Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7](=O)[C:8]([F:11])([F:10])[F:9]>C(O)C>[F:9][C:8]([F:11])([F:10])[C:7]1[N:1]=[C:2]([NH2:4])[S:3][CH:6]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: Nc1nc(C(F)(F)F)cs1
Temperature: 50 °C
Yield: 78.5 %

Procedure:
Add thiourea (4.0 g, 52.3 mmol) and 3-bromo-1,1,1-trifluoropropan-2-one (5.5 mL, 10 g, 52.3 mmol) to ethanol (100 mL) and heat at 50° C. for 2 h. Cool to room temperature and concentrate to dryness. Dissolve the residue in water and adjust the pH to >12 with 2 M NaOH. Extract with diethyl ether (4×). Dry the combined organic extracts with sodium sulfate, filter, and concentrate under vacuum. Purify the resulting material by silica gel chromatography (CH2Cl2) to obtain the title compound (6.9 g, 79%). ES/MS m/z 169 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[N:7][CH:8]=1)[CH3:2].[N+](C1C=CC=CC=1C=CC1C=CC=CN=1)([O-])=O>>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: CCc1ccc(C=Cc2ccccc2[N+](=O)[O-])nc1
Agent: O=[N+]([O-])c1ccccc1C=Cc1ccccn1
Product: CCc1ccc(CCc2ccccc2N)nc1

Procedure:
Reduction of 5-ethyl-2-(o-nitrostyryl)pyridine as described in Example 2 (a) for 2-(o-nitrostyryl)pyridine provides 2-(o-aminophenethyl)-5-ethylpyridine having a melting point of 52.5° -53.5° C. (corr.) when crystallized from isopropyl ether-heptane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O[CH2:35][CH3:36])(=O)C>CN(C)C=O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:10]2[CH:9]=[N:8][CH:6]=[CH:35][CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2Br)CC1
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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2-c2cccnc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
After dissolving 575 mg of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-bromophenyl)ethanone in 10 ml of N,N-dimethylformamide, there were added 489 mg of 2-(3-pyridyl)-1,3,2-dioxabornane, 173 mg of tetrakis(triphenylphosphine)palladium(0) and 1.47 g of anhydrous cesium carbonate, and the mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (379 mg, 66% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][F:43]>CN(C)C=O.C(OCC)(=O)C>[F:43][CH2:42][CH2:41][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1
Reactant: FCCBr
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCCF)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 100 %

Procedure:
A solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g), potassium carbonate (0.48 g) and 1-bromo-2-fluoroethane (0.25 mL) in N,N-dimethylformamide (10 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.1 g, 100%) as a pale-yellow liquid.
Reaction SMILES: C1(NC=CP(=O)(OCC)[O:11][CH2:12][CH3:13])CCCCC1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:36]([CH:37]=O)=[C:35]([CH:39]([CH3:41])[CH3:40])[N:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31](=[O:42])[NH:32]3)=[CH:23][CH:22]=1.O.O.C(O)(=O)C(O)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:36](/[CH:37]=[CH:13]/[CH:12]=[O:11])=[C:35]([CH:39]([CH3:40])[CH3:41])[N:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31](=[O:42])[NH:32]3)=[CH:25][CH:26]=1
Reactant: CCOP(=O)(C=CNC1CCCCC1)OCC
Reactant: CC(C)c1nc2[nH]c(=O)ccc2c(-c2ccc(F)cc2)c1C=O
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc2[nH]c(=O)ccc2c(-c2ccc(F)cc2)c1/C=C/C=O
Reaction time: 0.5 h

Procedure:
A solution of 13.1 g (50 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 80 ml of tetrahydrofuran is added dropwise at 0° C. under argon to a suspension of 3.0 g (100 mmol) of 80% strength sodium hydride in 80 ml of anhydrous tetrahydrofuran and the mixture is stirred at this temperature for 30 min. A solution of 13.0 g (42 mmol) of the compound from Example 4 in 80 ml of tetrahydrofuran is then added dropwise at 0° C.-5° C. and the mixture is then heated under reflux for 1 h. 200 ml of water are added cautiously and the mixture is extracted three times with ethyl acetate. After concentrating the organic phases, the residue is heated under reflux for 2 h with a mixture of 500 ml of toluene, 500 ml of water and 27.5 g (218 mmol) of oxalic acid dihydrate. The toluene phase is concentrated and the residue is treated with ethyl acetate. 11.35 g (80% of theory) of colorless crystals of m.p. 261° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[N:6]=[N:5]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:7]2[N:6]=[N:5][N:4]([CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])[C:8]=2[CH:9]=[CH:10][C:11]=1[OH:13]
Reactant: [Br-]
Reactant: CC(C)(C)Cn1nnc2cc(O)ccc21
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Temperature: 25 °C

