Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].F[C:38](F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCC1CCCN(C(OCC2C=CC=CC=2)=O)C1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:38]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 3-(4-bromobutyl)-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][C:14]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:33][S:34]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)(=[O:35])=[O:36])=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11](=[CH:10][CH:9]=2)[N:12]=[CH:13][C:14]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[N:15]3)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5)c4)cc3n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(-c2ccc3ncc(NCC4CCCNC4)nc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
(Some starting materials may be obtained from Asta Tech, Inc., Princeton, N.J.) To a solution of tert-butyl 3-((7-(6-chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)quinoxalin-2-ylamino)methyl)piperidine-1-carboxylate (5 mg, 8 μmol) in DCM (1 mL) was added TFA (1 mL) and the reaction was stirred at 23° C. for 15 min. The reaction was then concentrated in vacuo and coevaporated with DCM (3×; 1 ml) to give the desired product as a yellow film. MS (ESI pos. ion) m/z calc'd for C25H24ClFN6O2S: 526.1; found 527.0. 1H NMR (300 MHz, CDCl3) δ ppm 1.23-1.38 (m, 2 H) 1.78 (m, 1 H) 1.89 (m, 2 H) 2.22 (br. s., 1 H) 2.66 (t, J=11.84 Hz, 1 H) 2.79 (d, J=3.07 Hz, 1 H) 3.36-3.52 (m, 3 H) 7.05-7.12 (m, 2 H) 7.48 (dd, J=8.48, 2.05 Hz, 1 H) 7.71-7.88 (m, 4 H) 8.19-8.23 (m, 2 H) 8.38-8.41 (m, 1 H)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH3:20])[C:9]=1[CH2:10]Br>CN(C)C=O.C(N(CC)CC)C.O>[CH3:19][O:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:8]([O:7][CH3:6])=[C:9]([CH3:10])[C:12]=1[CH2:20][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1c(C)c(C)c(OC)c(CBr)c1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(OC)c(Cn2ccnc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of 499 mg (7.33 mmol) of imidazole and 2.0 g (7.33 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide in 12 ml of dimethylformamide, 1.2 ml of triethylamine was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried, from which the solvent was evaporated off. The residue was purified with silica gel column chromatography (chloroform-methanol(1:1)) and recrystallized from isopropyl ether, to give 0.9 g (47.3%) of 1-(2,5-dimethoxy-3,4,6-trimethylbenzyl)imidazole. m.p. 82°-83° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.C([Mg]Br)(C)C.O.[CH2:14]1[CH2:18]O[CH2:16][CH2:15]1>>[N:2]1[C:3]2[C:4](=[CH:18][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:1]=1
Reactant: C1CCOC1
Reactant: CN1CCCC1=O
Agent: CC(C)[Mg]Br
Solvent: O
Product: c1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
0.2 g (6.38×10−4 mol) of 1,1-dibromo-2-(2-quinolyl)ethene obtained from 2-formylquinoline, carbon tetrabromide (CBr4) and triphenylphosphine (PPh3) (Ramirez et al., J. Am. Chem. Soc., 1962, 84: 1745) and 11.28 mg (3.19×10−5 mol, 5 mol %) of iron triacetylacetonate (Fe(acac)3) are dissolved in 3 ml of anhydrous THF and 3 ml of anhydrous N-methylpyrrolidone (NMP) at −10° C., in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. 0.39 ml (7.02×10−4 mol) of a 1.8M solution of isopropyl magnesium bromide in THF is added dropwise to the solution. After stirring for 30 minutes, the reaction is hydrolyzed with 10 ml of water and the solution is brought back to ambient temperature. Next, the two phases are separated and the aqueous phase is extracted with diethyl ether (3×30 ml).
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:15][C:16]=2[O:20][CH:21]([CH3:23])[CH3:22])[N:11]=[CH:10]1)(=O)C(C)(C)C.N>CO>[CH2:25]([O:24][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[NH:9][CH:10]=[N:11]2)=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Agent: N
Solvent: CO
Product: CC(C)Oc1cc(OCc2ccccc2)cc2nc[nH]c(=O)c12
Yield: 87 %

