Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[C:8]([O:10]C)=O.[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:16][O:15][C:13]1[CH:12]=[C:7]([C:8](=[O:10])[CH:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:22][CH:23]=2)[C:28]([O:30][CH3:31])=[O:29])[CH:6]=[C:5]([O:4][CH3:3])[CH:14]=1
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Reactant: COC(=O)Cc1ccc(OC(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C(=O)c1cc(OC)cc(OC)c1)c1ccc(OC(C)C)cc1
Temperature: 2.5 °C

Procedure:
14.4 g of 60% sodium hydride in mineral oil (0.36 mol) which are washed with 2 times 50 ml of toluene are introduced into a three-necked round-bottomed flask. 90 ml of toluene and 28.3 g of methyl 3,5-dimethoxybenzoate (0.144 mol) are then introduced. The mixture is brought to reflux and a solution of 30 g of methyl p-isopropyloxyphenylacetate (0.144 mol) dissolved in 95 ml of toluene is added over 10 h. The mixture is maintained at reflux for 2 h. It is cooled to a temperature of 0-5° C. and a solution of glacial acetic acid (22.5 g, i.e. 0.374 mol) in 25 ml of toluene is added slowly. Then, at ambient temperature, 135 ml of water are added slowly.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=[O:3].Cl[CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[Mg].[Cl-].[NH4+]>O1CCCC1>[OH:3][C:2]([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C[Si](C)(C)CCl
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(C[Si](C)(C)C)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Under a nitrogen atmosphere and with ice cooling, a solution of 293 g diethyl oxalate in 500 ml tetrahydrofuran was slowly added dropwise to a Grignard reagent solution which had been prepared from 540 g of chloromethyltrimethylsilane, 107 g of magnesium and 2,000 ml of tetrahydrofuran. The solution was stirred for 3 hours at room temperature, after which an aqueous solution of ammonium chloride was added for hydrolysis. Usual work-up procedure including extraction, washing, drying and concentration yielded 525 g (crude yield 95%) of ethyl 2-hydroxy-3-trimethylsilyl-2-trimethylsilylmethylpropionate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].Br[C:13]#[N:14].O>C(O)C>[N+:1]([C:4]1[C:5]2[NH:11][C:13]([NH2:14])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CBr
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CCO
Solvent: O
Product: Nc1nc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 1.53 g (10 mmol) of 3-nitro-benzene-1,2-diamine in ethanol (20 mL) was added 1.3 g (12.5 mmol) of BrCN and water (5 mL). The mixture was refluxed for 1.0 h. After cooling to room temperature, the solvent was concentrated, then the residue was dissolved in water, the pH was adjusted to 8.0 with sat. NaHCO3 solution. The resulting solid was filtered, washed with water and dried under vacuum to afford 1.42 g (80%) of the 7-nitro-1H-benzoimidazol-2-ylamine. LCMS: 179 (M+1)+.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][CH2:23][CH2:24]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCC#C)(=O)C1C=CC=CC=1>>[NH2:18][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:21][CH2:22][C:23]#[CH:24])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: C#CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: C#CCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-5-nitro-3-propargyloxybenzoic acid, and following the procedure described, 5-amino-4-benzoyl-3-propargyloxybenzoic acid is obtained with a melting point of 191.5°-192.5° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][CH:53]=1)[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)=[CH:56][CH:57]=1)[CH3:50]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 41% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[F:40])#[N:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[C:32]([F:40])[CH:33]=2)[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:16][CH2:15]1
Reactant: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)c(Cl)c1=O
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Yield: 35 %

Procedure:
A mixture of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-4,5-dichloro-6-oxo-6H-pyrimidin-1-yl]-acetic acid methyl ester (5.76 g, 13.2 mmol), 4-cyano-3-fluoro benzeneboronic acid (2.24 g, 16.1 mmol), Pd(PPh3)4 (306 mmol, 0.26 mmol) and Na2CO3 (2.8 g, 26.5 mmol) in DMF:H2O (50 mL:10 mL) was stirred at 65° C. overnight under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by silica chromatography (1:20 to 1:0, EA:PE) to give 2.4 g of the title product (43%). 1H NMR (400 MHz, CDCl3): δ 1.27-1.37 (m, 2H), 1.45 (s, 9H), 1.99-2.02 (m, 2H), 2.99-3.06 (m, 2H), 3.68-3.76 (m, 1H), 3.78 (s, 3H), 4.42-4.52 (m, 3H), 4.90 (s, 2H), 7.63-7.66 (m, 1H), 7.67-7.71 (m, 2H). [M+H] Calc'd for C24H27ClFN5O5, 520. Found, 520.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[NH:3])[CH3:2].Br[CH2:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:23])[C:21]=1[Br:22])=O.C(N(CC)C(C)C)(C)C>CC1CCCO1.COCCOC>[C:9]([O:8][C:6](=[O:7])[NH:5][N:4]1[CH:14]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[Br:22])[N:3]=[C:1]1[CH3:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cn1ncc(C(=O)CBr)c1Br
Reactant: CC(=N)NNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: CC1CCCO1
Product: Cc1nc(-c2cnn(C)c2Br)cn1NC(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
tert-Butyl 2-ethanimidoylhydrazinecarboxylate (5.9 g, 34 mmol), 2-bromo-1-(5-bromo-1-methyl-1H-pyrazol-4-yl)ethanone (from the previous step, 8.00 g, approximately 24 mmol) and N,N-diisopropylethylamine (10.9 mL, 62.6 mmol) were heated to reflux in a mixture of 2-methyltetrahydrofuran (200 mL) and 1,2-dimethoxyethane (50 mL). After 2.5 hours, the reaction was cooled and washed with 50% saturated aqueous sodium chloride solution (75 mL). The aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (Gradient: 0% to 8% methanol in dichloromethane), and the purified material (7.5 g) was dissolved in diethyl ether (25 mL), treated with hexane (4 drops), and allowed to crystallize. The resulting solid was collected and washed with a small amount of cold diethyl ether to provide the product as a very pale pink solid. Yield: 6.49 g, 18.2 mmol, 59% over 2 steps. LCMS m/z 358.4 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.49 (br s, 9H), 2.16 (br s, 3H), 3.85 (s, 3H), 7.17 (s, 1H), 7.89 (s, 1H), 8.8-9.3 (v br s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[CH2:15]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:14]=2)[C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)=[C:11]1[CH:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
General Procedure F. To a solution of ethyl1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 43, 609 mg, 1.24 mmol) in EtOH (15 ml) was added NaOH (248 mg, 6.21 mmol) and H2O (1 ml). The reaction was stirred at 50° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.[ClH:37]>C(OCC)(=O)C.CC(O)C>[ClH:37].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccoc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (253 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as a white solid (yield 134 mg, 62%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32]OS(C3C=CC(F)=CC=3)(=O)=O)[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][N:12]3[CH2:13][CH2:14][N:9]([C:5]4[CH:4]=[C:3]([N:2]([CH3:15])[CH3:1])[CH:8]=[CH:7][CH:6]=4)[CH2:10][CH2:11]3)[CH2:28][CH2:27]2)(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: O=S(=O)(OCC1CCN(S(=O)(=O)c2ccc(F)cc2)CC1)c1ccc(F)cc1
Reactant: CN(C)c1cccc(N2CCNCC2)c1
Product: CN(C)c1cccc(N2CCN(CC3CCN(S(=O)(=O)c4ccc(F)cc4)CC3)CC2)c1

Procedure:
Reaction of dimethyl-(3-piperazin-1-yl-phenyl)-amine and 4-fluoro-benzenesulfonic acid 1-(4-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl ester as described in Example 1 gave the desired product, (3-{4-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-piperazin-1-yl}-phenyl)-dimethyl-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 91.4 %

Procedure:
An amount of 2 g (9.85 mmol) of 2-bromo-5-nitro-pyridin is stirred in dichloromethane (50 mL), followed by addition of 1-methylpiperazine (10.9 mL, 98.5 mmol). The reaction mixture is refluxed for 1 h. After cooling, the mixture is extracted 3× with sodium bicarbonate, followed by additional washing with brine, dried over sodium sulfate, evaporated, to afford 2 g (91% yield) of yellow crystals; mp 75-76° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1)(=[O:24])=[O:23]
Reactant: O=C1NC(CO)Cc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1Cc2ccccc2C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Dissolve 3-(hydroxymethyl)-3,4-dihydro-2H-isoquinolin-1-one (6.0 g, 33.86 mmol) in DCM (60 mL) and add triethylamine (7.25 g, 67.72 mmol). Cool to 0° C. and add methanesulfonyl chloride (4.65 g, 40.63 mmol) drop-wise. Stir for one hour; dilute with DCM; and wash with water and then brine. Remove the solvents under reduced pressure to give the title compound (8.0 g, 92%). MS (m/z): 256 (M+1).