Procedure:
To a solution of 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (10) (3 mg, 0.015 mmol, 1.0 equiv.) in CHCl3 (500 μL), was added slowly pyridinium tribromide (4.67 mg, 0.015 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature until LCMS showed mostly the desired product. The reaction mixture was quenched with water, neutralized to pH=7, then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to give 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (Example 1-2). LRMS m/z (M+H) 283.9 and 285.9 (intensity ratio ˜1:1) found, 284.0 and 286.0 required.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Cl.Cl[CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CCOC(C)=O.CN(C)C(=O)C>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: ClCCN1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCNCC2)cc1C1=CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCN(CCN3CCOCC3)CC2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A flask was charged with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (830 mg, 1.34 mmol) (as prepared in Example 39, step (a)), K2CO3 (600 mg, 4.34 mmol), sodium iodide (40 mg, 0.27 mmol), 4-(2-chloro-ethyl)-morpholine hydrochloride (260 mg, 1.40 mmol), and 5.0 mL of N,N-dimethylacetamide and stirred for 8 h at 80° C. The reaction was diluted with EtOAc (50 mL) and washed with NaHCO3 (2×50 mL), brine (50 mL) and concentrated. The title compound was purified by flash chomatography (silica gel, 5% MeOH/DCM) to give 650 mg (78%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C34H50N6O3Si, 619.4 (M+H). found 619.3.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[C:18]([C:20]1[N:25]=[C:24]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:23]=[CH:22][CH:21]=1)#[N:19]>>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][O:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]#[N:19])[N:25]=2)[CH2:30][CH2:31]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Reactant: N#Cc1cccc(OCCN2CCNCC2)n1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)n2)CC1)c1ccc(C#N)s1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide and 1-[2-(6-cyano-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10].[CH2:12](N(CC)CC)[CH3:13].[Si](C#C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CN(C=O)C.CCOC(C)=O.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.CO.O>[C:12]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10])#[CH:13]
Reactant: NC(=O)Cc1ccccc1I
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C#Cc1ccccc1CC(N)=O
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-iodophenyl)acetamide (I38) (1.75 g, 6.70 mmol) in dry THF (50 mL) and dry DMF (10 mL) was added Pd(PPh3)4 (0.194 g, 0.168 mmol) and Cu(I)I (0.064 g, 0.34 mmol), triethylamine (3.27 mL, 23.5 mmol). The mixture was stirred for 10 minutes and TMS-acetylene (1.52 mL, 10.7 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours, concentrated in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid. This material was dissolved in dry THF (25 mL) under an atmosphere of nitrogen and TBAF (1.0 M in THF, 2.805 mL, 2.805 mmol) was added dropwise at 0° C. The solution was stirred at this temperature for 1 hour and 15 minutes after which water (5 mL) was added. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and aqueous layer was extracted with EtOAc (100 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I39) (0.239 g, 22% yield over 2 steps) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.21 (dd, J=7.6, 1.1 Hz, 1H), 7.18-7.05 (m, 3H), 7.04-6.98 (m, 1H), 6.70 (s, 1H), 4.08 (s, 1H), 3.36 (s, 2H). LCMS Method C: rt 4.71 min; m/z 160.2 [M+H]+.
Reaction SMILES: S(OS([O-])=O)([O-])=O.[Na+].[Na+].[Cl:10][C:11]1[S:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[CH:23][C:24]=1[NH2:25].O>CN1CCCC1=O>[Cl:10][C:11]1[S:12][C:13]([C:16]2[NH:25][C:24]3[CH:23]=[CH:22][C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][C:19]=3[N:18]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Cl)s1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)Cc1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
3.1 3.89 g (20.5 mmol) of sodium disulfite are added to a solution of 3.00 g (20.5 mmol) of 2-chlorothiophene-5-carbaldehyde and 3.98 g (20.5 mmol) of ethyl 3,4-diaminophenylacetate in 30 ml of 1-methyl-pyrrolidone, and the mixture is stirred at 110° C. for 18 hours. Water is added to the reaction mixture, which is extracted with dichloromethane. The organic phase is dried using sodium sulfate and evaporated, giving ethyl [2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetate as a brown oil (ESI 321), which is employed without further purification for the next reaction.
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:20]=[CH:19][C:11]2[N:12]=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[S:14][C:10]=2[CH:9]=1)C>C(Cl)Cl>[OH:7][C:8]1[CH:20]=[CH:19][C:11]2[N:12]=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[S:14][C:10]=2[CH:9]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A 1 M solution of BBr3 in CH2Cl2 (23 mL, 0.022 mol) was cooled to -80° C. in a dry ice/acetone bath under a N2 atmosphere. A suspension of 6-ethoxy-2-benzothiazolesulfonamide (0.5 g, 0.002 mol) in 75 mL of CH2Cl2 was added slowly to the cooled BBR3 solution The reaction was removed from the cooling bath and stirred at room temperature for 15 hours. It was poured into ice-water, stirred for 30 min, and filtered to Yield 0.35 g of product (73.8%). The product was purified by recrystallization from MeOH/H2O; mp 209°-212° C.; M/S m/e 230 (M,calcd 230).
Reaction SMILES: Br[CH2:2][C:3]1(C)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Cl.ClC1C=CC=CC=1N1CCNCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:2][CH:3]1[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: Cl
Agent: Clc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)O2
Temperature: 145 °C
Reaction time: 20 h

