Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:4][N:3]=1.[CH3:18][C:19]([C:26]1[C:27](=[O:33])[CH:28]=[CH:29][C:30](=[O:32])[CH:31]=1)([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CO>[CH2:13]([C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([S:1][C:29]2[CH:28]=[C:27]([OH:33])[C:26]([C:19]([CH3:25])([CH3:18])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:31][C:30]=2[OH:32])=[N:3][N:4]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCc1nnc(S)n1-c1ccccc1
Reactant: CC(C)(C)CC(C)(C)C1=CC(=O)C=CC1=O
Solvent: CO
Product: CCCCCc1nnc(Sc2cc(O)c(C(C)(C)CC(C)(C)C)cc2O)n1-c1ccccc1
Yield: 20.3 %

Procedure:
13 g of 3-mercapto-5-n-pentyl-4-phenyl-1,2,4-triazole was dissolved in 200 ml of methanol, and the solution was stirred under ice cooling. To the solution was added 12 g of 2-(1,1,3,3-tetramethylbutyl)benzoquinone in small portions. After the addition, the solution was stirred under ice cooling for 2 hours, and then allowed to stand at room temperature (25°±5° C.) overnight. The methanol was removed under reduced pressure, and 20 ml of diethyl ether was added to the residue. The crystals obtained were collected by filtration, and recrystallized from ethyl acetate to obtain 5 g of 2-(5-n-pentyl-4-phenyl-1,2,4-triazol-3-ylthio)-5-(1,1,3,3-tetramethylbutyl)hydroquinone having a melting point of 198° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.[CH3:17][C:18](=O)[CH2:19][C:20](=[O:22])[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[C:19]([C:20](=[O:22])[CH3:21])=[C:18]([CH3:17])[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]=12
Reactant: CC(=O)CC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred solution of 50 mg (0.21 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-furan-2-yl-methanone in 2 ml acetic acid was added 0.016 ml (0.21 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 20 mg (31%) 1-(4-furan-2-yl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 298 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[N:19]1([CH:24]([CH2:30][CH3:31])[CH2:25][CH2:26][C:27](=O)C)[CH:23]=[N:22][CH:21]=[N:20]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C@H:27]1[CH2:26][CH2:25][C@H:24]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:30][CH2:31]1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N
Reactant: CCC(CCC(C)=O)n1cncn1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N[C@H]1CC[C@H](n2cncn2)CC1

Procedure:
Reductive amination of 3-amino-5-(4,4-dimethyl-cyclohex-1-enyl)-thiophene-2-carboxylic acid methyl ester (0.630 g, 2.37 mmol) and 5-[1,2,4]triazol-1-yl-heptan-2-one (0.560 g, 3.39 mmol) was performed under the same conditions previously described (example 3, step I) using dibutyltin dichloride and phenylsilane to give 5-(4,4-Dimethyl-cyclohex-1-enyl)-3-(trans-4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (0.800 g, 64%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([C:7]1[N:11]([CH3:12])[C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]=1[OH:24])=[O:6].[H-].[Na+].O>CN(C=O)C>[CH2:22]([O:21][C:19]([C:9]1[C:8]2[O:24][CH2:2][C:3]3[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=3[C:5](=[O:6])[C:7]=2[N:11]([CH3:12])[C:10]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20])[CH3:23]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccccc2CCl)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2c(n1C)C(=O)c1ccccc1CO2
Reaction time: 1 h
Yield: 88.9 %

Procedure:
Ethyl 5-[o-(chloromethyl)benzoyl]-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (525 mg, 1.29 mmol) is suspended in 5 ml dry DMF under nitrogen followed by subsequent addition of sodium hydride (68 mg, 1.42 mmol, 50% dispersion in oil). Gas is evolved and the reaction turns dark brown. The mixture is stirred for one hour, then the solution is poured into water (50 ml). Upon agitation, a solid separates which is filtered and dried. The crude material is recrystallized from ethanol to give 426 mg (90%) of ethyl 5,10-dihydro-3-ethoxycarbonyl-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].C1(C)C=CC=CC=1>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[CH:24][N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(CNc1ncnc(N2CCC(c3ccc4c(n3)NCCC4)CC2)c1C=O)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1

