.07(s, 3H), 2.36(s, 3H), 2.50(s, 3H), 2.65(s, 3H), 7.00(s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([CH:16]=O)[S:8][C:7]=2[CH:18]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20].CCCCCC>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:16]/[C:9]1[S:8][C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCc1c(C=O)sc2cc(OC)ccc12
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)OC)sc2cc(OC)ccc12
Yield: 85 %

Procedure:
As in Example 111, 6-methoxy-3-pentyl-2-benzo[b]thiophenecarboxaldehyde (7.37 g) and (carbomethoxymethylene)triphenylphosphorane (9.7 g) in dichloromethane (100 mL) was stirred at room temperature for 42 hours. Crystallization of the crude reaction product, obtained by using the normal work up, from hexane gave 7.6 g of (E)-3-(6-methoxy-3-pentyl-benzo[b]thien-2-yl)-2-propenoic acid methyl ester, mp 49°-50° C. Anal. Calcd for C18H22O3S: C, 67.90; H, 6.96: S, 10.07 Found: C, 68.21; H, 6.80; S, 10.22
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.[CH3:44][O:45]C[C@@H]1CCCN1>>[CH3:44][O:45][CH2:6][C@@H:5]1[CH2:4][CH2:3][CH2:2][N:1]1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1
Reactant: COC[C@@H]1CCCN1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COC[C@@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B18 was prepared following the procedure reported for B1 using A1 and (S)-2-(methoxymethyl)pyrrolidine. MS (ES) C16H22N6O3S requires: 378. found: 379 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]([CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]([CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(C)(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC(C)(c4ccccc4)CC3)cnc12
Yield: 27.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-methyl-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.13 mmol) obtained in step 4 and ethanesulfonamide (56 mg, 0.51 mmol), the title compound (20 mg, 28%) was obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:18]2[CH2:19][CH:7]([CH:8]3[CH:17]2[C:16]2[CH2:20][CH:9]3[CH:10]3[C:15]=2[CH:14]2[CH2:21][CH:11]3[CH2:12][CH2:13]2)[CH2:6]1)=[O:4].[OH-].[K+]>C(O)C>[C:3]([CH:5]1[CH:18]2[CH2:19][CH:7]([CH:8]3[CH:17]2[C:16]2[CH2:20][CH:9]3[CH:10]3[C:15]=2[CH:14]2[CH2:21][CH:11]3[CH2:12][CH2:13]2)[CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Yield: 64.3 %

Procedure:
Next, 3.6 g of the 12-methoxycarbonylhexacyclo-[6.6.1.13,6.110,13.02,7.09,14]heptadecene were dissolved in 30 ml of 95% ethanol, into which 1.25 g of potassium hydroxide were added. The resultant mixture was then heated under reflux. Two hours later, the reaction mixture was allowed to cool down and was then concentrated to ⅓ volume in an evaporator. Water (50 ml) and ether (50 ml) were added, and the resultant water layer was separated. When the water layer was acidified with 3% HCl, a white precipitate was formed. The precipitate was collected by filtration and was then washed with water until the washing became neutral, whereby 2.2 g of 12-carboxyhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene were obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:27])[C@@H:15]([NH:19]C(=O)OC(C)(C)C)[CH2:16][C:17]#[CH:18].[ClH:28]>O1CCOCC1>[ClH:28].[NH2:19][C@@H:15]([CH2:16][C:17]#[CH:18])[C:14]([NH:13][CH2:12][CH2:11][NH:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:27]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNc1nc2ccccc2o1
Agent: Cl
Solvent: C1COCCO1
Product: C#CC[C@H](N)C(=O)NCCNc1nc2ccccc2o1
Reaction time: 2.5 h

