Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[O:4][N:3]=1.[NH2:21][CH2:22][CH2:23][SH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]3[NH:21][CH2:22][CH2:23][S:24]3)=[CH:15][CH:14]=2)[O:4][N:3]=1
Reactant: NCCS
Reactant: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(CCCCCOc2ccc(C3NCCS3)cc2)on1
Yield: 39.7 %

Procedure:
A solution of 4.00 g of 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde (Example 35a), 1.22 g of 2-aminoethanethiol and a trace of p-toluenesulfonic acid in 30 ml of toluene was heated at reflux for 2 hours using a Dean-Stark trap. The product was isolated and recrystallized from isopropyl acetate-hexane to give 1.93 g of the above-indicated product, m.p. 82-84° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].[NH2:22][C:23]1[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:27][CH:28]=1>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: NCc1cccc(F)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: Fc1cccc(CNc2ccc3cc(Nc4cccc(C(F)(F)F)c4)ccc3n2)c1

Procedure:
The title compound, MS: m/e=412.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-fluorobenzylamine and 3-aminobenzotrifluoride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.N>N1C=CC=CC=1.O>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1c(N)cnc2ccccc12
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(-c2ccccc2)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g (0.012 mole) of crude product of 3-amino-4-methylaminoquinoline was dissolved in 20 ml of pyridine, and 1.5 ml (0.013 mole) of benzoyl chloride was added followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and 20 ml of phosphorus oxychloride was added to the concentrate, followed by refluxing with heating for 3 hours. The residues obtained by concentration under reduced pressure were dissolved in water and the solution was made alkaline with ammonia water. The precipitate was collected by filtration, washed with water and purified by silica gel column chromatography (eluting solvent: chloform/methanol=30/1), to afford 2.1 g of Compound a.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH3:8])[CH:2]=1.Cl.[NH2:11][OH:12].C(=O)(O)[O-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH3:8])[CH:2]=1
Reactant: CC(=O)c1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cccnc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 50 g (0.41 mol) of 1-(3-pyridinyl)ethanone and 29 g (0.42 mol) of hydroxylamine hydrochloride in 250 ml of methanol was heated under reflux for five hours. Upon cooling to room temperature, a white solid separated from the reaction mixture. This material was collected by filtration and the filtrate was concentrated to yield additional white solid. The combined solids were dissolved in water and the solution was made weakly basic by the addition of sodium bicarbonate solution while cooling. The white precipitate which formed was separated by filtration to yield 55.4 g of 1-(3-pyridinyl)ethanone oxime, mp 115° -117° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([C:16]1[C:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:18]([C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2[C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=2)[C:32]([OH:34])=[O:33])[CH:19]=[CH:20][CH:21]=1)([F:15])[F:14]>O1CCOCC1>[F:12][C:13]([C:16]1[C:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:18]([C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2[C:27]2[CH:28]=[N+:29]([O-:9])[CH:30]=[C:31]([CH:35]=2)[C:32]([OH:34])=[O:33])[CH:19]=[CH:20][CH:21]=1)([F:15])[F:14]
Reactant: O=C(O)c1cncc(C2=C(c3cccc(C(F)(F)F)c3OCc3ccccc3)CCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: O=C(O)c1cc(C2=C(c3cccc(C(F)(F)F)c3OCc3ccccc3)CCC2)c[n+]([O-])c1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
3-Chloroperbenzoic acid (25 mg, 0.11 mmol) was added to a solution of 5-{2-[trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinic acid (44 mg, 0.1 mmol) in dioxan (2 ml) and left overnight at room temperature. The resulting mixture was evaporated to dryness and purified by preparative mass directed chromatography to give the title compound as an off-white solid (8 mg, 18%).
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([Cl:18])[CH:3]=1.COC1C(OCOCC[Si](C)(C)C)=CC(C)=C([B:27]([OH:29])[OH:28])C=1>>[Cl:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:27]([OH:29])[OH:28])[CH:3]=1
Reactant: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Reactant: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1B(O)O
Yield: 54 %

