Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C@@H]([NH:9][C@H:10]2[C@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11]2)C)C=CC=CC=1>CO.[Pd]>[NH2:9][C@H:10]1[C@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:11]1
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N[C@@H](C)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N
Yield: 110.6 %

Procedure:
Trans-1-tert-butyl 4-ethyl 3-(((S)-1-phenylethyl)amino)piperidine-1,4-dicarboxylate 6 (3.7 g, 8.3 mmol, 1.0 equiv) was hydrogenated in the presence of 10% Pd/C (0.37 g) catalyst under H2 at 30 atmospheric pressure in MeOH (100 mL) at 50° C. for 8 h. The catalyst was filtered off and the solvent was removed in vacuo to give (trans)-1-tert-butyl 4-ethyl 3-aminopiperidine-1,4-dicarboxylate 7 as light yellow oil (2.5 g, yield: 92%). ESI-MS (M+H)+: 273.1. 1H NMR (400 MHz, CDCl3) δ: 4.18 (q, 2H), 3.97-3.94 (m, 2H), 3.37 (s, 1H), 3.07-3.02 (m, 1H), 2.89-2.85 (m, 1H), 2.60-2.55 (m, 1H), 2.01-1.91 (m, 1H), 1.70-1.54 (m, 3H), 1.46 (s, 9H), 1.28 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=O)[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=[S:38])[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=S)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamoylcyclohexylcarbamate (4.8 g, 0.01 mol) in 50 ml of dry THF was added Lawesson's reagent (2.97 g, 0.007 mol) portionwise under nitrogen. After the completion of addition the reaction mixture was stirred for 5 h at RT. THF was removed and the crude product was dissolved in ethyl acetate. The organic layer was washed with 10% sodium hydroxide, water, brine and concentrated. The crude product was purified by recrystallization from pet-ether and ether mixture to give 3.5 g crude of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[OH-].[K+]>CO>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[C:2]1[C:3](=[O:9])[CH:4]2[CH2:7][CH2:8][N:1]1[CH2:6][CH2:5]2
Reactant: O=Cc1ccccc1Cl
Reactant: O=C1CN2CCC1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2Cl)N2CCC1CC2