Procedure:
(S)-tert-Butyl 1-(2-(benzo[d]oxazol-2-ylamino)ethylamino)-1-oxopent-4-yn-2-ylcarbamate (99.5 mg, 0.267 mmol) was dissolved in 1,4-dioxane (3.5 mL) and treated with 4N HCl in 1,4-dioxane (3.5 mL). The resulting mixture was stirred for 2.5 h and a solid separated from the solution. HCl in 1,4-dioxane (1 mL) was added and the resulting mixture was stirred for 3 h. The solid product was collected by filtration, washed with 1,4-dioxane, then dried in vacuum oven for 1 day at room temperature to yield the title compound as its corresponding hydrochloride salt, as a white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12]/[C:13](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:15]O>ClCCl>[CH3:12]/[C:13](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:15][Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a stirred solution of 4.75 g (35.6 mmol) of N-chlorosuccinimide in 180 mL of dichloromethane at -35° C. (internal thermometer) under argon was added 3.3 mL (45.4 mmol) of dimethyl sulfide over 10 minutes. The mixture was allowed to warm to 0° C. for 15 minutes then cooled again to -35° C. A solution of 5.0 g (32.4 mmol) of (E)-3,7-dimethyl-2,6octadien-1-ol (geraniol) in 25 mL of dichloromethane was added dropwise over 10 minutes. After addition, the reaction was allowed to warm gradually to 0° C. over 2 hours. After 1 hour at 0° C., the reaction was quenched with ice-cold water, diluted with 500 mL of hexane, and the organic layer was separated. The hexane extract was washed with water, brine, dried over MgSO4 and evaporated to provide 5.21 g (93%) of title compound in the form of a yellow liquid.
Reaction SMILES: [Br:1][CH:2]([NH:4][C:5](Br)=[O:6])[CH3:3].C(N=C=O)=C>ClC1C2C(=CC=CC=2)C=CC=1>[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3].[Br:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3]
Reactant: CC(Br)NC(=O)Br
Agent: C=CN=C=O
Solvent: Clc1cccc2ccccc12
Product: CC(Br)N=C=O
Reaction time: 2 h
Yield: 88 %

Procedure:
48.5 parts of 1-bromoethylcarbamic acid bromide are dissolved in 100 parts by volume of α-chloronaphthalene and a solution of 16 parts of vinyl isocyanate in 20 parts by volume of 1-chloronaphthalene is added to the above mixture in the course of 0.4 hour at 2° C. The mixture is then kept at 24° C. for 2 hours. 3.6 parts (11% of theory) of vinyl isocyanate and 58.5 parts (88% of theory) of 1-bromoethyl isocyanate (determined by gas chromatography) are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[C:30]3[NH:32][CH2:33][C:34]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:29]3=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:32]3[C:30]4[C:29](=[CH:28][CH:27]=[C:26]([N:23]5[CH2:22][CH2:21][O:20][CH2:25][CH2:24]5)[CH:31]=4)[C:34]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:33]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccncc2)nc2cc(F)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccncc2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepare according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(pyridin-4-yl)quinoline (60 mg, 220 μmol), 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (60 mg, 220 μmol) and a 4.0M solution of HCl in 1,4-dioxane (0.05 mL, 0.22 mmol). After purification 1-(7-fluoro-3-methyl-2-(4-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 8.80 (2H, dd, J=4.3, 1.8 Hz), 7.74-7.92 (2H, m), 7.49-7.62 (2H, m), 7.25-7.32 (1H, m), 7.15 (1H, d, J=8.1 Hz), 6.36 (1H, dd, J=8.2, 2.3 Hz), 5.60 (1H, d, J=2.2 Hz), 4.01-4.08 (2H, m), 3.95 (2H, s), 3.74 (4H, t, J=5.1 Hz), 3.49-3.63 (2H, m), 2.90-3.03 (4H, m), 2.28 (3H, s), 2.10-2.22 (2H, m, J=14.2, 14.2, 12.0, 4.6 Hz), 1.85-1.93 (1H, m), 1.74-1.82 (1H, m). Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C1CCCCC1
Product: ClCc1coc(C2CCCCC2)n1
Yield: 2.7 %