Procedure:
5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 54% yield from [2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid. 1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 7.09 (s, 1H), 5.37 (s, 2H), 3.84 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C13H22BClO4Si—H2O) C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98; H, 6.84.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1([P:21](Cl)(Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([P:21]2(=[O:22])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)C1CCCCC1
Product: O=P1(C2CCCCC2)c2ccccc2CN1c1ccccc1
Yield: 14.5 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and cyclohexyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation yielded without additional purification 1-cyclohexyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.7 g, 14.5% yield) as a beige solid having a melting point of 167°-169° C. and the following analysis:
Reaction SMILES: [N+](C1C=[CH:8][C:7]([O:10][C:11](=[O:22])[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=CC=1)([O-])=O.OCC[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.CN1CCOCC1>C(Cl)Cl>[C:11](=[O:22])([O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[O:10][CH2:7][CH2:8][N:26]1[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
Bis(p-nitrophenyl)carbonate (1.52 g, 5.0 mmol) was dissolved in DCM (20 mL). tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate from the previous step (1.15 g, 5.0 mmol) and NMM (0.55 mL, 5.0 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (40 mL) and washed with sat aq NaHCO3 solution (5×50 mL), dried (Na2SO4) and concentrated in vacuo to give a yellow oil. The oil was purified by recrystallisation from EtOAc and heptane to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (1.208 g, 61%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:9]=2)[C:5](I)=[CH:4][N:3]=1.[C:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])#[CH:36].C(N(CC)CC)C.CN(C)CCN(C)C>C(#N)C.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:9]=2)[C:5]([C:36]#[C:35][Si:37]([CH3:40])([CH3:39])[CH3:38])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2nc(N)ncc2I)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)CCN(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2nc(N)ncc2C#C[Si](C)(C)C)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
In a sealed tube filled with argon, a mixture of ethyl 5-(2-amino-5-iodopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate (612 mg, 1.0 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (19 mg, 0.1 mmol), ethynyl(trimethyl)silane (0.415 mL, 3 mmol) and triethylamine (10 mmol) in degassed ACN (10 mL) was stirred at room temperature overnight. To the reaction mixture was added N,N,N′,N′-tetramethylethylenediamine (0.3 mL, 2 mmol) and the reaction mixture stirred at the same temperature for 15 min. The solvent was evaporated under vacuum and the residue purified by flash chromatography (hexane/EtOAc 8/2) to obtain the title compound (495 mg, 85%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:31])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:16][CH:15]=1
Reactant: OC(CCCCc1ccccc1)c1ccc(CCBr)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCCCc1ccccc1)c1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a solution of dimethy sulfoxide (12.7 ml) in methylene chloride (320 ml) was added a solution of oxalyl chloride (7.7 ml) in methylene chloride (320 ml) over 10 minutes under a nitrogen atmosphere at −68 to −65° C., and the mixture was stirred at the said temperature for 10 minutes. Then, a solution of 1-[4-(2-bromoethyl)phenyl]-5-phenylpentan-1-ol (20.7 g) in methylene chloride (80 ml) was added thereto at −68 to −65° C. over 20 minutes and the mixture was stirred at the said temperature for an hour. Triethylamine (41.6 ml) was further added thereto over 10 minutes at the said temperature and the mixture was stirred for 2.5 hours while raising the temperature of the mixture to 0° C. gradually. The reaction mixture was washed with water (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance. The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=20:1) to give 1-[4-(2-bromoethyl)phenyl]-5-phenylpentan-1-one (18.2 g) as a yellow oily substance.
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[O:7]1[CH2:12][CH2:11][CH:10]([NH:13][NH2:14])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[CH3:6][C:2]1[CH:3]=[C:4]([NH2:5])[N:13]([CH:10]2[CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[N:14]=1
Reactant: NNC1CCOCC1
Reactant: C/C(N)=C/C#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)n(C2CCOCC2)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
(2Z)-3-Amino-2-butenenitrile (0.538 g, 6.55 mmol), tetrahydro-2H-pyran-4-ylhydrazine (1 g, 6.55 mmol) and triethylamine (0.913 mL, 6.55 mmol) were added to ethanol (300 mL), and the reaction mixture was stirred at 75° C. for 16 hours. The solvent was removed in vacuo, and the crude material suspended in EtOAc. The organic phase was washed with water and then brine. The organic layer was then dried over MgSO4, filtered, and concentrated in vacuo. Half of the crude material was purified by reverse HPLC (mobile phase: 0-30% ACN/H2O, 0.1% TFA) to afford 380 mg of the desired product. The other half of the crude material was purified via silica gel chromatography (eluent: 0% to 100% EtOAc:Hex then 0% to 20% MeOH:DCM). An additional 300 mg of the desired product was obtained (overall yield: 57%). LCMS E-S (M+H)=182.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.78 (dd, 2 H), 1.94 (qd, J=12.13, 4.55 Hz, 2 H), 2.19 (s, 3 H), 3.30-3.46 (m, 2 H), 3.99 (dd, J=11.49, 4.17 Hz, 2 H), 4.49 (m, J=11.65, 11.65, 4.11, 3.92 Hz, 1 H), 5.53 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CS(O[CH2:20][CH2:21][CH2:22][C:23]#[CH:24])(=O)=O>O1CCCC1>[CH3:1][C:2]([CH2:24][CH2:23][CH2:22][C:21]#[CH:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCC(C)(C(=O)OCC)C(=O)OCC

