Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11]([O:13]CC)=[O:12].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:16])([F:17])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 68 %

Procedure:
In 2 ml of ethanol was dissolved 160 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 2 ml of a 1N aqueous sodium hydroxide solution at 0°-5° C. The mixture was subjected to reaction at the same temperature for 10 minutes. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained, and the resulting crystals were collected by filtration to obtain 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.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:12][C:13]1[CH:14]=[C:15]([C:2]2[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: CSc1ncc(Br)c(=O)n1C
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc(SC)n(C)c2=O)cc1F
Temperature: 100 °C
Reaction time: 6.25 h

Procedure:
5-Bromo-3-methyl-2-methylthio-4(3H)-pyrimidinone (Step 3, 14.77 g, 62.8 mmol), 3-fluoro-4-methoxyphenylboronic acid (20.11 g, 118.3 mmol), Pd2(dba)3 (1.869 g, 2.04 mmol), S-phos ligand (Strem Chemical, 3.45 g, 8.40 mmol) and K3PO4 (42.27 g, 199.1 mmol) were suspended in toluene (200 mL). Ar was bubbled through the solution for 5 min, and the reaction was placed in an oil bath (100° C.) and stirred for 6.25 h, at which time LCMS analysis indicated a complete reaction. The reaction was cooled to RT and allowed to stand overnight. It was diluted with CH2Cl2 (200 mL) and filtered through a 1-inch plug of silica gel which was washed exhaustively with MeOH, EtOAc, and CH2Cl2. (Some solid material stuck in the flask had to be taken up in water and extracted with EtOAc separately). The filtrate (and EtOAc extracts) were all combined and concentrated, resulting in an orange solid. This was treated with hexanes and filtered, and the resultant light yellow solid was washed repeatedly with hexanes and then put on the high vacuum overnight. The title compound was obtained as a light yellow solid. MS (ESI pos. ion) m/z: 281. Calc'd for C13H13FN2O2S: 280.07.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:22][C:17]=2[N:16]=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:21]2[CH:20]=[CH:19][C:18]3[N:14]([CH3:13])[N:15]=[N:16][C:17]=3[CH:22]=2)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(c2)nnn3C)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(c2)nnn3C)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 30).
Reaction SMILES: Br[C:2]1(Br)[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]1=O.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH:21][C:22]([NH2:24])=[S:23]>C(O)C>[CH3:11][C:10]1([CH3:12])[CH2:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]2[N:24]=[C:22]([NH:21][C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[S:23][C:2]1=2
Reactant: CC1(C)Cc2[nH]ncc2C(=O)C1(Br)Br
Reactant: NC(=S)Nc1ncccn1
Solvent: CCO
Product: CC1(C)Cc2[nH]ncc2-c2nc(Nc3ncccn3)sc21
Reaction time: 0.67 h
Yield: 1.6 %

Procedure:
According to Scheme 2 Step 4: A solution of 5,5-dibromo-6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.96 g) and of 1-(pyrimidin-2-yl)thiourea (7.31 mmol, 1.13 g) in ethanol (15 mL) was microwaved at 150° C. for 90 minutes and then at 140° C. for 40 minutes. After filtration, the reaction mixture was concentrated to dryness. The crude residue was partitioned between DCM and a saturated solution of Na2CO3. The aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated. The crude residue was purified by flash chromatography over silica gel using DCM/MeOH (98:2 to 90:10) as eluent to yield 4,4-dimethyl-N-(pyrimidin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (0.10 mmol, 31 mg) as a brown solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[CH:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)=[O:36].O1CCOCC1>C(OCC)(=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.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([CH:35]=[O:36])[CH:42]=4)=[CH:32][C:17]=3[C:18]=2[C:28]([NH:29][CH3:30])=[O:31])=[CH:26][CH:25]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C=O)c3)cc12
Temperature: 90 °C
Yield: 41 %