Procedure:
120 mg (0.195 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{5-formyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in 10 ml of dichloromethane with 1 ml of trifluoroacetic acid is stirred at ambient temperature for 24 hours. Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 60 mg of expected product is obtained in the form of a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:20])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.32M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-bromo-phenyl)-acetic acid methyl ester (1.48 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.2 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Iodomethylcyclopentane (1.49 g, 7.13 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.60 g, 79.3%) as a clear oil: EI-HRMS m/e calcd for C15H19O2Br (M+) 310.0568 found 310.0564.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1>N.CO.[Pd]>[CH3:9][C:6]1[C:7]([CH3:8])=[CH:2][N:3]=[C:4]([NH2:10])[N:5]=1
Reactant: Cc1nc(N)nc(Cl)c1C
Agent: [Pd]
Agent: N
Solvent: CO
Product: Cc1cnc(N)nc1C
Reaction time: 18 h
Yield: 115.3 %

Procedure:
A solution of 4-chloro-5,6-dimethylpyrimidin-2-amine (0.35 g, 2.22 mmol) in 2M ammonia in methanol (100 ml) was flushed with nitrogen and palladium on carbon (0.035 g, 0.33 mmol) was added, flushed with nitrogen and the reaction was hydrogenated at 1 atm, ambient temperature for 18 h. The reaction mixture was flushed with nitrogen and filtered through celite and the celite pad washed with methanol. The filtrate was evaporated to dryness in vacuo to afford 4,5-dimethylpyrimidin-2-amine (0.35 g, 2.56 mmol, 90% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (1H, s), 6.19 (2H, s), 2.18 (3H, s), 1.99 (3H, s). MS (LC/MS) R.T.=0.56; [M+H]+=124.20.
Reaction SMILES: [I:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.IC1NC=CN=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:4]2[CH:3]=[C:2]([I:1])[N:6]=[CH:5]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1cnc[nH]1
Agent: Ic1ncc[nH]1
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
As depicted in Scheme II, imidazole was reacted with iodine under basic conditions at reduced temperature in an appropriate solvent, yielding a mixture of iodoimidazoles (v), for example, 2,4,5-triiodoimidazole and 2,5-diiodoimidazole. The mixture of iodoimidazole derivatives (v) was then treated with aqueous sodium sulfite at elevated temperature in an appropriate solvent, yielding a single iodo derivative (vi), for example, 5-iodoimidazole. The free amine in the 1-position of the iodoimidazole (vi) ring was then protected by reacting it with triphenylmethyl chloride under basic conditions in an appropriate solvent, affording the corresponding 1-(triphenylmethyl)-4-iodoimidazole (vii). The iodoimidazole (vii) was in turn treated with ethylmagnesium bromide in an appropriate solvent, then reacted with an appropriate cyclic ketone (ii), for example, 6-methoxy-5-methylindan-1-one (X is —CHR17—), affording the corresponding 1,2-unsaturated heterocyclic derivative (viii), for example, 3-(imidazol-5-yl)-5-methoxy-6-methylindene. Heterocyclic derivative (viii) was then hydrogenated under conditions set forth above, yielding the corresponding compounds of formula (I), for example, 1-(imidazol-5-yl)-6-methoxy-5-methylindane. Example 4 set forth below provides in detail the synthesis route shown in Scheme II.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:23][CH3:22])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Solvent: CCO
Product: CNc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Temperature: 90 °C