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g), 1-(2-chlorophenyl)piperazine hydrochloride (1.4 g), and potassium carbonate (2.1 g) in N,N-dimethylformamide (15 mL) was stirred under nitrogen gas at 145° C. for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate (Na2SO4) and silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethylacetate=5:1 to 2:1). The 2-[[4-(2-chlorophenyl)-1-piperazinyl]methyl)]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine thus obtained was dissolved in methanol and a stoichiometric excess of 10% hydrogen chloride solution in methanol was added. The mixture was concentrated under reduced pressure and recrystallized from ethanol/diethyl ether to provide 1.0 g of the title compound. Yield 44%.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].[OH-].[Na+].[F:18][CH:19]([F:29])[C:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]([CH3:28])[N:21]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:25]([C:24]1[C:20]([CH:19]([F:29])[F:18])=[N:21][N:22]([CH3:28])[CH:23]=1)=[O:26]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 56 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (3.92 g, 0.014 mol) prepared as described in example P5a in xylene (30 g) was added an aqueous sodium hydroxide solution (30%, 2.3 g, 0.017 mol) in parallel to the addition of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (3.2 g, 0.046 mol) dissolved in xylene (10 g) at 56° C. during 2 hours. After complete addition of acid chloride the mixture was stirred 2 hours at 56° C. The solution was washed twice with water (10 and 5 g) and the volatiles were removed from the organic layer under reduced pressure. The resulting crude mass 7.4 g (sticky dark brown oil) was purified by crystallization from a mixture of xylene (7 g) and methylcyclohexene (14 g) to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]amide (5.3 g, 87.8%) as off white solid. m.p: 115-116° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C@H:6]1[C@H:11](OS(C)(=O)=O)[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7]1>CN(C=O)C.O.C(Cl)Cl>[N:1]([C@H:11]1[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:7][C@H:6]1[F:5])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@H](F)C1
Temperature: 115 °C