Reaction SMILES: C1C=CC(C(NC(C(N[C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=O)CCCN=C(N)N)=O)=CC=1.Cl.CS(C)=[O:33]>Cl>[CH:23]1[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:21]([OH:33])[CH:22]=1
Reactant: CS(C)=O
Reactant: NC(N)=NCCCC(NC(=O)c1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 5.5 h

Procedure:
Substrate stock solutions were prepared by dissolving ˜50 mg BAPNA or suc-AAPF-PNP in DMSO; these stock solutions were then diluted with DMSO and 0.1 M TRIS/HCl buffer (pH 7.4) to provide substrate solutions of various concentrations (final concentration of DMSO in each substrate solution was 15% v/v). A measured quantity of particles, 30-100 mg, were placed in a microcentrifuge tube, 1.3 ml of substrate solution was added, and the mixture was bath-sonicated to completely disperse the particles. The mixture was then placed in a water bath at 30° C. for 5-6 hours, with additional agitation provided every 45-60 minutes. The mixture was then removed from the water bath and centrifuged at 14,000 rpm for 30 minutes. The reaction time was measured from initial sonication to the beginning of centrifugation. Catalytic activity was determined from the increase in free p-nitrophenol concentration, measured by UV/VIS spectroscopy at 410 nm with an extinction coefficient of 8500 M−1 cm−1. The measured absorbance was compared to that of the substrate solution at 410 nm and from the absorbance due to light scattering of the particle dispersion of particles in 0.1 M Tris buffer (prepared identically as above) at 410 nm. These contributions to the absorbance were subtracted from the total absorbance at 410 nm to obtain the absorbance due to free p-nitrophenol. Each data point was calculated based on the average of 3 to 7 trials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1>CO.[Pt]>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Agent: [Pt]
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A suspension of D5 (15.0 g, 45 mmol) and 5% Pt/C (1.5 g) in methanol (500 mL) in an autoclave (1000 mL) was put under an atmosphere of hydrogen (˜40 atm). The mixture was stirred at room temperature for 3 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound (13.5 g, 100% yield) as a dark brown solid that was used without further purification. (Rf: 0.3 (ethyl acetate/hexane 7:8))
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH2:9][CH2:10][NH:11][C:12]1[N:17]2[N:18]=[C:19]([CH3:34])[C:20]([C:21]3[C:26]([Cl:27])=[CH:25][C:24](OS(C)(=O)=O)=[CH:23][C:22]=3[Cl:33])=[C:16]2[N:15]=[C:14]([CH3:35])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:49][Si:50]([C:53]#[CH:54])([CH3:52])[CH3:51]>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>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][NH:11][C:12]1[N:17]2[N:18]=[C:19]([CH3:34])[C:20]([C:21]3[C:22]([Cl:33])=[CH:23][C:24]([C:54]#[C:53][Si:50]([CH3:52])([CH3:51])[CH3:49])=[CH:25][C:26]=3[Cl:27])=[C:16]2[N:15]=[C:14]([CH3:35])[CH:13]=1)[CH:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCOCC2)n2nc(C)c(-c3c(Cl)cc(OS(C)(=O)=O)cc3Cl)c2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCOCC2)n2nc(C)c(-c3c(Cl)cc(C#C[Si](C)(C)C)cc3Cl)c2n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
A suspension of methanesulfonic acid 4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-phenyl ester (1.5 g, 2.2 mmol) in acetonitrile (5 mL)/triethylamine (1.9 mL) was degassed (3×) by alternately pulling a vacuum followed by repressurization with nitrogen. Trimethylsilylacetylene (0.50 mL, 3.6 mmol), dichlorobis(triphenylphosphine)palladium (65 mg, 0.093 mmol), and copper(I) iodide (42 mg, 0.22 mmol) were added, and the mixture was degassed (3×) again. The mixture was stirred for 4 hours at 65° C., the black mixture was extracted from saturated aqueous sodium bicarbonate with methylene chloride, dried (Na2SO4), filtered through Celite, concentrated under reduced pressure, and then chromatographed (7:3 hexanes/ethyl acetate) to give the product as a light brown foam (1.2 g, 89%): +APcI MS (M+1)+630; 1H NMR (CDCl3) δ: 7.51 (s, 2H), 5.82 (s, 1H), 2.44 (s, 3H), 2.23 (s, 3H), 1.53 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3](CC)/[C:4](/[CH3:13])=[CH:5]/[CH2:6][CH2:7]/[C:8](/[CH3:12])=[CH:9]/CN)C.C(C(CC)C(C)=CCC/C(/C)=C\CN)C.C(O)(=[O:33])C.O>C1COCC1>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][CH:4]([CH2:3][CH:1]=[O:33])[CH3:13])[CH3:12]
