Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][NH2:25])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Cl:26][CH2:27][C:28](Cl)=[O:29].O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][NH:25][C:28](=[O:29])[CH2:27][Cl:26])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: Cc1nnc(CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 5-chloro-2-(3-aminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone dihydrobromide (0.5 g) in dimethylformamide (3 ml), chloroacetyl chloride (0.2 g) is dropwise added under ice cooling, and the resultant mixture is stirred. The reaction mixture is allowed to stand at room temperature overnight, mixed with water (3 ml), neutralized with aqueous sodium bicarbonate and shaken with methylene chloride. The methylene chloride layer is washed with water and saturated aqueous saline solution in order, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from ethyl acetate/n-hexane to give 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.35 g) as crystals melting at 140° to 141° C.
Reaction SMILES: Br[C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6](Cl)[C:5]1=[O:11].[OH-:14].[Na+]>>[Br:13][C:2]([Br:12])=[CH:3][CH:4]1[C:7]([CH3:8])([CH3:9])[CH:6]1[C:5]([OH:11])=[O:14]
Reactant: CC1(C)C(Cl)C(=O)C1CC(Br)(Br)Br
Reactant: [OH-]
Agent: [Na+]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)O
Temperature: 80 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 800 mg (0,02 mole) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-chlorocyclobutan-1-one and 5,6 ml of 5% by weight of aqueous sodium hydroxide solution is stirred for 18 hours at 0° C. and subsequently for one additional hour at 80° C. Then the reaction mixture is cooled to room temperature washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract is washed with water and dried over magnesium sulphate. After evaporation of the diethyl ether there is obtained 0,59 g (100% of theoriy) of 2-(2',2'-dibromovinyl)-3,3-dimethylcyclopropane-1-carboxylic acid consisting to 80% of the cis-isomer and to 20% of the trans-isomer.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][O:14][C:15](=[O:31])[C:16]1[C:21]([CH2:22][O:23]C2CCCCO2)=[C:20]([Cl:30])[CH:19]=[N:18][CH:17]=1>CO>[CH3:13][O:14][C:15](=[O:31])[C:16]1[C:21]([CH2:22][OH:23])=[C:20]([Cl:30])[CH:19]=[N:18][CH:17]=1
Reactant: COC(=O)c1cncc(Cl)c1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1cncc(Cl)c1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Toluenesulfonic acid monohydrate (26.7 mg, 0.140 mmol) was added to a stirred solution of 5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-nicotinic acid methyl ester (20 mg, 0.070 mmol) in MeOH (4 mL). After stirring for 60 min at room temperature, the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (10 mL) and saturated NaHCO3 solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 202.0 [M+H+].
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[O-]CC.[Na+].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>C(O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=1
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Reactant: ClCc1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Cc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-hydroxyphenyl)propan-2-one ethylene ketal (28 g) in ethanol (40 ml) was added to a stirred solution of sodium ethoxide in ethanol (7.1 g of sodium in 100 ml) and the resulting solution stirred at room temperature for 20 minutes. A suspension of 2-picolyl chloride hydrochloride (25 g) in ethanol (60 ml) was added and the resulting mixture was boiled under reflux for 5 hours, cooled and filtered. 2M Hydrochloric acid (100 ml) was added, the solution boiled for 5 h, cooled and neutralised with 2M sodium hydroxide solution. After dilution with water the solution was extracted with dichloromethane and the washed organic phase dried and evaporated to give a dark oil. Bulb to bulb distillation gave [4-(2-pyridylmethyloxy)phenyl]propan-2-one, b.pt. 96°-100° C./0.2 mm, which was used without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@:4]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([CH2:21][CH:22]=[CH2:23])[CH2:5][CH2:6][N:7]([C@H:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH3:13])[C:8](=O)[O:9]C>C1COCC1.C(Cl)Cl>[CH2:21]([C:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:5][CH2:6][N:7]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH3:13])[C:8](=[O:9])[NH:3]1)[CH:22]=[CH2:23]
Reactant: C=CC[C@](N)(CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1