Procedure:
Sodium azide (4.045 g, 62.22 mmol) was added to a solution of (trans)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (3.700 g, 12.44 mmol) dissolved in DMF (25 mL). The reaction was heated to 115° C. for 24 hours. The mixture was cooled and diluted with water and methylene chloride. After separation, the organic layer was dried over Na2SO, filtered and concentrated in vacuo to provide the desired product (quantitative yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[C:14]([O:25][CH3:26])[CH:13]=1)P(OCC)(=O)OCC.[CH:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[C:28]1=O)[CH2:34]2.P(=O)([O-])[O-].[Li]CCCC>C1COCC1>[CH3:26][O:25][C:14]1[CH:13]=[C:12]([C:3]([O:2][CH3:1])=[C:28]2[CH:29]3[CH2:35][CH:33]4[CH2:32][CH:31]([CH2:36][CH:27]2[CH2:34]4)[CH2:30]3)[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH:15]=1
Reactant: CCOP(=O)(OCC)C(OC)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Temperature: -68 °C
Reaction time: 0.08 h

Procedure:
Phosphonate 30, dissolved in anhydrous THF, is cooled to -68° C. under an argon atmosphere. Similarly, 2-adamantanone (1.1 eq) is dissolved in anhydrous THF and cooled to -68° C. under argon in a separate flask. To the phosphonate solution is added 2.5 M nBuLi at -68° C. under argon until the red color of the ylid persists. At this point, 1.2 eq nBuLi is added to complete the ylid formation and the resulting colored solution is stirred at -68° C. for 5 min. While maintaining the low temperature, 2-adamantanone in THF is slowly added to the ylid over an hour. After the final addition of ketone, the reaction mixture is stirred for 2 h while warming to room temperature. The reaction is then heated at reflux for 1 h, cooled and quenched by partitioning with EtOAc and saturated NH4Cl. The organic layer is dried over Na2SO4 and chromatographed with EtOAc/hexanes on a silica gel column to give enol ether 31.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14](C)=[C:15]([CH3:18])[C:16]=1[NH2:17])=[O:11]>C(O)=O>[CH3:8][O:9][C:10]([C:12]1[S:13][CH:14]=[C:15]([CH3:18])[C:16]=1[NH:17][CH:1]=[O:3])=[O:11]
Reactant: COC(=O)c1sc(C)c(C)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)c1scc(C)c1NC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Formic acid (53 mL) was added to acetic anhydride (53 mL) while cooling in an ice bath. Solid methyl 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (1, 18.2 g, 0.11 mol) was added to the cold solution in small portions. The cooling bath was removed and the resulting suspension was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (100 mL) and the solid product collected by vacuum filtration to yield 3-(formylamino)4-methyl-2-thiophenecarboxylic acid methyl ester (20.2 g, 95% yield) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.FC1C(F)=C(F)C(F)=C([O:22][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]2[C@@H:37]3[C@@H:32]([NH:33][C:34]([NH:36]3)=[O:35])[CH2:31][S:30]2)=O)C=1>CN(C=O)C>[C:23]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])(=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:37]2[C@@H:32]([NH:33][C:34]([NH:36]2)=[O:35])[CH2:31][S:30]1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2cc(F)c(F)c(F)c2F)N1
Reactant: CC(N)CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Preparation was accomplished as described by Wilbur [Bioconj. Chem. 1997, 8, 572]. To a 0.13 g (1.3 mmol) quantity of 3-aminobutyric acid dissolved in 20 mL of DMF under argon atmosphere was added 0.4 mL (2.5 mmol) of triethylamine followed by 0.5 g (1.3 mmol) of biotin tetrafluorophenyl ester. The reaction was stirred at 25° C. for 24 h and the solvent was removed under vacuum. The residue was triturated with acetonitrile and filtered. The isolated solid was dried under vacuum to yield 0.5 g (98%) of product as a colorless solid, mp 161-163° C. 1H NMR (DMSO-d6): O 7.6 (m, 1H), 6.2 (d, J=11.2 Hz, 2H), 3.9-4.2 (m, 3H), 2.6 (m, 2H), 2.35 (d, J=12.6 Hz, 1H), 1.7-2.1 (m, 4H), 0.7-1.5 (m, 10H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])=[CH:5][CH:6]=1
Reactant: CCOP(=O)(/C=C/c1ccncc1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CCc1ccncc1)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
Diethyl (E)-2-(4-pyridyl)ethenylphosphonate (10.3 g, 42 mmol) was dissolved in ethanol (25 ml), and 10% palladium-carbon (1.0 g) was added thereto. The mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs. Palladium-carbon was filtered off, and the filtrate was concentrated to give the titled compound (10.3 g, 100%).