Procedure:
Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)4 (20 mg, 0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.359 mmol), 3-formylphenylboronic acid (59 mg, 0.395 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was heated to 90° C. overnight. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the titled compound (55 mg, 41%). LC-MS retention time: 1.49 min; m/z (MH+): 374. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][P:36]([O:40]CC)[O:37][CH2:38][CH3:39])[CH3:34]>C1(C)C(C)=CC=CC=1>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:36]([O:37][CH2:38][CH3:39])(=[O:40])[O:35][CH2:33][CH3:34])[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O)OCC
Yield: 75.2 %

Procedure:
A solution of 1,4,5-triphenyl-3-(7-bromoheptyl)-imidazol-2-one (1.0 g) and triethylphosphite (1.66 g) in xylene (5 ml) was heated at reflux temperature for 40 hours. The solution was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol)The resulting oil was taken up in diethyl ether, filtered and evaporated to give diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanephosphonate as a clear oil (0.84 g, 75%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:5][N:6]([CH3:8])[CH:7]=1.Cl[CH2:22][CH2:23][N:24]1[C:28]2=[N:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:27]2[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CC(N(C)C)=O>[N:24]1([CH2:23][CH2:22][O:1][C:2]2[C:3](=[O:20])[C:4]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:5][N:6]([CH3:8])[CH:7]=2)[C:28]2=[N:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:27]2[CH2:26][CH2:25]1
Reactant: ClCCN1CCn2c1nc1ccccc12
Reactant: Cn1cc(O)c(=O)c(-c2ccnn2-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: Cn1cc(OCCN2CCn3c2nc2ccccc23)c(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 13 h
Yield: 66.8 %

Procedure:
A suspension of 5-hydroxy-1-methyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (201 mg), 1-(2-chloroethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (249 mg), cesium carbonate (428 mg) and sodium iodide (253 mg) in dimethylacetamide (10 mL) was stirred at 80° C. for 13 hr. The reaction mixture was filtered to separate an insoluble material, which was washed with ethyl acetate. The filtrate and washing were combined, and the mixture was concentrated under reduced pressure to dryness. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) to give the title compound (227 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34].[CH:35](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[NH:30][CH:35]=[N:31][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34]
Reactant: Nc1ccc(CC(NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)C(=O)N2CCS(=O)CC2)cc1[N+](=O)[O-]
Reactant: O=CO
Agent: [Pd]
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCS(=O)CC2)cc1Cl

Procedure:
Prepared from 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(1-oxido-thiomorpholin-4-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:38][CH2:39][CH:40]=[CH2:41])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C@@:9]([O:36]C)([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2)[CH2:8]1)=[O:5].CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1]/[C:2](/[CH2:38][CH2:39][CH:40]=[CH2:41])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:10][C@@:9]([OH:36])([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[NH:22]2)[CH2:8]1)=[O:5]
Reactant: C=CCC/C(C)=C\C(=O)O[C@@H]1C[C@@H](CCc2ccccc2)O[C@@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)C1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCC/C(C)=C\C(=O)O[C@@H]1C[C@@H](CCc2ccccc2)O[C@@](O)([C@@H]2CSC(=O)N2)C1

Procedure:
Application of the method shown in Example 46, with the modification that (Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl) 3-methylhepta-2,6-dienoate is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[F:28])([C:15]([F:18])([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[F:28])([C:15]([F:17])([F:16])[F:18])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc([N+](=O)[O-])ccc2F)(C(F)(F)F)CCOC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)(F)F)CCOC1
Reaction time: 6 h
Yield: 87.9 %

Procedure:
A solution of [5-(2-fluoro-5-nitro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (1.69 g, 4.01 mmol) in 10 mL ethanol and 10 mL THF was brought under nitrogen atmosphere and 500 mg of 5% Pd on charcoal was added. The reaction mixture was then stirred under a hydrogen atmosphere (balloon) for 6 hours. Then it was filtered over celite and evaporated. The crude product was crystallized from hexane/TBME to give 1.38 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](N)=[O:22].S(=O)(=O)(O)[OH:25]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:22])=[O:25]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl

Procedure:
2.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide and 10 g of 63 % sulfuric acid are heated for 1.5 hours at 100°C and prepared in accordance with example 2. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; F 179.5°-181°.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@@H:9]1[C:19]([OH:21])=[O:20])(OC(C)(C)C)=O.[ClH:22]>O1CCOCC1>[ClH:22].[C:13]1([C@H:12]2[NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][CH2:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)CC[C@H]1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2R,5S)-Boc-5-phenyl-pyrrolidine-2-carboxylic acid (1.3 g, 4.5 mmol, obtained from SNPE North America LLC, 5 Vaughn Drive—Suite 111, Princeton, N.J. 08540, USA) was added to 10 mL of 4N HCl in dioxane and the mixture was stirred at room temperature for 2 hr. The mixture was concentrated under vacuum to give 1.0 g (100%) of (2R,5S)-5-phenyl-pyrrolidine-2-carboxylic acid HCl salt as a white solid. The solid was dissolved in 7 mL of anhydrous THF and the solution was added slowly into a stirred solution of 1 M LiAlH4 in THF (10.3 mL, 10.3 mmol, 3 eq) at room temperature. The mixture was then heated at reflux for 4 hr. After cooling to room temperature, the reaction mixture was treated sequentially with 0.42 mL of water, 0.85 mL of 1 N NaOH, and 1.26 mL of water. The mixture was stirred for 1 hr and the white precipitate was filtered off. The filtrate was dried (Na2SO4) and concentrated under vacuum to give 0.78 g (98%) of (2R,5S)-(5-phenyl-pyrrolidin-2-yl)-methanol as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ7.60–7.30 (5H, m), 4.40 (1H, m), 3.78 (1H, m), 3.60 (2H, m), 2.60 (2H, br.s), 2.25 (1H, m), 2.10 (1H, m), 1.80 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([CH2:34][CH2:35][C:36](=O)[CH2:37][CH3:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]([CH2:37][CH3:38])[CH2:35][CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCC(=O)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(CC)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-pentan-3-one.
Reaction SMILES: P(Br)(Br)Br.O[CH2:6][C:7]1[CH:12]=[C:11]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:24].CC[N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>CC#N>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:14]=[N:13][C:11]2[CH:10]=[CH:9][C:8]3[O:24][C:30]4([C:31]5[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=5)[C:11]([CH3:12])([CH3:10])[C:29]5[C:28]([N:27]4[CH2:6][C:7]=3[CH:12]=2)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)c(CO)c2)cc1
Agent: BrP(Br)Br
Solvent: CC#N
Product: CC1(C)c2ccccc2N2Cc3cc(N=Nc4ccc([N+](=O)[O-])cc4)ccc3OC21c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of PBr3 in MeCN (1:10 v/v, 190 μL) was added over 20 min to a solution of 4 (185 mg, 0.6 mmol) in MeCN (25 mL) maintained at 0° C. under Ar. After addition of Et3N (80 μL), the mixture was stirred for a further one hour at 0° C. and then heated under reflux for 4 h. At this point, 6 (400 mg, 1.8 mmol) was added and the temperature was allowed to lower to ambient conditions. After 36 h, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography [SiO2, hexane/CH2Cl2 (1:1 v/v)] to give 8a (135 mg, 51%) as an orange-red solid. HPLC [analytical, MeCN/H2O (90:10 v/v)]: RT=4.1 min, PA=1.6, APP=303.2±1.0 nm; mp=200° C.; FABMS: m/z=476 [M]+; 1H-NMR (400 MHz, chloroform-d): δ=0.85 (3H, s), 1.60 (3H, s), 4.57 (1H, d, 11 Hz), 4.67 (1H, d, 11 Hz), 6.75 (1H, d, 8 Hz), 6.90 (1H, t, 7 Hz), 6.97 (1H, d, 9 Hz), 7.16-7.19 (2H, m), 7.35-7.42 (3H, m), 7.64-7.73 (4H, m), 7.93 (2H, d, 9 Hz), 8.34 (2H, d, 9 Hz); 13C-NMR (100 MHz, chloroform-d): δ=22.9, 31.8, 41.2, 49.8, 104.8, 109.2, 118.7, 120.6, 120.7, 122.4, 122.6, 123.3, 124.3, 124.9, 127.8, 128.3, 128.7, 129.0, 137.0, 138.0, 146.6, 147.5, 148.4, 156.2, 157.9.