Procedure:
To a mixture of NaH (100 mg, 4 mmol) and anhydrous THF (8 mL) was added dropwise a solution of crude methyl (S)-3-amino-3-(4-fluorophenyl)hex-5-enyl((S)-1-(4-bromophenyl)ethyl)carbamate (39 mg, 0.1 mmol) in anhydrous THF (8 mL) at 0° C. The reaction mixture was refluxed overnight. The reaction mixture was quenched with methanol in an ice bath and evaporated to leave a residue, which was dissolved in CH2Cl2. The combined organic phase was dried, filtered and concentrated to give the crude product, which was purified by TLC to provide (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyptetrahydropyrimidin-2(1H)-one (1.2 mg, 3%). LC-MS Method 1 tR=1.603 min, m/z=419; 1H NMR (CD3OD) 1.36 (d, 3H), 1.81-1.92 (m, 1H), 2.16-2.22 (m, 1H), 2.46-2.53 (m, 1H), 2.61-2.84 (m, 3H), 5.12-5.19 (m, 1H), 5.56-5.69 (m, 1H), 7.06-7.13 (m, 2H), 7.18-7.24 (m, 2H), 7.22-7.29 (m, 2H), 7.42-7.51 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=[CH:20]2)=[O:11]>CN(C=O)C.[Pd]>[CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[C:23]([NH2:26])=[CH:22][CH:21]=[CH:20]2)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c([N+](=O)[O-])cccc3nc2-1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1

Procedure:
A solution of 0.6 g of 9-nitro-20(S)-camptothecin in 7.5 ml of DMF was hydrogenated at room temperature and atmospheric pressure in the presence of 0.02 g of 10% Pd/C for four hours. The catalyst was filtered off, and washed with warm DMF repeatedly. The solution was evaporated in vacuo and the crude reaction mixture was purified by column chromatography, to yield the title product.
Reaction SMILES: C(O[C@@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCCC(C)C)C1)(=O)C.[O:32]1[C@@H:34]2[CH2:35][C@@H:36]3[C@@H:52]([C@@:53]4([CH3:62])[CH2:54][CH2:55][C@@H:56]([O:58][C:59](=[O:61])[CH3:60])[CH2:57][C@@:33]124)[CH2:51][CH2:50][C@@:49]1([CH3:63])[C@H:37]3[CH2:38][CH2:39][C@@H:40]1[C@H:41]([CH3:48])[CH2:42][CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46]>>[O:32]1[C@@H:34]2[CH2:35][C@@H:36]3[C@@H:52]([C@@:53]4([CH3:62])[CH2:54][CH2:55][C@H:56]([O:58][C:59](=[O:61])[CH3:60])[CH2:57][C@@:33]124)[CH2:51][CH2:50][C@@:49]1([CH3:63])[C@H:37]3[CH2:38][CH2:39][C@@H:40]1[C@H:41]([CH3:48])[CH2:42][CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46]
Reactant: CC(=O)O[C@@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@H]3O[C@]32C1
Agent: CC(=O)O[C@@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@H]3O[C@]32C1

Procedure:
Following the procedure of Example 3 above, 3α-acetoxycholest-5-ene was epoxidized to 5β,6β-epoxy-3α-acetoxycholestane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[C@:18]12[O:26][CH2:25][CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:27]C(=O)OC(C)(C)C)=[N:19]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:24][CH2:25][O:26][C@:18]2([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:17])[C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ncccc4F)ccc3F)OCC[C@H]2CS1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ncccc4F)ccc3F)OCC[C@H]2CS1
Yield: 149.4 %

Procedure:
A solution of tert-butyl ((4aR,7aR)-7a-(2-fluoro-5-(3-fluoropicolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol) and TFA (18.85 μL, 0.245 mmol) in DCM (122 μL) was stirred at rt for 3 h, and the solvents were removed to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-3-fluoropicolinamide (7 mg) as its TFA salt as a colorless oil. 1H NMR (500 MHz, METHANOL-d4) δ 8.84-8.37 (br. s, 2H), 8.17 (dd, J=7.2, 2.3 Hz, 1H), 7.92-7.76 (m, 2H), 7.26 (dd, J=11.1, 8.9 Hz, 1H), 4.37-4.19 (m, 2H), 3.46 (dd, J=13.6, 3.8 Hz, 1H), 3.35-3.25 (m, 1H), 3.19-3.04 (m, 1H), 2.32 (q, J=7.0 Hz, 2H). MS (M+H)+: 391.10.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].[OH-].[K+].[CH3:12]OS(OC)(=O)=O>CC(C)=O>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:12])=[CH:5][CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1nc(O)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(Br)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.9 %

Procedure:
A suspension of 11.58 g (61 mmol) 6-amino-5-bromo-pyridin-2-ol in 200 ml acetone was treated with 10.3 g (184 mmol) KOH pellets and 10 g (80 mmol) dimethylsulfate. The mixture was stirred for 4 h at room temperature and evaporated to dryness. 400 ml water was added and the mixture was extracted four times with 300 ml ethyl acetate. The combined organic phases were dried with MgSO4 and evaporated. The residue was purified by flash column chromatography on silica eluting with hexane/ ethyl acetate 1:1 to yield 3.455 g (28%) of the title compound as orange oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]1([CH:13](C2C=CC=CC=2)[C:14]2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O.C1(CCBr)CCCCC1>O1CCCC1.CCOCC>[CH:2]1([CH2:14][CH2:13][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:1][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Reactant: C#CCCCC
