Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9](O)[C@H:8]([O:11][CH2:12][O:13][CH3:14])[CH2:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:45]([N:1]1[C@@H:4]2[C@H:9]1[C@H:8]([O:11][CH2:12][O:13][CH3:14])[CH2:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5]2)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: COCO[C@@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCO[C@@H]1CC(C(=O)OC)=C[C@H]2[C@@H]1N2C(C)=O
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a solution of azido alcohol 15 (150 mg, 0.58 mmol) in toluene (5 mL) was added triphenylphosphine (152 mg, 0.58 mmol) and the reaction mixture was refluxed for 3 h at 110° C. After removal of the solvent under reduced pressure, diethylether (1 mL) was added, and the mixture cooled with ice-bath. The precipitated triphenylphosphine oxide was removed by filtration and the filtrate evaporated. This procedure was repeated to remove any traces of triphenylphosphine oxide. The residue obtained was then dissolved in dry CH2Cl2 (20 mL) cooled at 0° C. To this solution was added Et3N (175.74 mg, 1.74 mmol), DMAP (4-Dimethylamine pyridine) (5 mg) and acetic anhydride (118.32 mg, 1.16 mmol) and the mixture stirred at 25° C. for further 45 minutes. After completion of reaction (monitored by TLC), the reaction mixture was quenched by addition of H2O (10 mL). The organic layer was separated, washed with brine, dried (Na2SO4) and subjected to column chromatographic purification with petroleum ether/ethyl acetate (7:3 v/v) to afford the cyclic acetamide aziridine 16.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH:30]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH:30]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc3ccccc3c3ccccc23)cc1)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(-c2cc3ccccc3c3ccccc23)cc1)C(=O)O
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 98 (124 mg, 0.31 mmol) in THF/water, 2:1 (9 mL) was added lithium hydroxide monohydrate (26 mg, 0.62 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organics were dried and evaporated to yield the title compound (65 mg, 0.17 mmol, 55%) as a white solid. Mp 128-132° C. [α]D20+36.8 (c. 0.1, EtOH). 1H NMR (CD3OD, 300 MHz): δ 8.71 (d, J=8.1 Hz, 1H, ArH4″); 8.66 (d, J=8.4 Hz, 1H, ArH3″); 7.79 (s, 1H, ArH1″); 7.76 (s, 1H, ArH10″); 7.51 (m, 5H, ArH7″, ArH6″, ArH5″, ArH2″ and ArH1″); 7.32 (m, 2H, Ar′H); 4.76 (dd, J=5.1, 9.0 Hz, 1H, H2); 3.29 (dd, J=4.8, 13.5 Hz, 1H, H3a); 3.03 (dd, J=8.7, 13.5 Hz, 1H, H3b); 1.95 (s, 3H, COCH3). Mass Spectrum (ES, +ve) m/z 384 (50%) [MH+]. HRMS calcd for C25H22NO3 384.1600, found 384.1628.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([S:22][CH3:23])=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][N:25](C=O)C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:8]1[N:7]=[C:6]([S:22][CH3:23])[C:5]2[C:10](=[CH:11][C:2]([C:24]#[N:25])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C#N)ccc12
Temperature: 90 °C
Yield: 79 %

Procedure:
To a mixture of 1,1′-bis(diphenylphosphino)ferrocene (25 mg, 0.045 mmol), zinc cyanide (55 mg, 0.47 mmol), and 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 7 Step E (150 mg, 0.376) was added tris(dibenzylideneacetone)dipalladium (34 mg, 0.031 mmol) in DMF (3 mL). The reaction vessel was evacuated, and flushed with argon (2×), then the mixture was heated at 90° C. overnight during which time most of the solvent evaporated. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL), 2N NH4OH (20 mL), and brine, dried over Na2SO4, and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel chromatography eluting with a 10-60% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-7-carbonitrile as a solid (0.103 g, 79%). LC-MS (ESI) m/z 347 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1)=[S:12])([O-])=O.[Cl-].[NH4+].CO.Cl>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1)=[S:12]
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2N)C1
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of 34 parts of ethyl 3-[[[(2-nitrophenyl)amino]thioxomethyl]amino]-1-pyrrolidinecarboxylate, 56 parts of iron-powder, 2 parts of ammonium chloride, 160 parts of methanol and 30 parts of water was stirred and acidified with hydrochloric acid. Stirring was continued for 2 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 30 parts (97.5%) of ethyl 3-[[[(2-aminophenyl)amino]thioxomethyl]amino]-1-pyrrolidinecarboxylate as a residue (interm. 23).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=N[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.BrC1C=CC=[C:30]([F:34])C=1>>[F:25][C:2]([F:26])([F:1])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:30]([F:34])[CH:19]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Reactant: Fc1cccc(Br)c1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=397.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](O)=[O:13]>[OH-].[Na+].O>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(S)cccc1Cl
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CSc2cccc(Cl)c2N1
Yield: 95.3 %

