Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C>C1COCC1>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:20]([OH:23])[OH:21])=[C:3]([O:13][CH3:14])[CH:4]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COc1cc(-n2ccnc2)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-n2ccnc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-bromo-3-methoxyphenyl)-1H-imidazole in THF (5 mL) was added 2.5 M n-butyl lithium in hexanes (0.348 ml, 0.869 mmol) dropwise at −78° C. over 15 min. After addition was complete, the reaction solution was stirred at −78° C. for 15 min, and trimethyl borate (0.353 mL, 3.16 mmol) was added. The reaction was allowed to warm to RT, and continued to stir overnight. The reaction was quenched with 1 M HCl aqueous solution to pH 2, diluted with water and extracted with DCM (3×). The product remained in the aqueous solution which was concentrated in vacuo to give crude (4-(1H-imidazol-1-yl)-2-methoxyphenyl)boronic acid (120 mg, MS: 219.2 [M+H+]).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH:15]([CH3:29])[C:16]([C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=1)=O.FC1C=C(C2N=C(C3C(C)=C(C(OC)=S)SC=3)SC=2C)C=C(C(F)(F)F)C=1.C1C(/C=C(/C(O)=O)\C#N)=CC=C(O)C=1>>[F:28][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][C:15]=2[CH3:29])[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=1
Reactant: CC(Br)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Agent: COC(=S)c1scc(-c2nc(-c3cc(F)cc(C(F)(F)F)c3)c(C)s2)c1C
Agent: N#C/C(=C\c1ccc(O)cc1)C(=O)O
Product: COC(=S)c1cc(-c2nc(-c3cc(F)cc(C(F)(F)F)c3)c(C)s2)c(C)s1

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 90 mg (0.3 mmol) of 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one in a manner similar to Example 8, step (a) to give, methyl 4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-methylthiothiophene-2-carboxylate (31.9 mg, 24%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.17 (s, 1H), 7.98 (m, 1H), 7.95 and 7.92 (m, 1H, 1:1 ratio conformers), 7.77 and 7.74 (m, 1H, 1:1 ratio conformers), 3.87 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H13NO2S3F4, 448.0 (M+H), found 448.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([Cl:27])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:27].[CH3:9][C:10]1[C:11]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(N2CCc3ccccc3C2)nc(Cl)c1C
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3C2)nc(N(C)c2ccccc2)c1C
Product: Cl
Yield: 36.8 %

Procedure:
After N-methylaniline(0.5 ml, 4.2 mmol) was added to a mixture solution of 5,6-dimethyl-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.6 g, 2.0 mmol) and dimethylformamide(10 ml), 0.28 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [CH3:1][C:2]([CH:14]([CH3:21])[CH2:15][CH:16]=[C:17]([CH3:20])[CH2:18][CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.ClCCl>[O:30]1[C:17]([CH3:20])([CH2:18][CH3:19])[CH:16]1[CH2:15][CH:14]([CH3:21])[C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(C)=CCC(C)C(C)=CCOc1ccc(CC)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(OCC=C(C)C(C)CC2OC2(C)CC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10 g. of p-ethylphenyl 3,4,7-trimethyl-2,6-nonadienyl ether are dissolved in 110 ml. of dichloromethane and treated portionwise at -10° C. with 7.8 g. of 80% m-chloroperbenzoic acid. After completion of the treatment, the mixture is stirred for a further 2 hours at 0° C., shaken out with 10% sodium sulfite solution, 1-N sodium hydroxide solution and water, dried over sodium sulfate and evaporated. There is obtained pure 6,7-epoxy-1-(p-ethylphenoxy)-3,4,7-trimethyl-2-nonene; NMR (CDCl3): 7.25-6.7 ppm (AB-quartet of the four aromatic protons); 5.5 ppm (a vinyl proton at C-2); 4.52 ppm doublet of the --O--CH2 group); 2.59 ppm (quartet of the aromatic-bound --CH2 group); 2.8-2.2 ppm (multiplet of the protons at C-4 and C-6); 1.65 ppm (wide singlet of the methyl group at C-3); 1.78-0.8 ppm (complicated multiplet of 19 protons).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][N:8]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:7]1=[O:23]>C(#N)C.O>[N:1]([CH:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][N:8]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:7]1=[O:23])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C(Br)CC(c2ccccc2)CCN1CC1CC1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=NC1CC(c2ccccc2)CCN(CC2CC2)C1=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Sodium azide (0.24 g, 3.72 mmol) was added to a solution of 3-bromo-1-(cyclopropylmethyl)-5-phenylazepan-2-one (0.3 g, 0.93 mmol) in acetonitrile (4 mL) and water (1 mL), and the mixture heated to 100° C. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with water (3×), saturated brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17]>ClCCl.CCOCC>[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]
Reactant: OCc1cccc(I)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
A suspension of pyridinium chlorochromate (2.45 g, 11.4 mmol) and dry celite (˜2.00 g) in dry dichloromethane (20 ml) was stirred at room temperature for 15 min. 3-Iodobenzyl alcohol (11) (1.02 g, 4.35 mmol) in dry dichloromethane (5 ml) was added. The suspension was shielded from light and stirred at room temperature for 2 h after which it was diluted with ether, and filtered through celite. The cloudy brown filtrate was concentrated to a red-brown gummy paste which was re-dissolved in dichloromethane and passed through a short silica column, eluting with dichloromethane. This gave a clear, colourless solution which was concentrated to give 3-iodobenzaldehyde (12) as a white solid (0.953 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]
Reactant: NCCc1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccccc1Cl