Procedure:
In substantially the same manner as in Reference Example 31, cyclohexanecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-cyclohexyloxazole as an oily product. The yield was 2.7%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([I:18])=[CH:20][CH:21]=1)[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClCc1ccc(I)cc1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(Br)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C)n(Cc2ccc(I)cc2)c2ccc(Br)cc12
Temperature: 20 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
To a solution of the product of Step 1 (536.2 mg, 2 mmol) and 4-iodobenzyl chloride (504 mg, 2 mmol) in dry DMF (10 mL) at 0° C. was added sodium hydride (80 mg, 2 mmol, 60% in oil). The mixture was stirred at 20° C. for 20 hours and a saturated NH4Cl solution (10 mL) was added. The mixture was extracted with EtOAc, the extracts were dried over MgSO4 and concentrated to an oil. The oil was purified by flash chromatography on silica gel, eluting with 20% EtOAc in hexane to afford 704 mg (69%) of the title compound. 1H NMR (CDCl3) 1.23 (3H, t, J=7.1 Hz), 2.28 (3H, s), 3.65 (2H, s), 4.12 (2H, q, J=7.1 Hz), 5.19 (2H, s), 6.64 (2H, d, J=8.3 Hz), 6.98 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=8.6 Hz, 1.8 Hz), 7.56 (2H, d, J=8.3 Hz), 7.68 (1H, d, 1.8 Hz).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH:29]1[C:33](=[O:34])[O:32][C:31]2([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[O:30]1)(=O)OCC)C.CN(C)C(=N)N(C)C>O1CCCC1.C(OC)(C)(C)C>[CH3:20][C:12]1[CH:13]=[C:14](/[CH:15]=[C:29]2\[C:33](=[O:34])[O:32][C:31]3([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[O:30]\2)[CH:17]=[C:18]([CH3:19])[C:11]=1[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOP(=O)(OCC)C1OC2(CCCCC2)OC1=O
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(/C=C2/OC3(CCCCC3)OC2=O)cc(C)c1OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4.2 g lithium chloride (0.1 Mol), 20.0 g (83.2 mmol) of 4-benzyloxy-3,5-dimethylbenzaldehyde (D) and 31.62 g (108.2 mmol) of diethyl (3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate (C) are suspended in 130 mL tetrahydrofuran and cooled to −20° C. At this temperature 12.5 mL (0.1 Mol) tetramethylguanidine are added dropwise. After the addition has ended the suspension formed is heated to ambient temperature and stirred for 1 hour. After the addition of 190 mL tert.butyl-methylether the organic phase is washed with 150 mL water and 30 mL saturated saline solution, dried and evaporated down. The resulting yellow oil is taken up in 145 mL methanol and stirred intensively for 1 hour at −10° C., during which time a white solid is formed. The solid formed is suction filtered, washed twice with 20 mL methanol/water (1:1) and dried at 45° C. Yield: 26.0 g (86% of theory)
Reaction SMILES: [Na].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)CC>[CH2:8]([O:9][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:7][CH3:6]
Reactant: O=C(O)CCCCCBr
Agent: [Na]
Solvent: CCCO
Product: CCCOCCCCCC(=O)O
Temperature: 25 °C
Yield: 155.8 %

Procedure:
Sodium (354 mg, 15.38 mmol) was added to a solution of 6-bromohexanoic acid (300 mg, 1.54 mmol) in propyl alcohol (15 ml), and the mixture was heated under reflux for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give 6-propoxy-hexanoic acid (209 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].C(O)(=O)C.[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cn1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
(5-Benzyloxy-indol-1-yl)-acetic acid ethyl ester (3.49 g, 11.31 mmol) is dissolved in EtOH (50 mL) and glacial acetic acid is added (2.0 mL). Palladium on carbon (20% by wt., 0.700 g) is then added to the homogenous solution, and a hydrogen filled balloon is connected to the round bottom flask. A vacuum is created within the flask until the ethanol began to bubble, and the hydrogen allowed to enter the flask; this procedure is repeated three times, then the reaction is left to stir at room temperature overnight. Upon completion, the reaction is diluted with DCM (200 mL), and water (100 mL) is added. The mixture is filtered through a celite plug and the two phases are separated. The organic layer is washed with brine (2×75 mL), then dried over anhydrous magnesium sulfate, and concentrated to yield the title compound (2.42 g) in 98% yield. The residual acetic acid is removed by flash column chromatography.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].Br[CH2:31][C:32]#[N:33].[Cl-].[NH4+]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:31][C:32]#[N:33])=[CH:25][CH:26]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CCBr
Reactant: Oc1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CCOc1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)-phenol (357 mg; 1 mmol) was dissolved in tetrahydrofuran (20 ml) under argon and treated portionwise with sodium hydride (60% dispersion in oil; 60 mg; 1.5 mmol). When effervescence had ceased, bromoacetonitrile (178.5 mg; 103.5 μl ; 1.5 mmol) was added and the mixture was stirred at ambient temperature for 18 h. Saturated aqueous ammonium chloride solution was added and the nitrile extracted into ethyl acetate. The organic extracts were combined, washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was purified by chromatography through SiO2, eluting with ethyl acetate in 60-80° petroleum ether (50→100% ethyl acetate gradient), to give [4-(4-benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)-phenoxy]-acetonitrile (120 mg; 30%). This nitrile (120 mg; 0.31 mmol) was treated with ethanol (30 ml) and 2M aq. sodium hydroxide solution and the resulting mixture heated at reflux for 3 h. Cooled and evaporated to dryness under reduced pressure. The residue was treated with water and acidified to pH4-5 with 5M hydrochloric acid. The yellow precipitate was collected by filtration, washed with water and dried at 40° C. under reduced pressure (92 mg; 73%). 1H NMR (250 MHz; CD3OD) δ: 4.77 (2H, s), 6.12 (2H, s), 7.02 (1H, d), 7.12-7.14 (2H, m), 7.18 (2H, d), 7.44-7.49 (1H, m), 7.60 (1H, d), 7.86-7.92 (1H, m), 8.05 (2H, d), 8.72 (1H, d); m/z (API): 416.3 [M+H]⊕.