Agent: BrCCC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCCCC#CCCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice cold solution of 1-hexyne (49.6 mmoles) in freshly distilled tetrahydrofuran (50 ml) containing a trace of triphenylmethane was added dropwise n-butyl lithium in hexane (49.5 mmoles). About 10 minutes after the addition was stopped, sieve dried hexamethylphosphoramide (57.5 mmoles) was added and the solution stirred for 10 minutes. A solution of 2-cyclohexylethyl bromide (51.3 mmoles) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred for about 3 hours as the temperature rose to room temperature. The mixture was taken up in ether (100 ml) and washed with water (3×100 ml) and sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate and evaporated to leave an oil which was purified by flash chromatography to give 1-cyclohexyloct-3-yne. This compound (20.8 mmoles) was treated with potassium hydride (36.8 mmoles) in propylene diamine to obtain the isomeric 8-cyclohexyloct-1-yne as an oil. A mixture of 2-bromobenzaldehyde (12.59 mmoles), 8-cyclohexyloct-1-yne (14.87 mmoles), cuprous iodide (0.17 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.26 mmoles) in triethylamine (35 ml) was refluxed under argon for 1.5 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The resulting residue was dissolved in ether (100 ml), washed with 3N hydrochloric acid (50 ml) and saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate and charcoal. The solution was evaporated to afford an oil which was purified by flash chromatography (2% ether/hexane) to yield 2-(8-cyclohexyl-1-octynyl)benzaldehyde as an oil. This benzaldehyde (10.22 mmoles) was hydrogenated with 10% palladium on charcoal in ethyl acetate to give the desired product as an oil, after chromatography (3% ether/hexane).
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]2)=[CH:10][CH:9]=1>ClC(Cl)Cl>[ClH:3].[ClH:5].[Cl:5][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:16]2[N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:26][CH2:27]1
Reactant: O=S(Cl)Cl
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Yield: 83 %

Procedure:
A mixture of 15 parts of thionyl chloride, 4 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol dihydrochloride and 375 parts of trichloromethane is stirred and refluxed overnight. The precipitated product is filtered off and dried, yielding 13 parts (83%) of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride; mp.>260° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH:32]([O-])=O.[NH4+]>[Pd].C(O)C>[F:31][C:2]([F:1])([F:30])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:32])=[O:25])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: O=C[O-]
Reactant: COC(=O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
10% Palladium on carbon (0.536 g, 0.50 mmol) was added to methyl 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (1.096 g, 2.52 mmol) and ammonium formate (1.587 g, 25.17 mmol) in ethanol (50 mL). The resulting mixture was stirred at 78° C., with further portions of ammonium formate being added every 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was evaporated to dryness, redissolved in DCM (100 mL) and the solution was washed with water (50 mL) followed by brine (50 mL), then the solvents were evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with a gradient of 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to afford ethyl 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (0.820 g, 72.2%) as a gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(C)CC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.0 g, 10.3 mmol), 1-methyl-piperazine (3.5 mL, 30.9 mmol), copper(I) iodide (785 mg, 4.1 mmol), N,N-dimethylglycine hydrochloride (1.2 g, 8.2 mmol) and potassium carbonate (6.1 g, 44.1 mmol) in dimethyl sulfoxide (30 mL) was stirred at 120° C. for 16 hours. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×200 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.4 g, 80%) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C25H33N3O2 (M+H)+: 408.56, observed: 408.2.