Procedure:
In close analogy to the procedure described above, 2-(2-chloro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[S:3])[NH2:2].Br[CH:24]([CH2:34][CH3:35])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]>>[Cl:18][C:16]1[N:17]=[C:13]([C:11]([NH:10][C@H:7]2[CH2:8][CH2:9][N:4]([C:1]3[S:3][C:24]([CH2:34][CH3:35])=[C:25]([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[N:2]=3)[CH2:5][C@H:6]2[O:21][CH3:22])=[O:12])[NH:14][C:15]=1[CH2:19][CH3:20]
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(N)=S)C[C@H]2OC)nc1Cl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)sc1CC
Yield: 78 %

Procedure:
The same operation as in Example (22b) was performed using cis(±)-N-(1-carbamothioyl-3-methoxypiperidin-4-yl)-4-chloro-5-ethyl-1H-imidazole-2-carboxamide obtained by the method described in Example (65c) (78.5 mg, 0.23 mmol) and butyl 3-bromo-2-oxopentanoate obtained in Example (110a) (95 mg, 0.38 mmol), to obtain 87.8 mg of the title compound (78%).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH2:9](CN)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:18]([N:20](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:9]([N:20]([CH3:18])[C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: NCCc1ccccc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)C1CC(=O)C1
Yield: 64.9 %