Procedure:
A solution of diethyl methylmalonate (Aldrich Chemical Company, 35.6 ml) in dry tetrahydrofuran (200 ml) was added, dropwise, to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 9.1 g) in tetrahydrofuran (50 ml) under nitrogen. After the addition was complete, the mixture was heated to gentle reflux for 1 hour and then allowed to cool before a solution of pent-4-ynyl methanesulphonate (35.2 g) in tetrahydrofuran (50 ml) was added. The resulting mixture was heated to gentle reflux for a further 2 hours. The bulk of the solvent was then removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phase was separated and washed with water and brine before drying over anhydrous magnesium sulphate and evaporation under reduced pressure. Distillation gave diethyl 2-methyl-2-(pent-4-ynyl)malonate (45.8 g) as a colourless oil (b.p. 92°-97°, 0.5 mm Hg)
Reaction SMILES: [Na].C(O)C.[C:5]([O:13]CC)(=[O:12])[CH2:6][C:7]([O:9]CC)=[O:8].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[CH2:28]Br>CCOCC>[F:25][C:24]([F:26])([F:27])[C:21]1[CH:20]=[C:19]2[C:18](=[CH:23][CH:22]=1)[CH2:17][C:6]([C:7]([OH:9])=[O:8])([C:5]([OH:13])=[O:12])[CH2:28]2
Reactant: FC(F)(F)c1ccc(CBr)c(CBr)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)C1(C(=O)O)Cc2ccc(C(F)(F)F)cc2C1

Procedure:
Sodium (1.12 g, 48.6 mmol) was added to ethanol (16 mL). The solution was heated to reflux until all sodium was dissolved. To this solution was added diethyl malonate (3.71 g, 23.19 mmol) in ether (45 mL) and the above 1,2-bis-bromomethyl-4-trifluoromethylbenzene (7.7 g, 23.19 mmol) in ether (45 mL). The mixture was refluxed for 16 hrs and the precipitate was filtered out. The filtrate was evaporated and the residue was treated with water (35 mL) and potassium hydroxide (5.30 g). The mixture was stirred and refluxed for 5 hrs and treated with water (20 mL). The resulting mixture was extracted with ether (50 mL). The aqueous phase was acidified with concentrated hydrochloric acid and cooled in an ice bath. Solids were filtered and washed with water. After air drying, 5-trifluoromethyl-indan-2,2-dicarboxylic acid was obtained (3.08 g). LC-MS showed a single peak, C12H19F3O4 (m/e) calcd 274.0453, obsd 273.0 (M−H).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1[CH:13]=[C:12]2[C:14]([O:16][C:17](=O)[C:10]3=[C:11]2[C:6](=[CH:7][C:8]([N+:19]([O-:21])=[O:20])=[CH:9]3)[CH:5]=1)=[O:15]>N1C=CC=CC=1.O>[OH:3][N:2]1[C:17](=[O:16])[C:10]2[CH:9]=[C:8]([N+:19]([O-:21])=[O:20])[CH:7]=[C:6]3[C:11]=2[C:12](=[CH:13][CH:4]=[CH:5]3)[C:14]1=[O:15]
Reactant: NO
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2cccc3cc([N+](=O)[O-])cc(c23)C(=O)N1O
Yield: 99.2 %