Procedure:
[7-(benzyloxy)-5-isopropoxy-4-oxoquinazolin-3(4H)-yl]methyl pivalate was stirred in a 7N solution of ammonia in methanol (250 ml) at room temperature for 24 hours. The mixture was evaporated under reduced pressure and the residue purified by silica gel chromatography eluting with a 0 to 10% mixture of methanol in dichloromethane to give 7-(benzyloxy)-5-isopropoxyquinazolin-4(3H)-one (4.6 g, 87% yield over 2 steps) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](OCC)(OCC)OCC>COCCOCCOC>[Cl:9][CH2:10][C:11]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1ncccc1O
Solvent: COCCOCCOC
Product: ClCc1nc2ncccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The commercially available 2-amino-3-hydroxypyridine (5.0 g) and diglyme (30 ml) were heated at 125° C. to obtain a solution. To this solution was added 2-chloro-1,1,1-triethoxyethane (9.9 g) and the mixture was held at 125° for 1 hour. The solution was cooled to room temperature and then decanted to remove a black byproduct residue. The filtrate was diluted with water (50 ml) and the resulting yellow precipitate was collected (1.5 g). A small sample was crystallized from isopropanol (m.p. 115°-118° C.).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][O:12][CH2:13][CH:14]=[CH:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC[C@@H](O)C1>>[Si:1]([O:8][C@H:9]1[CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CCOCC1
Agent: O[C@@H]1CCCCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCCOCC1
Yield: 95 %

Procedure:
Hydrogenolysis of 15 was carried out as described for 8e to afford (S)-4-(tert-butyldimethylsilyloxy)oxepane in 95% yield as a colourless oil: 1H NMR (CDCl3) δ 4.03-3.96 (m, 1H), 3.79-3.57 (m, 4H), 1.98-1.69 (m, 5H), 1.64-1.51 (m, 1H), 0.88 (s, 9H), 0.044 (s, 3H), 0.038 (s, 3H); 13C NMR (CDCl3) δ 70.2, 69.4, 64.2, 40.1, 34.5, 25.7, 23.7, 18.0, −4.9. Deprotection of the above compound was performed as described for compound 11 and afforded the title compound in 75% yield as a colorless oil: 1H NMR (CDCl3) δ 4.03-3.98 (m, 1H), 3.82-3.59 (m, 4H), 2.02-1.98 (m, 1H), 1.89-1.80 (m, 4H), 1.66-1.64 (m, 1H); 13C NMR (CDCl3) δ 70.5, 69.6, 64.7, 38.9, 34.9, 24.3.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[F:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(F)c(OC3CCOCC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2c(cc1OC1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-fluoro-6-(tetrahydro-pyran-4-yloxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. 238.1 ([M+H]+, 100%).
Reaction SMILES: Br[CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][NH:33][CH2:32]2.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:26][N:33]2[CH2:34][C:35]3[C:31](=[CH:30][C:29]([O:28][CH3:27])=[C:37]([O:38][CH3:39])[CH:36]=3)[CH2:32]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCC(C)Br)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(CCCCCCN2Cc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 61.1 %

Procedure:
A mixture of 1.79 g of 4-[6-bromo-1-[(4-methylphenyl)thio]heptyl]-1,2-dimethoxybenzene, 3.29 g of 5,6-dimethoxyisoindoline, 25 mL of acetonitrile, and 1.74 mL of N,N-diisopropylethylamine is heated under reflux for 2 days. The reaction is concentrated in vacuo and the black residue partitioned between chloroform and aqueous ammonia. The organic layer is dried (sodium sulfate) and the solvent removed at reduced pressure. Chromatography on silica gel with gradient elution progressing from hexane to chloroform to methyl alcohol, twice, gives 1.34 g of the desired product as a brown gum. MS(Hi res): m/z Calcd for C32H41NO4S 535.2756 Found 535.2723 Calcd for C32H41NO4S H2O C=69.41, H=7.83, N=2.53, S=5.78 Found C=69.59, H=7.51, N=2.53, S=6.19
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]=[C:8]([O:13][CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[CH:7]=[C:8]([O:13][CH3:14])[C:9](=[O:12])[NH:24][C:10]=2[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=CC(=O)c2ccc(Cl)cc2C1=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
7-Chloro-2-methoxy-1,4-naphthoquinone (14.74 g) was added to trifluoromethanesulfonic acid (153 mL) chilled in an ice bath, and sodium azide (4.74 g) was added. The reaction mixture was maintained in an ice bath for 0.33 hour then allowed to warm to room temperature and maintained thus for 90 hours. The reaction mixture was recooled in an ice bath, and an additional portion of sodium azide (2.15 g) was added. After 0.08 hour the mixture was allowed to warm to room temperature for 19 hours. The reaction mixture was then poured into ice cold aqueous sodium bicarbonate (2.3 L). The resulting precipitate was filtered, washed (water) and dried under vacuum (25° C., 15 Pa) to give a tan solid (13.83 g). The solid was recrystallized from hot dimethylformamide (300 mL) and dried under vacuum (25° C., 15 Pa) to give the benz[b]azepine as a light tan solid (8.12 g); mp 340°-342° C. (dec). Analysis for C11H8ClNO3 : Calculated: C, 55.60; H, 3.39; N, 5.89; Found: C, 55.35; H, 3.38; N, 6.07.
Reaction SMILES: ClCCl.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=[O:10].Cl.C(N=C=NCCCN(C)C)C.[OH:24][CH:25]([CH3:29])[C:26](=O)[CH3:27]>O>[O:24]=[C:25]([CH3:29])[CH:26]([C:6]1[CH:7]=[CH:8][O:4][C:5]=1[C:9]([OH:11])=[O:10])[CH3:27]
Reactant: CC(=O)C(C)O
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(C)c1ccoc1C(=O)O
Yield: 99.9 %