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[CH2:38][CH3:39])[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:20]1[CH:21]=[C:22]([CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:10]1[N:9]=[C:8]([CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[CH2:3][C:2]([NH2:1])=[O:44])[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=1)[CH3:39]
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylate, (I44) (120 mg, 0.20 mmol) was dissolved in DCM (20 mL), TFA (2 mL) was added and the mixture stirred for 16 hours at room temperature. The mixture was concentrated and the residue suspended in 10% sodium hydroxide (10 mL) and brine (10 mL). The mixture was extracted with ethyl acetate (4×20 mL), the combined extracts washed with brine, dried (sodium sulphate) evaporated and the residue evaporated for ether to give the title compound (8) (93 mg, 93% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.47 (s, 1H), 8.49 (s, 1H), 7.37 (s, 1H), 7.26-7.18 (m, 2H), 7.17-7.09 (m, 4H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 6.89 (s, 1H), 3.44 (s, 2H), 3.09-2.88 (m, 6H), 2.62-2.54 (m, overlaps with DMSO), 1.70 (d, J=11.4 Hz, 2H), 1.52 (qd, J=12.3, 3.7 Hz, 2H), 1.10 (t, J=7.5 Hz, 3H), LCMS Method C: 4.96 min; m/z 512.2 [M+H]+, 534.2 [M+Na]+; m/z 510.2 [M−H]−.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].C([CH2:15][SiH:16]([Cl:18])[Cl:17])C=C>>[Cl:17][Si:16]([Cl:18])([CH3:15])[CH2:7][CH:6]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:10].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: C=CCC[SiH](Cl)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: CC(C[Si](C)(Cl)Cl)[c-]1cccc1
Reaction time: 2 h
Yield: 21 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 0.60 g (3.22 mmol) of ferrocene was reacted with 1.00 g (6.44 mmol) of allylmethyldichlorosilane under dry nitrogen atmospheric pressure for 2 hrs. After the addition of the catalyst solution, the reaction mixture was stirred for 2 hrs to complete the alkylation. The solvent was distilled at atmospheric pressure and the products were then extracted with 20.0 mL of hexane. Vacuum distillation of the reaction products at 180° C. and at 0.5 torr, produced (3,3-dichloro-1-methyl-3-silabutyl)ferrocene [yield: 21% (based on the reacted ferrocene), bp:(104°-110° C./0.5 torr)]. By vacuum distillation of the remaining products at 300° C. and at 0.5 torr, bis(3,3-dichloro-1-methyl-3-silabutyl)ferrocene as a mixture of isomers(m=1, n=1, yield; 7%, bp; 165°-170° C./0.5 torr) was obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH+:4]1[O-:13])[CH3:2].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(ON1C(CC)(C)CCC(C)C1(CC)C)(=O)C>>[C:15]([O:13][N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:14])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCC1(C)CCC(C)C(C)(CC)[NH+]1[O-]
Agent: CCC1(C)CCC(C)C(C)(CC)N1OC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)ON1C(C)(CC)CCC(C)C1(C)CC

Procedure:
2,6-Diethyl-2,3,6-trimethylpiperidine 1-oxide (for preparation, see U.S. Pat. No. 4,131,599) is converted by a method analogous to Example A 30 using stearoyl chloride into the compound 137 which is obtained in the form of a colourless oil.