Procedure:
Hydroxylamine hydrochloride (0.9 g, 13.0 mmol) was added to a suspension of 3-nitro-1,8-naphthalic anhydride (2.0 g, 8.2 mmol) in pyridine (30 mL). The mixture was refluxed for 3 hours and concentrated in vacuo to give a brown solid. The solid was suspended in water, stirred, filtered, and dried to give 2.1 g of the title compound, mp 277-279° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (0.67 g, 2.01 mmol) in DCM (25 ml), were sequentially added triethylamine (0.84 ml, 6.04 mmol) and benzoyl chloride (0.28 ml, 2.42 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The crude was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-phenylacetate (310 mg; 42% yield).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:16][CH2:17][OH:18])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:18][CH2:17][CH2:16][N:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: OCCn1cnc2cnc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCCn2cnc3cnc4ccccc4c32)cc1
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, sodium hydride (16.88 g of 60% in mineral oil, 422 mmol) was added in portions to a solution of 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethanol (60.0 g, 281 mmol) in anhydrous N,N-dimethylformamide (600 mL). The alkoxide was allowed to stir for about 1.5 hours. Benzyl bromide (50.2 mL, 422 mmol) was slowly added over a period of about 30 minutes. The reaction mixture was allowed to stir at ambient temperature overnight. Solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed several times with water, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1-[2-(benzyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a dark oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6]CN)[CH3:2].[CH3:15][NH:16]CC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:31].[NH2:32][C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=O)=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:31].[NH2:32][C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([N:16]([CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:4]=2[O:3][CH2:1][CH3:2])[CH3:15])=[O:43])=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Reactant: CCOc1c(CCN)cccc1OC
Reactant: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCOCC3)c2)cccc1OC
Yield: 70 %

Procedure:
According to the procedure of Example 1, except substituting (2-ethoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.27 g, 70%) was prepared as pale yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 8.83-8.65 (m, 1H), 8.40 (s, 1H), 7.52-7.45 (m, 1H), 7.29-7.24 (m, 1H), 7.04-6.96 (m, 2H), 6.65-6.64 (m, 1H), 4.80-4.64 (m, 2H), 4.35 (br s, 2H), 4.02-3.79 (m, 10H), 3.39-2.83 (m, 8H), 1.31-1.25 (m, 3H); MS (ESI) m/e 441 (M+H)+.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12].C(N(CC)CC)C>C(O)C>[C:4]1([CH2:3][CH2:2][C:1](=[O:10])[CH2:12][CH2:11][C:13](=[O:14])[CH3:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(C)=O
Reactant: O=CCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)CCc1ccccc1

Procedure:
67.1 g (0.5 mol) of hydrocinnamaldehyde, 35.1 g (0.5 mol) of methyl vinyl ketone, 13.5 g (0.05 mol) of Cat. 1, 20.2 g (0.2 mol) of triethylamine and 500 ml of ethanol are brought together, in the manner described in Example 1. The product is worked up as described in Example 21. Fractional distillation gives 1-phenyl-heptane-3,6-dione.
Reaction SMILES: Cl.[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:11][CH2:10]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(#N)C.[Cu](I)I>[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[C:19]([C:31]#[C:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:11][CH2:10]1
Reactant: COc1ccc(Br)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1

Procedure:
1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(5-bromo-2-methoxyphenyl) piperidine hydrochloride (compound no. 187) (60 mg, 0.15 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (11 mg, 0.015 mmol) and copper iodide (6 mg, 0.030 mmol) were suspended in anhydrous acetonitrile (500 μL) in a microwave vial and treated with phenylacetylene (77 mg, 0.75 mmol), followed by triethylamine (250 μL). The vial was flushed with nitrogen, capped and microwaved at 140° C. for 20 min. The reaction was diluted with methanol (750 μL), filtered (Whatman 0.20 μm PTFE) and subjected to reverse-phase HPLC purification (5-50% CH3CN/0.08% TFA) to yield 1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(2-methoxy-5-(phenyl-ethynyl)phenyl)piperidine (compound no. 64) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 386.2 [M+H]+, retention time 2.86 min.