Procedure:
The dichloromethane (150 mL) solution of furan-2-carboxylic acid (11.2 g, 100 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (28.8 g, 150 mmol), N,N-dimethylaminopyridine (1.2 g, 10 mmol), and acetoin (9.69 g, 110 mmol) was stirred at room temperature for 5 hrs. The reaction mixture was added water and extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain 3-oxobutan-2-yl furan-2-carboxylic acid (18.2 g, 100%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.CN(C=O)C.I[CH:19]([CH3:21])[CH3:20]>CCOC(C)=O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1cc(Br)cn1
Temperature: 25 °C

Procedure:
A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo-1H-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt. The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The desired compound (as determined by TLC, I2 stain) was collected as a colorless liquid.
Reaction SMILES: C([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>Cl>[NH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:14][CH2:15]1
Reactant: O=C(NC1CCN(CCc2ccc3ccccc3c2)CC1)c1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: NC1CCN(CCc2ccc3ccccc3c2)CC1
Reaction time: 96 h
Yield: 78.6 %

Procedure:
4-Benzamido-1-[2-(2-naphthyl)ethyl]piperidine (1.0 g.) was suspended in 6N HCl (40 ml.) and boiled for 96 hr. The resulting solution was worked up in the manner of Example 72 to give the title compound (0.558 g.) as the dihydrochloride, pale yellow needles, m.p. >300° (decomp.)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[C:16]3[C:21]([C:22]([C:29]4[C:34]5=[CH:35][CH:36]=[C:37]6[C:46]([CH:45]=[C:44]7[C:39]([CH:40]=[CH:41][CH:42]=[CH:43]7)=[CH:38]6)=[C:33]5[CH:32]=[CH:31][CH:30]=4)=[C:23]4[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C=O)C>[Br:1][C:38]1[C:37]2[C:46]([CH:45]=[C:44]3[C:39]=1[CH:40]=[CH:41][CH:42]=[CH:43]3)=[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[CH:27]4)[C:34]1=[CH:35][CH:36]=2
Reactant: c1ccc(-c2c3ccccc3c(-c3cccc4c3ccc3cc5ccccc5cc34)c3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1c2ccccc2cc2c1ccc1c(-c3c4ccccc4c(-c4ccccc4)c4ccccc34)cccc12
Reaction time: 3 h

Procedure:
20 g (116 mmol) of N-bromosuccinimide are added at 100° C. to a suspension of 55 g (116 mmol) of 4-(9-phenylanthracen-10-yl)benz[a]anthracene in 500 ml of DMF. After 3 h, 500 ml of ethanol are added at room temperature, and the solid is filtered off with suction, washed with ethanol and dried. Yield: 63 g (113 mmol), 65%.
Reaction SMILES: CO.N.[C:4]([CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)#[N:5]>[Ni].C(O)(=O)C>[NH2:5][CH2:4][CH:6]([C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(CN)C2(O)CCCCC2)cc1
Yield: 70 %