Procedure:
1-Azabicyclo[2.2.2]octan-3-one (3.86 g) was heated at reflux with 2-chlorobenzaldehyde (8.33 ml), potassium hydroxide (0.4 g) and methanol (60 ml) under nitrogen for 2.5 hours. The volatiles were removed in vacuo and the residue washed with sodium hydrogen carbonate. This was extracted (×4) with dichloromethane. The organic layer was washed with water and dried (MgSO4). The dichloromethane was removed in vacuo and the residue recrystallised from methanol-dichloromethane, to afford the title compound as yellow crystals:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[N:37]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)=[C:38]=[O:39]>CN(C)C(=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:40]6[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)[CH:41]=6)=[O:39])=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Nc2cccc(Oc3ccccc3)c2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 28 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.0875 M and 0.042 in N,N-dimethylacetamide, respectively, 497 μL, 0.042 mmol Example 23e and 0.126 mmol N,N-diisopropylethylamine) and 1-isocyanato-3-phenoxybenzene (0.40 M in N,N-dimethylacetamide, 208 μL, 0.084 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 150° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0067 g (28%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.90 (d, J=2.44 Hz, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.27 (m, 3H), 7.16 (m, 3H), 7.03 (m, 2H), 6.97 (s, 1H), 6.78 (m, 2H), 6.64 (m, 1H), 6.51 (m, 2H), 4.60 (m, 2H), 4.06 (s, 3H). MS (APCI+) m/z 572.1 (M+H)+.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:2]12[C:11]([O:13][CH3:14])=[O:12].[N-:15]=[N+]=[N-].[Na+].[Cl-].[NH4+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.CO>[NH2:15][C:2]1([C:11]([O:13][CH3:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[OH:1]
Reactant: COC(=O)C12OC1Cc1ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)C1(N)c2ccccc2CC1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To 500 mg of methyl 6,6a-dihydro-1aH-indeno[1,2-b]oxirene-1a-carboxylate were added 860 mg of sodium azide, 309 mg of ammonium chloride, 4 ml of methanol, and 0.5 ml of water, followed by stirring at 80° C. for 2 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate to carry out a layer separation operation, and the organic layer was dried over anhydrous magnesium sulfate. To a solution of the obtained intermediate product in ethyl acetate-methanol was added 61 mg of 10% palladium-carbon (wet), followed by stirring for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure to obtain 0.51 g of methyl rac-(1R,2R)-1-amino-2-hydroxyindane-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:15][C:14]=3[CH:38]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:47])[CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:15][C:14]=3[CH:38]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3=O)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
In methylene chloride (6 ml) was dissolved 7-(4-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzothiepine-4-carboxamide (199 mg). To the mixture was added at −30° C. m-chloroperbenzoic acid (93 mg), and the mixture was stirred at −30° C. for 30 minutes and added to an aqueous solution of saturated sodium thiosulfate. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol=3/1→2/1, 1% triethylamine) to give 7-(4-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-oxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 83) (28 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:4].S(=O)(=O)(O)O.[CH2:24]=O>CC(O)=O>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:17])([F:18])[F:1])[CH2:24]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=C(NCCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc([N+](=O)[O-])cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
2,2,2-Trifluoro-N-[2-(4-nitrophenyl)ethyl]acetamide (21.9 g, 83.4 mmol) was dissolved in HOAc (80 mL) and sulfuric acid (120 mL) and paraformaldehyde (4.0 g, 125 mmol) were added at rt. The solution was stirred at rt for 24 h. The reaction was poured cautiously into approximately 1 L of ice with stirring. The resulting suspension of brown sludge was extracted into EtOAc. The organic was washed with saturated aqueous NaHCO3, brine and dried over MgSO4. The solvent was removed and the brown solid was triturated with hexanes. The brown solid was dried under vacuum and provided 15 g (66%) of the desired tetrahydroisoquinoline product. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=27.0 Hz, 1H), 8.05 (m, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.88 (d, J=18.1 Hz, 2H), 3.81 (m, 2H), 3.06-2.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([C:29]#[N:30])C(OCC)=O)=[CH:18][CH:17]=2)[N:12]=1.[OH-].[Na+].C(O)C.O>ClC1C=CC=CC=1Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:29]#[N:30])=[CH:20][CH:21]=2)[N:12]=1
Reactant: CCOC(=O)C(C#N)Cc1ccc(OCCc2nc(-c3ccccc3Cl)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc(CCC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A mixture of ethyl 3-[4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]phenyl]-2-cyanopropionate (2.24 g), 1N NaOH (15 ml) and ethanol (50 ml) was stirred for one hour at room temperature. The reaction mixture was poured into water and made acidic, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure to leave a crystalline product, which was added to pyridine (5 ml)--o-dichlorobenzene (50 ml), and the mixture was heated for 2 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was subjected to a silica gel column chromatography. From the fractions eluted with chloroform was obtained 3-[4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]phenyl]propionitrile (1.5 g, 80%), which was recrystallized from dichloromethane--isopropyl ether to give pale yellow crystals, m.p.88°-89° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C>FC(F)(F)C(O)=O>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:27]([OH:29])=[O:28])[NH2:8])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 0.35 g (0.75 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate were added 10 mL of trifluoro acetic acid and the solution was stirred for 2 days at room temperature. The excess of trifluoro acetic acid was evaporated and the residue was taken up three times in tetrahydrofuran and then evaporated. The resulting oil was chromatographed on C-18 reversed phase silica gel using a water/acetonitrile gradient, the appropriate fractions were combined and concentrated.
Reaction SMILES: C([O:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)C.C(OCC)(=O)C>O>[F:16][C:13]1([F:17])[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]1
Reactant: O=C(OC1CCC(F)(F)CC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC1CCC(F)(F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A mixture of 4,4-difluorocyclohexyl benzoate (2.0 g), 1M sodium hydroxide solution (10 mL) and ethanol (20 mL) was stirred at 70° C. for 3 hr. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (1.0 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:4]=2[N:3]=1.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2[nH]c(C)nc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2cc(CO)ccc2[nH]1
Temperature: 20 °C

Procedure:
27.8 g (0.146 mol) of 18b in 500 ml of THF are treated with 365.4 ml (0.438 mol) of DIBAL (20% strength solution in toluene) at -70° C. overnight in analogy to Example 1a. The crude product is vigorously stirred in boiling ethyl acetate and, after cooling to 20° C., the remaining material is filtered off with suction.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[S:12]1[CH:16]=[CH:15][C:14]2[CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:13]1=2.Cl>C(Cl)Cl>[S:12]1[C:16]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:15][C:14]2[CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:13]1=2
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2c(c1)CCc1sccc1C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
11.0 g of succinic acid anhydride are dissolved in 220 cc of anhydrous methylene chloride with heating, the resulting solution is cooled to 20° and 30 g of aluminium chloride are added portionwise. After stirring for 15 minutes at room temperature, a solution of 22.0 g of 9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene in 100 cc of anhydrous methylene chloride is added dropwise within 30 minutes, the resulting mixture is stirred for a further 45 minutes at room temperature and is poured on a mixture of 200 cc of concentrated hydrochloric acid and 200 g of ice. After adding 300 cc of methylene chloride, the entire mixture is heated for 15 minutes on a water bath, is cooled, the methylene chloride is removed and the aqueous phase is further extracted with methylene chloride. The acidic portion is extracted from the combined methylene chloride solutions with 0.5 normal caustic soda, the basic extract is acidified with 5 N hydrochloric acid and extracted with chloroform. The chloroform solutions are washed with water, dried over magnesium sulphate, filtered through active charcoal and evaporated to dryness. The title compound, obtained as solid residue, is recrystallized from dimethyl formamide/acetone. M.P. 202° to 203°.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[I:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([I:12])[CH:14]=1)[CH2:4]2
Reactant: O=C(O)c1cccc(I)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cccc(I)c1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 3-iodobenzoic acid; the compound was purified by solid phase extraction on silica gel using ammoniated methanol/chloroform mixtures as the eluent followed by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were evaporated, the residue was dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated to give the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 357 (MH+).
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[C:13]4[C:18]([CH:19]=[CH:20][C:11]3=[C:10]([C:21]#[N:22])[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:7])=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>>[C:21]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:3][CH:4]=2)[N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[CH:20][C:11]=12)#[N:22]
Reactant: c1cn[nH]c1
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Product: N#Cc1cc(C(=O)c2ccc(-n3cccn3)cc2)n2c1ccc1ccccc12