Procedure:
2-Amino-3-chlorothiophenol (2.5 g) was dissolved in a solution of sodium hydroxide (690 mg) in water (40 ml), and bromoacetic acid (2.4 g) was added thereto with stirring. After stirring at 70° C. for 3 hours, the precipitated crystals were filtered, washed with water and dried to obtain 2.98 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-one (m.p. 160°-161° C.)
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].Cl>N1C=CC=CC=1>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.36 g of 4-isopropylbenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization. Thereupon, the mixture was boiled with 0.5 g of active charcoal and the active charcoal and insoluble constituents were filtered off. Crystals separated upon cooling and, after recrystallization from 40 ml of 50% ethanol, yielded 0.17 g of 4-isopropyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as colourless crystals.
Reaction SMILES: [C:1]1([C:7]([C:10]2[C:14]([NH:15][C:16](=[O:19])[CH2:17]Cl)=[C:13]([CH3:20])[O:12][N:11]=2)([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+]>O1CCCC1>[CH3:20][C:13]1[O:12][N:11]=[C:10]2[C:7]([CH3:8])([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:9][CH2:17][C:16](=[O:19])[NH:15][C:14]=12
Reactant: Cc1onc(C(C)(O)c2ccccc2)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc2c1NC(=O)COC2(C)c1ccccc1
Yield: 51.2 %

Procedure:
A solution of 7.25 g of N-[3-(1-phenyl-1-hydroxyethyl)-5-methylisoxazol-4-yl]chloroacetamide in 36 ml of tetrahydrofuran was added, dropwise under nitrogen, to a suspension of sodium hydride, from washing 2.5 g of a 50% (by weight) oil suspension with hexane, in 146 ml of tetrahydrofuran. The resulting mixture was refluxed for two hours, concentrated, and quenched with 250 ml of ice water. The resulting precipitate was collected, washed with hexane and dried under vacuum (phosphorus pentoxide). Recrystallization from methanol afforded 3.25 g of 4,8-dihydro-3,8-dimethyl-8-phenylisoxazolo[4,3-e][1,4]oxazepin-5(6H)-one, m.p. 177°-178° C.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].CN(C)C=O.[Cl:29]N1C(=O)CCC1=O>C(#N)C.O.FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([Cl:29])[CH:12]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1ncccc1C(=O)NCc1cc(Cl)c(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a mixture of 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-67 (21 mg, 0.064 mmol) and N,N-dimethylformamide (1 mL) was added N-chlorosuccinimide (13 mg, 0.096 mmol), and the solution was stirred overnight at room temperature. The reaction solution was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (7.4 mg, 0.016 mmol, 24%) was obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:9]=2[C:8]=1[Br:17].O>CCOCC>[Br:17][C:8]1[C:9]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=2[S:11][CH:7]=1
Reactant: Cc1ccc2c(Br)c(Br)sc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2c(Br)csc2c1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A solution of n-butyl lithium (22.3 ml. of 1.6 M solution in hexane) was added dropwise to a stirred solution of 2,3-dibromo-6-methylbenzo[b]thiophene (11.76 g.) in dry ether (150 ml.) at 0° under an atmosphere of dry nitrogen. The resulting solution was stirred at 0° for 1 hour and then water (50 ml.) was added. The mixture was stirred for a few minutes and then the ether layer was separated, dried (Na2SO4) and evaporated to give an oil. The oil was distilled to give 3-bromo-6-methylbenzo[b]thiophene (5.80 g.), b.p. 112°-114° C. @ 0.2 m.m., m.p. 51°-53° C. (from methanol).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[C:13]([N:17]1[CH2:21][CH2:20][O:19][P:18]1Cl)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([N:17]1[CH2:21][CH2:20][O:19][P:18]1[O:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[CH3:3])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N1CCOP1Cl
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(OP2OCCN2C(C)(C)C)c(C)c1
Yield: 75.6 %