Procedure:
To 500 mg of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 15 mL of absolute ethanol was added 4 mL of 40% aqueous methyl amine. The sealed reaction was heated at 90° C. for 24 hours, stripped of solvents, and purified by flash chromatography on silica gel with a gradient of 0-1% methanol/chloroform followed by purification by preparative thin-layer chromatography with 5% methanol/chloroform to yield 86 mg of 4-(3-bromo-phenylamino)-6-methylamino-[1.7]naphthyridine-3-carbonitrile as an amorphous solid: melting point 250° C. (decomposed); mass spectrum (m/e): M+H 354.1, 356.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])(=[O:3])[CH3:2].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>N1C=CC=CC=1>[CH:12]1([C:18]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[CH3:2])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)c1cccc(C)c1O
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cccc(C)c1OC(=O)C1CCCCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
2-Acetyl-6-methylphenol (3.0 g) was dissolved in pyridine (15 ml) and to the solution was added dropwise cyclohexanecarbonyl chloride (3.08 g) with stirring at room temperature. After stirring for 4 hours, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with water, diluted hydrochloric acid and then water and dried (MgSO4). The solvent was distilled off under reduced pressure to obtain the title compound (5.2 g) as oil in a quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:61]=[CH:62][CH:63]=1)[O:56][CH2:57][CH2:58]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:58][CH2:57][O:56][C:55]2[CH:61]=[CH:62][CH:63]=[C:53]([O:52][CH3:51])[CH:54]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cccc(OCCCO)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(OCCCOC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)c1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (85 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (116 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-methoxyphenoxy)-1-propanol (72 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (91 mg, yield 72%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[C:35]#[CH:36])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[F:44][C:45]([F:53])([F:52])[C:46]([C:48]([F:51])([F:50])[F:49])=[O:47]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[C:35]#[C:36][C:46]([C:48]([F:51])([F:50])[F:49])([OH:47])[C:45]([F:53])([F:52])[F:44])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C#C/C=C(\CC)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Li]CCCC
Product: CC/C(=C\C#CC(O)(C(F)(F)F)C(F)(F)F)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
In a manner analogous to example 21, by reaction of 5 g (9.1 mmol) of (E)-1-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)-phenyl]ethyl}phenyl)-1-ethyl-but-1-en-3-yne with 4 ml (10 mmol) of a 2.5 M solution of butyllithium and a flow of hexafluoroacetone. The desired product is obtained in the form of a yellow oil (m=3.7 g; Y=57%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O.CCOCC>O1CCCC1.C(N(CC)CC)C>[Cl:22][CH2:20][C:19]([C:7]1[CH:8]=[C:9]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1c(N2CCOCC2)cc(C(C)=O)cc1C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1c(N2CCOCC2)cc(C(=O)CCl)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
After dissolving 1-[3-(tert-butyl)-4-methoxy-5-morpholinophenyl]-1-ethanone (9.5 g) in tetrahydrofuran (60 ml), triethylamine (13 ml) and tert-butyl dimethylsilyltrifluoromethanesulfonate (9.8 ml) were added dropwise while cooling on ice. The reaction mixture was stirred for 30 minutes while cooling on ice and then N-chlorosuccinimide (5.3 g) was gradually added. After continuing to stir the reaction mixture for 30 minutes, ether (2 l) was added thereto and the resulting mixture was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (4.87 g) as light yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([NH:1][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Product: CC(C)(C)C(NC(=O)c1ccccc1)C(=O)O

Procedure:
Racemic tert-butylglycine and benzoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH:23]2[CH2:25][CH2:24]2)[CH2:18][CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1)C.[OH-:29].[Na+].[CH2:31]([OH:33])C>>[CH:23]1([N:19]2[C:20]3[C:15](=[CH:14][C:13]([C:12]4[C:5]([C:6]#[CH:7])=[C:10]([CH:9]=[CH:8][CH:11]=4)[C:31]([OH:33])=[O:29])=[CH:22][CH:21]=3)[C:16]([CH3:26])([CH3:27])[CH2:17][CH2:18]2)[CH2:24][CH2:25]1
Reactant: CCO
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: C#Cc1c(C(=O)O)cccc1-c1ccc2c(c1)C(C)(C)CCN2C1CC1