Procedure:
The reactor was charged with 25.0 g of Raney-Ni (Kawaken, Grace 2400, 2724, Degussa B111W, 112W), and 250 ml of MeOH and 25 ml of an ammonia solution (25% NH3) were added. To the mixture was added 50 g of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol, followed by 250 ml of MeOH. The reactor was settled and purged with N2 gas two or three times. After fully purged with N2, the reactor was purged with H2 gas two or three times. Internal pressure of the reactor was adjusted to 60 psi and the reaction mixture was stirred. After 20 to 30 hours of reaction at room temperature (about 10 to 20° C.), in-process analysis of a sample of mixture was made. After the reaction was completed, Ra—Ni was removed by filtration with a celite pad. The filtrate was distilled under reduced pressure until all of the solvent was evaporated, and 200 ml of isopropyl alcohol and 400 ml of ethyl acetate were added to the residue oil to dissolve the resulting product to give a clear or a little hazy solution. To the solution was added 10 ml of acetic acid dropwise, and an exothermic reaction began with some fumes given off. After about 10 to 20 minutes of adding all of the acetic acid, a solid began to form. The solution was stirred for about one hour, filtered and washed with ethyl acetate to give the desired product, 1-[2-amino-1-(4-methoxyphenyl)ethyl]-cyclohexanol, 44.2 g (yield 70%, purity 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:28]=[CH:27][C:26](=[O:29])[C:25]([O:30][CH3:31])=[CH:24][CH:23]=1.[Sn]>O1CCOCC1.[Pd].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>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:28]=[CH:27][C:26](=[O:29])[C:25]([O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: COc1ccc([Sn](C)(C)C)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Sn]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A slurry of (S)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide described above (4.200 g, 11.11 mmol) and trimethyl(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)tin (4.150 g, 13.88 mmol) in 1,4-dioxane (50 mL) was degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.545 g, 0.78 mmol) was added, the reaction again degassed, and then the mixture was brought to reflux under nitrogen. After 3 h TLC revealed some of the iodide still remained. Additional tin reagent (0.400 g, 1.34 mmol) and palladium catalyst (0.100 g, 0.14 mmol) were added and the mixture refluxed for 4 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 20% methanol/chloroform, filtered through Celite and concentrated in vacuo. The crude solids were triturated with dichloromethane/diethyl ether, the solids filtered, washed with diethyl ether and dried in vacuo to give 4.200 g (98%) of the title compound. The following characteristics were noted:
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C([Si](C#C)(CC)CC)C.[CH2:15]([CH2:22][C:23](=[O:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CCOCC>[CH3:24][C:23]([OH:25])([CH2:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]#[CH:2]
Reactant: [Li]CCCC
Reactant: CC(=O)CCc1ccccc1
Agent: C#C[Si](CC)(CC)CC
Agent: Cl
Solvent: CCOCC
Product: C#CC(C)(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 Parts by volume of 2.5 molar n-butyl lithium is added to a solution of 3.1 parts of triethylsilyl acetylene in 20 parts by volume of ethyl ether at -30° C. The resulting solution is allowed to warm to room temperature, then it is cooled again to -30° C. and 3 parts of benzyl acetone is added. The reaction mixture is allowed to warm to room temperature and is then stirred for 1 hour. The reaction mixture is poured into ether and dilute hydrochloric acid. The ethereal layer is washed with water and dried over anhydrous sodium sulfate. The ether is removed under reduced pressure and the residual oil is dissolved in 15 parts by volume of dimethylformamide containing 2 parts of powdered potassium fluoride. This reaction mixture is stirred and heated at 70°-80° C. for 1 hour, after which time it is diluted with water and extracted with ether. The ether layer is separated and washed with water and dried over anhydrous sodium sulfate. The ether is removed under reduced pressure and the residue is chromatographed on silica gel using 30% ethyl acetate/hexane as eluent to provide 3-methyl-3-hydroxy-5-phenyl-1-pentyne.
Reaction SMILES: P([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(O)(O)=O.C([Li])CCC.[CH2:18]([O:20][C:21]([C:23]1[S:27][C:26]2[CH:28]=[C:29]([CH:32]=O)[CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])[CH3:19]>C1COCC1>[CH2:18]([O:20][C:21]([C:23]1[S:27][C:26]2[CH:28]=[C:29]([CH:32]=[CH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc2ccc(C=O)cc2s1
Reactant: CC(C)(C)OC(=O)CP(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C=CC(=O)OC(C)(C)C)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a stirred solution of tert-butyl phosphonoacetate (1.7 g, 7.27 mmol) in THF (20 mL) was slowly added n-butyllithium (1.6 M, 5 mL) with cooling to −78 degrees Celsius. After stirring for 30 minutes at −78 degrees Celsius, this solution was added into a solution of 6-formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (1.83 g, 7.27 mmol). The resulting solution was stirred at −78 degrees Celsius for 30 minutes before being allowed to warm to room temperature. The solution was subsequently cooled back to −78 degrees Celsius and quenched with sat. aq NH4Cl. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate. After being filtrated and concentrated, the residue was purified by flash column chromatography to give 1.7 g (71%) of 6-(2-tert-butoxycarbonyl-vinyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester. MS: calc'd 333 (MH+), exp 333 (MH+). 1H NMR (d6-DMSO, 400 MHz), 8.38 (s, 1H), 8.18 (s, 1H), 8.02 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=8.4 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.66 (d, 1H, J=16.0 Hz), 4.36 (q, 2H, J=7.2 Hz), 1.49 (s, 9H), 1.34 (t, 3H, J=7.2 Hz).
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:46]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47]1>CC#N>[CH:41]1([N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:50]([CH:46]3[CH2:49][CH2:48][CH2:47]3)=[O:51])[CH2:20][NH:19][CH2:24]2)=[O:44])[CH2:43][CH2:42]1
Reactant: O=C(Cl)C1CCC1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C3CCC3)C2)C2CC2)ccc1C

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 98A.) and cyclobutane-carbonyl chloride. MS: 458.7 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.88 min.