Procedure:
The title compound was prepared as described for Example 21, using (4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline-3-carbonitrile (50 mg, 0.16 mmol) and pyrazole, and yielded 44.9 mg (78%). 1H NMR (CDCl3): 8.19 (m, 2H), 8.07 (m, 2H), 7.93 (m, 2H), 7.85 (dd, J=9.6, 1.8 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 7.71 (m, 2H), 7.58 (m, 2H), 7.44 (s, 1H), 6.56 (t, J=2.1 Hz, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.CN(C)CCOCCN(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.[B:32](OC)([O:35]C)[O:33]C>C1COCC1>[N:26]1([C:24]([C:21]2[CH:22]=[CH:23][C:18]([B:32]([OH:35])[OH:33])=[CH:19][CH:20]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COB(OC)OC
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: CN(C)CCOCCN(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
Isopropylmagnesium chloride (27.8 mL, 2 M in THF, 55.6 mmol) was added to a solution of bis(2-dimethylaminoethyl)ether (10.5 mL, 55.6 mmol) in THF (230 mL) 15° C. After 20 minutes, (4-iodophenyl)-(morpholino)methanone (14.7 g, 46.4 mmol) was added and the reaction was removed from the cooling bath. After 1 hr, another 0.8 eq of isopropylmagnesium chloride was added. Trimethyl borate (10.6, 93 mmol) was added after 15 minutes, and after stirring 40 min, the reaction was quenched with 150 ml 1 N aqueous HCl. After stirring at room temperature for 2 hr, THF was removed on the rotary evaporator and the residue was extracted three times with EtOAc. The organic extracts were dried with Na2SO4. The solvent was removed and the residue was twice suspended in toluene and the solvent removed on the rotary evaporator. The resulting white solid was suspended in hexane and this was heated at reflux for 5 minutes. After cooling to room temperature, the white solid was collected by filtration and air-dried to afford 4-(morpholine-4-carbonyl)phenylboronic acid (8.7 g). MS (ESI) m/z 236.1 (M+H). 1H NMR (MeOD) δ ppm 7.78 (2H, d, J=7.30 Hz), 7.36 (2H, d, J=8.06 Hz), 3.72-3.41 (8H, m).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:32]([CH2:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([NH:45]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:46][CH:47]=1)[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCCCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CCCCN(Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C33H37N3O5
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:10][CH:11]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14][CH2:13][CH2:12]1
Reactant: O=C(NC1CCCC(O)CCC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC1CCCC(O)CCC1

Procedure:
Benzyl chloroformate (4 mL, 28.02 mmol) was added to a stirred and cooled (0° C.) solution of the product of Example 5C (14.01 mmol) and diisopropylethyl amine (7.5 mL, 42.03 mmol) in dry dichloromethane (50 mL). After the addition, the solution was warmed to room temperature and stirred for another three hours. It was quenched with NaHCO3 solution. The phases were separated and the organic phase was washed with NaHSO4 solution brine, dried (Na2SO4), filtered, and evaporated. The crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester was isolated as an oil and was used without further purification. Tetrabutyl ammonium fluoride (42 mL, 1 M in tetrahydrofuran, 42.03 mmol) was added to a solution of crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester (about 14.01 mmol) in tetrahydrofuran (35 mL). The resulting solution was stirred for two hours at 23° C. before it was partitioned with diethyl ether and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-50% ethyl acetate in hexanes to give (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester as an oil. (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester (2.68 g, 9.66 mmol) was stirred in the presence of Pd(OH)2/C (0.5 g) in methanol under H2 (balloon) for two hours at 23° C. before it was filtered through a pad of Celite and the solvent was evaporated. The title compound was isolated as an oil and used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:13][CH3:14])[CH2:9][N:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:13][CH3:14])[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@@H](CN)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A mixture of (S)-tert-butyl(1-azidobutan-2-yl)carbamate (7 g, 33 mmol) and 10% Pd/C (777 mg, 0.73 mmol) in EtOAc (150 mL) was stirred under hydrogen (60 psi) for 2 h. The reaction mixture was filtered through Celite and concentrated to give the desired product as a white semi-solid. 1H NMR (400 MHz, DMSO-d6) δ 6.50 (d, J=8.7 Hz, 1H), 3.23-3.12 (m, 1H), 2.45 (d, J=6.0 Hz, 2H), 1.51-1.40 (m, 1H), 1.38 (s, 9H), 1.32-1.20 (m, 3H), 0.80 (t, J=7.4 Hz, 3H).