Reactant: CCC(CC)/C(C)=C/CC/C(C)=C/CN
Reactant: CC(=O)O
Agent: CCC(CC)C(C)=CCC/C(C)=C\CN
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)CC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Precursor complex: [Rh(COD)2 ]+X- (X=anion as defined above) In a glove box, a solution of 0.025 mmole of the respective precursor complex (for example [Rh(COD)2 ]+SO3CF3-) in 2.5 ml of THF (0.01 M) was added to 0.025 mmole of the respective ligand in a one-necked flask equipped with a stopcock. The solution was stirred for 1 h, then a solution of 10 mmole of diethylgeranylamine or diethylnerylamine in 10 ml of the respective solvent was added. The flask was then equipped with a reflux condenser connected to a Schlenk line, the apparatus was purged with argon and the solution brought to reflux. Reaction temperature was held constant during the reaction time indicated in the table. The mixture was then cooled to 0° C. before adding 5 ml of a 1:4 of acetic acid/water. The reaction mixture was raised to room temperature and the solution extracted with diethyl ether. The extract was washed with water (10 ml), 15% NaOH solution (2×10 ml), then neutralized with water and thereafter dried over MgSO4. After concentration of the resulting solution, the residue was distilled in a bulb-to-bulb apparatus to give optically active citronellal and with the conversions and ee's as indicated in the tables below.
Reaction SMILES: C(OC[O:5][C:6]1[C:11]2=[N:12][C:13]([CH3:35])=[C:14]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[C:29]5[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=5[O:27][N:26]=4)[CH2:21][CH2:20]3)[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1)C.C(O)C.[ClH:39]>>[ClH:39].[ClH:39].[F:34][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([CH:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][C:14]4[C:15](=[O:16])[N:10]5[CH:9]=[CH:8][CH:7]=[C:6]([OH:5])[C:11]5=[N:12][C:13]=4[CH3:35])[CH2:24][CH2:23]3)=[N:26][O:27][C:28]=2[CH:33]=1
Reactant: CCOCOc1cccn2c(=O)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c(C)nc12
Agent: Cl
Solvent: CCO
Product: Cc1nc2c(O)cccn2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 95.7 %

Procedure:
A mixture of 9-(ethoxymethoxy)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.008 mol) in hydrochloric acid, 12N (25 ml) and ethanol (100 ml) was stirred and refluxed for 6 hours. The reaction mixture was cooled and the precipitate was filtered off and dried, yielding 4 g (95.7%) 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.dihydrochloride.sesquihydrate; mp. 288.3° C. (interm. 18).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](Cl)=[O:27].O>C1COCC1>[Cl:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])=[O:27]
Reactant: O=C(Cl)CCOCCCl
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)CCOCCCl)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.70 g (10.3 mmol) methyl 4-amino-3-methyl-benzoate in 10 ml THF are combined with 2.84 ml (20.6 mmol) triethylamine and stirred for 20 minutes at ambient temperature. Then a solution of 1.78 g (10.4 mmol) 3-(2-chloro-ethoxy)-propionic acid-chloride in 25 ml THF is added dropwise and the mixture is stirred for a further 2.5 hours at ambient temperature. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=7:3->6:4).