Procedure:
Following general procedure L and using 4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoic acid ethyl ester Compound 61, 0.05 g, 0.13 mmol), 5 mL of ethanol and 5M sodium hydroxide solution (2 mL) followed by recrystallization from hot ethyl acetate, the title compound was obtained as a solid (0.030 g, 64%).
Reaction SMILES: [H-].[Na+].[S:3]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[NH:6]1)(=[O:5])=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]2)[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1>CN(C=O)C>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:6]3[C:7](=[O:8])[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[S:3]3(=[O:4])=[O:5])[CH2:30][CH2:31]2)[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: ClCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C1c2ccccc2S(=O)(=O)N1CCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1

Procedure:
To a stirred suspension of sodium hydride (0.31 g, 13 mmol) in 12 ml of dry DMF was added saccharin (2.29 g, 13 mmol) in 12 ml of dry DMF. Stirring was continued for 10 minutes before 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(2-chloroethyl)piperazine (4.12 g, 13 mmol) (which can be obtained as described in EP-A-0190472) in 20 ml of dry DMF was added. The reaction mixture was heated under a nitrogen atmosphere for 7 hours, cooled down and extracted with ethylacetate (3×100 ml). The combined organic layers were washed with 5% NaHCO3, brine, dried and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (silicagel/acetone:hexane=1:3) and the so-obtained free base was converted to its hydrochloride salt. Yield 3.13 g, (50%), m.p. 267°-70° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH:9]([OH:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([F:1])[CH:13]=[CH:12][C:5]=2[N:6]=1)(=[O:11])[CH3:10]
Reactant: CC(O)c1nc2ccc(F)cc2o1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1nc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
6-Fluoro-2-(1-hydroxyethyl)benzoxazole (4.71 g, 26 mmol) was dissolved in 100 ml of methylene chloride, and pyridinium chlorochromate (8.38 g, 39 mmol) was added portionwise to the solution. The mixture was stirred for 4 hours at room temperature, then diluted with ether, and filtered. The filtrate was concentrated and the resulting residue was subjected to column chromatography and then recrystallization from methanol to afford 2-acetyl-6-fluorobenzoxazole (1.92 g, yield: 41%).
Reaction SMILES: [CH:1]([O:14][CH2:15]CC1CCNCC=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C1C=CC=CC=1.O1CC1CC1C=CC=CC=1>C(O)C>[CH2:15]1[O:14][C@@H:1]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1=C(CCOC(c2ccccc2)c2ccccc2)CCNC1
Agent: c1ccc(CC2CO2)cc1
Solvent: CCO
Product: c1ccc([C@@H]2CO2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirring solution of cis-(−)-8-benzydryl-1,4-diazabicyclo[3.3.1]nonane 5 (0.100 g, 0.341 mmol) in dry ethanol was added 2,3-epoxypropyl benzene (0.068 g, 0.512 mmol). The reaction mixture was stirred overnight at 65° C. (Procedure A). The diastereomers were separated by preparative TLC using acetone/diethyl ether (20:80) as mobile phase to afford 6a and 6b. Upper Fraction gave 6a (0.026 g, 18%). 1H NMR (400 MHz, CDCl3): δ 1.24-1.43 (2H, m, H-7), 1.54-1.66 (1H, m, H-6a), 2.03-2.06 (1H, m, H6eq), 2.28 (1H, t, J=12.4 Hz, NCH2CH), 2.39 (1H, bs, H-5), 2.57-2.87 (6H, m, NCH2CH, NCH2CH2N, Ph-CH2), 2.98-3.01 (1H, m, H-9ax), 3.10 (1H, bd, J=11.8 Hz, NCH2CH2N), 3.22-3.25 (1H, m, H-9eq) 3.77 (1H, dt, J=4.8 Hz, J=11.2 Hz, H-8ax), 3.84-3.91 (2H, m, CH—OH, (Ph)2CH), 7.11-7.15 (2H, m, ArH), 7.19-7.31 (1H, m, ArH), 7.35-7.38 (2H, m, ArH). [α]25D (oxalate salt)=(−) 24.7° (c 0.42, MeOH).