Procedure:
The procedure of Example 1 is repeated using 4.4 g (0.11 mol) of sodium hydride with 45 ml of THF, 13.62 g (0.10 mol) of 2,4,6-trimethylphenol in 150 ml of THF and 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 150 ml of THF to give a (75.6%) of colorless liquid: bp. 99°-103° C. (0.01 mm Hg).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NCCCCBr)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
An ethanol (130.2 ml) solution of sodium ethoxide (5.83 g) was added with diethyl malonate (13 ml) and stirred at room temperature for 5 minutes. This solution was added with an ethanol (55.8 ml) solution of the 1-benzyloxycarbonylamino-4-bromobutane (4.9 g) obtained in the above step (b), and stirred at 40° C. for 20 hours. The reaction system was concentrated under reduced pressure without any treatment, and the residue was added with saturated aqueous ammonium chloride, and then the organic substances were extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1.2 kg, hexane:ethyl acetate=2:1) to obtain diethyl 2-(4-benzyloxycarbonylaminobutyl)malonate (5.2 g, 83%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=C[CH:4]=[CH:3][CH:2]=1.[S:21]1C=CC=C1B(O)O>>[S:21]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccs1
Product: O=C1NCCc2c(-c3cccs3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and thiophene-2-boronic acid (159 mg, 1.24 mmol) were coupled to yield 2-thiophen-2-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 171 mg (56%) as a beige solid: m.p. 220.5-222.5° C.; 1H NMR (300 MHz d6-DMSO) δ 3.08 (m, 2H), 3.48 (m, 2H), 7.23 (m, 2H), 7.52 (m, 2H), 7.69 (m, 2H), 8.05 (br t, 1H), 11.60 (br s, 1H). MS (electrospray, MH+) 269. Anal. (C15H12N2)S.0.8 H2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:29][C:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:12]3=O)[CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.C[OH:31]>[Pd]>[NH2:1][C:4]1[C:9](=[O:31])[NH:8][C:7]2[CH2:10][C:11]3([CH2:29][C:6]=2[CH:5]=1)[C:19]1[C:14](=[N:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:12]3
Reactant: CO
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc([N+](=O)[O-])cnc3C2)c2cccnc21
Agent: [Pd]
Product: C[Si](C)(C)CCOCN1CC2(Cc3cc(N)c(=O)[nH]c3C2)c2cccnc21
Reaction time: 4.5 h

Procedure:
A mixture of 10% Pd/C (20 mg) and (±)-3-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (117 mg, 0.284 mmol) was stirred vigorously in MeOH (5 mL) under an atmosphere of hydrogen (ca. 1 atm). After 4.5 h, the mixture was filtered through a pad of Celite, washing extensively with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=383 (M+1).
Reaction SMILES: ClC(C(O)C1C=CC=C([N+]([O-])=[O:13])C=1)(Cl)Cl.[F-].[K+:17].[F-].[F:19][Al-3:20]([F:25])([F:24])([F:23])([F:22])[F:21].[K+].[K+].[K+]>C(Cl)(Cl)Cl>[F:19][Al-3:20]([F:25])([F:24])([F:23])([F:22])[F:21].[K+:17].[K+:17].[K+:17].[OH-:13]
Reactant: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Agent: F[Al-3](F)(F)(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: [OH-]