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:25])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH:10]([CH3:26])[CH2:9]1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:25])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH:10]([CH3:26])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)N1CCC(C)(c2cccc(-c3cnco3)c2)C(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CCC(C)(c2cccc(-c3cnco3)c2)C(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-hexanoyl-3,4-dimethyl-4-(3-(1,3-oxazol-5-yl)phenyl)piperidine (Preparation 36, 292 mg, 0.83 mmol) in tetrahydrofuran (6.0 mL) at 0° C. was added lithium aluminium hydride (1.0 M solution in tetrahydrofuran, 0.80 mL, 0.80 mmol) dropwise over a few minutes. The solution was stirred at room temperature under a nitrogen atmosphere for 30 minutes and then heated at reflux for 30 minutes before it was cooled back to 0° C. The reaction was cautiously quenched by the addition of 1 N sodium hydroxide (1.0 mL) and then ethyl acetate (excess) and solid sodium hydrogencarbonate (excess) were added. The mixture was stirred vigorously for 1 h and then filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane:ammonia (90:10:1). The title compound was isolated as clear oil (233 mg, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1COCC1>[CH2:21]([O:20][C:18]([NH:17][C@H:12]1[CH2:11][CH2:10][C@@H:9]2[CH2:16][C@H:13]1[CH:14]([OH:15])[N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To a cooled (0° C.) solution of (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (4.6 g, 12.3 mmol) in CH2Cl2 (100 mL) was added DIBAL-H (37 mL of a 1.0 M solution in THF). The mixture was stirred for 105 min at 0° C. The reaction was quenched with 1N HCl and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried,(Na2SO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,2S,5R,7R/S)-2-(benzyloxycarbonylamino)-7-hydroxy-6-aza-bicyclo[3.2.1]octane-6-carboxylate as a mixture of diastereomers. MS found: (M−H2O+H)+=359.2. This material was dissolved in THF (20 mL) and added by cannula (6 mL THF rinse) to a pre-mixed (15 min), pre-cooled (0° C.) solution of ethyltriphenylphosphonium iodide (6.4 g, 14.8 mmol) and KHMDS (31 mL of a 0.5 M solution in toluene). The reaction was stirred for 25 min at 0° C. before being quenched with the addition of sat. NH4Cl. The biphasic mixture was extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue via flash chromatography afforded the desired [(1R,3R,4S)-(4-benzyloxycarbonyl-amino-3-propenyl-cyclohexyl)-carbamic acid tert-butyl ester as a colorless oil (3.44 g, 72% yield). MS found: (M+H)+=389.3.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[C:10]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:7]=2[N:6]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2ccc(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CC)CN(c2ccccc2)c2ccc(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 98 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 116; 0.48 g, 1.04 mmol) was dissolved in ethanol (10 ml). NaOH (0.30 g, 7.5 mmol) was added and the mixture was refluxed for 30 min. Acetic acid (1 ml) was added. The solvent was evaporated under reduced pressure and the residue was extracted with DCM/water. The DCM layer was separated, dried and evaporated. 0.44 g (97%) of the title compound was obtained. NMR (300 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 8H), 3.1–3.3 (m, 2H), 3.5–3.8 (m, 2H), 4.6 (s, 3H), 6.8–7.3 (m, 7H), 7.5 (s, 1H).
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[CH2:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[CH2:11]([C:13]1[CH:18]=[C:17]2[C:16]([C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][C:6]2([CH3:9])[CH3:7])=[C:15]([OH:19])[CH:14]=1)[CH3:12]
Reactant: CCc1cccc(O)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
Next, 2,5-dimethyl-2,5-dichlorohexane (183 g, 1 mol) is stirred with 3-ethylphenol (146.4 g, 1.2 mol) and aluminum chloride (4 g) is added. The mixture is heated at 95° C., with stirring, for 1.5 hr, after which ethylene dichloride (100 ml) is added, and then the heating continued. After 1 hr, the mixture is cooled to 20° C., and poured onto an ice water/hydrochloric acid mixture (150 ml, 10% HCl solution). The mixture is then extracted with toluene (500 ml), the organic layer separated, washed with brine (3×50 ml) and dried (Na2SO4). The solvent is removed by distillation and the residue crystallized from a hexane/benzene solvent mixture to give 7-ethyl-1,1,4,4-tetramethyl-5-hydroxy-1,2,3,4-tetrahydro-naphthalene.