Procedure:
In this invention we describe the preparation of trichloromethyl-3-nitrobenzyl alcohol in high yield with no detectable Cannizzaro product and demonstrate the generality of the method for the condensation of chloroform with other aldehydes and ketones. Initially, potassium fluoride supported on alumina was the base of choice for this condensation since the fluoride base would prevent the Cannizzaro side reaction. Characterization by infrared and Raman spectroscopy of this supported base showed the presence of potassium hexafluoroaluminate rather than potassium fluoride. Aqueous potassium fluoride had reacted with alumina to produce potassium hexafluoroaluminate and hydroxide. This observation prompted the use of potassium hydroxide supported on Super-Cel as the base to give TMBA in 93% isolated yield. The method described herein avoids the preparation and variable activity of the supported hydroxide base. A mixture of chloroform (2.25 equivalents) and 3-nitrobenzaldehyde (one equivalent) in dimethylformamide (DMF) at 0° C. was treated with a methanolic solution of potassium hydroxide (0.7 equivalents). After work-up, the desired alcohol TMBA was obtained in 98% yield and crystallized from toluene/hexane to give analytically pure trichloromethyl-3-nitrobenzyl alcohol in 90% yield.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH:13]=[N:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[C:1]([Si:5]([CH3:19])([CH3:20])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][NH:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN=Cc1cccc(OCCO[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1cccc(OCCO[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzylidene}-methyl-amine (1.174 g, 4.00 mmol) was dissolved in EtOH and cooled to 0° C. NaBH4 (189 mg, 5.00 mmol) was added and the mixture was allowed to stir for 4 h. The reaction was carefully quenched with water. The EtOH was removed in vacuo. The aqueous residue was extracted with CH2Cl2. The organic extracts were dried over Na2SO4 and concentrated in vacuo to give 1.185 g (quant) of a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([N:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(N(C(=O)OC(C)(C)C)c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccccc2)CC1
Reaction time: 3 h
Yield: 97.1 %

Procedure:
t-Butyl (1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)phenylcarbamate (2.5 g) was dissolved in ethanol, palladium on carbon (10%) was added and the mixture was shaken under hydrogen (50 psi.) for 3 h. The mixture was filtered through Hyflo and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with EtOAc/Hexane (5:95) to give the title compound as a clear oil (2.44 g), δH (CDCl3) 1.51 (9H, s), 1.55 (9H, s), 1.69 (2H, m), 1.79 (2H, m), 2.77 (3H, m), 4.24 (2H, m), 6.18 (1H, br s), 7.12-7.18 (3H, m), 7.52 (1H, m). m/e (CI+) 377 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>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.CN(C=O)C>[CH3:18][S@:10](=[O:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:9][C:7](=[O:8])[C:6]1[CH:19]=[C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:3]=[N:4][CH:5]=1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a degassed solution of 10.0 mL DMF at room temperature was added (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (1.02 g, 3.0 mmol), triethylamine (1.3 mL, 9.0 mmol), trimethylsilylacetylene (0.83 mL, 6.0 mmol), and dichlorobis(triphenylphosphine)palladium(II) (211 mg, 0.3 mmol). After 15 minutes added copper(I) iodide (29 mg, 0.15 mmol) and continued reaction for 4 hours. The reaction was then partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4 and rotary evaporated to 20 ml volume. The solution was placed overnight in the refrigerator and the resulting solid filtered and rinsed with 40% EtOAc/hexane to give the title compound (674 mg) as a tan solid. The filtrate was evaporated and purified by chromatography (silica gel, eluting with hexane/EtOAc) to give an additional 301 mg of the title compound. The product lots were combined and purified by chromatography (silica gel, eluting with hexane/EtOAc) to give the title compound as a tan solid (959 mg, 90%).
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3].OC(C(C1C=CC(CC(C)C)=CC=1)C)=O>>[CH3:3][C:2]1([CH3:4])[C:5](=[CH2:6])[C@H:7]2[CH2:10][C@@H:1]1[CH2:9][CH2:8]2
Reactant: C=C1C2CCC(C2)C1(C)C
Agent: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Product: C=C1[C@@H]2CC[C@@H](C2)C1(C)C

Procedure:
An emulsion of camphene in surfactant solution was prepared as in Example 1 (substituting camphene for ibuprofen). The hot camphene emulsion was pumped (peristaltic pump) at 6 lhr−1 through a cooled coil, to reduce the emulsion temperature to 20° C., then fed directly into a continuous sonication vessel (approximately 30 ml sonicated volume) fitted with a high intensity sonic probe (500 w). Two samples were collected. The first was untreated and the second was cooled rapidly in ice/water. The flow rate was then reduced to 2 lhr−1 and two samples collected and treated as above.