Procedure:
Acid, 3-oxocyclobutanecarboxylic acid (12.7 g, 0.11 mol), N-benzylmethylamine (15.7 mL, 0.12 mol), and triethylamine (48 mL, 0.33 mol) were dissolved in DMF (100 mL). BOP (49 g, 11 mol) was added at 0° C. under stirring in argon. The mixture was stirred at 20° C. for 20 h, evaporated, and the residue was dried at 0.5 mmHg. The residue was purified by chromatography (silica gel, 63-100 μm, 750 mL, CCl4→CHCl3, CHCl3/MeOH 100:0→95:5). The title compound (15.5 g, 64%) was obtained as a colorless oil. 1H NMR-data (DMSO-d6): 7.20 (m, 5H, Ph); 4.62 s, 4.55 s (2H, CH2); 3.46-3.62 (m, 1H); 3.28 (m, 4H,); 2.85 s, 2.94 s (3H, NCH3).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[Br:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[C:25](Cl)=[O:26].Cl>C(#N)C>[Br:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[C:25]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[O:26]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.9 g (0.167 mol) of magnesium chloride in 150 ml of anhydrous acetonitrile (dried over zeolite) are initially introduced into the reaction vessel and 26.9 g (0.167 mol) of diethyl malonate are added dropwise, while cooling. The mixture is cooled to 0° C., 46 ml (33.7 g=0.33 mol) of triethylamine are added dropwise and the mixture is subsequently stirred for 30 minutes. 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride are then added dropwise and the mixture is subsequently stirred at 0° C. for a further hour and brought to room temperature overnight. 100 ml of 5N hydrochloric acid are added, the mixture is extracted three times with methylene chloride and the extract is dried with Na2SO4 and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]([P:8]([OH:11])([OH:10])=[O:9])([P:4]([OH:7])([OH:6])=[O:5])[OH:3].[O-2].[Zn+2:13]>>[Zn:13].[CH3:1][C:2]([P:8]([OH:11])([OH:10])=[O:9])([P:4]([OH:7])([OH:6])=[O:5])[OH:3]
Reactant: [Zn+2]
Agent: CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [O-2]
Product: [Zn]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
First, 790 g of a solution of etidronic acid (158 g as etidronic acid) was heated to 70° C. and 461 g of a zinc oxide slurry (92.2 g as zinc oxide) held at 70° C. was added dropwise over about 30 minutes with constant stirring. The mol ratio of zinc oxide to etidronic acid was 1.5/1. This slurry was stirred at 60° to 70° C. for 4 hours, after which it was cooled to room temperature. The slurry was then filtered and the dehydrated cake was washed with distilled water 3 to 5 times. It was then filtered, dried and pulverized to give zinc etidronate.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[NH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20].CC(C)([O-])C.[Li+].F[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[CH:30][N:29]=1>CN(C)C=O.C1COCC1>[CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[CH:16]=[CH:17][N:18]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][O:39]5)=[CH:30][N:29]=4)[N:19]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20]
Reactant: Fc1ccc(OCCOC2CCCCO2)cn1
Reactant: COCn1c(=O)sc2cc(C(C)c3ccn[nH]3)ccc21
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCn1c(=O)sc2cc(C(C)c3ccn(-c4ccc(OCCOC5CCCCO5)cn4)n3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Dissolve 3-(methoxymethyl)-6-[1-(1H-pyrazol-5-yl)ethyl]-3H-1,3-benzothiazol-2-one (7.7 g, 26.6 mmoles) in dimethylformamide (0.2 M; 133 mL). Add lithium t-butoxide ((1.5 Eq of a 1.00 molar solution in THF), 39.9 mmoles; 39.9 mL)) and stir 15 min. Add 2-fluoro-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (2.00 Eq; 53.2 mmoles; 12.8 g). Heat the reaction in an oil bath to 140° C. and purge with N2 to remove THF. Heat the mixture at reflux for 5 hr. Cool the mixture to room temperature and quench with saturated ammonium chloride. Extract into EtOAc (2×200 mL), wash with water (2×100 mL), followed by brine (200 mL). Dry over sodium sulfate, filter and concentrate. Purify by HPLC (silica) eluting with 40% EtOAc/hexanes to give 3-(methoxymethyl)-6-{1-[1-(5-{2-(tetrahydro-2H-pyran-2-yloxy)ethoxy}pyridine-2-yl)-1H-pyrazol-3-yl]ethyl}-3H-1,3-benzothiazol-2-one as a pale yellow oil (10 g; 19.6 mmoles, 74% yield). LCMS (low) rt=2.6, M+1=511.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]=CC=C[N:5]2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.C[CH2:22][OH:23].[OH2:24].NN>>[CH:22]([O-:23])=[O:24].[CH3:1][C:2]1[N:3]=[C:4]([NH3+:9])[NH:5][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1
Reactant: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Reactant: O
Reactant: CCO
Agent: NN
Product: Cc1nc([NH3+])[nH]c1-c1ccc(C(F)(F)F)cc1
Product: O=C[O-]
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Suspend 2-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine (2.176 g, 7.849 mmol) in EtOH (15.00 mL, 257.646 mmol). Add hydrazine hydrate (4.00 mL, 81.821 mmol). Heat to 125° C. with microwave irradiation. Stir for 30 minutes, and concentrate under reduced pressure. Dissolve the residue in EtOAc (75 mL); wash the organic extracts with water (3×50 mL); and then wash with a saturated NaCl aqueous solution (50 mL). Dry the organic extracts over Na2SO4; filter; collect the filtrate; and concentrate the filtrate in vacuo. Purify by reverse phase flash chromatography (Analogix® 150 g @ 40 mL/min) eluting with a gradient of 5-30% ACN/water over 35 minutes. Material precipitates upon loading samplet. Collect the resulting white material from the samplet and reflux it MeOH for 15 minutes. Filter the MeOH mixture through diatomaceous earth collect the filtrate, and wash the diatomaceous earth with MeOH. Concentrate the combined filtrates under reduced pressure to give the title compound (1.643 g, 72.9% yield) as a white crystalline solid. 1H NMR (400.43 MHz, d6-DMSO) δ 13.14-13.11 (m, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.47 (s, 2H), 2.26 (s, 3H). ES/MS (m/z) 241.99 (parent+1, formate not detected).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13](C(O)=O)=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P([N:42]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(Cl)Cl.[C:48]([O-:51])(O)=O.[Na+]>O1CCOCC1>[CH:1]1([N:7]2[C:8]3=[C:9]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:10]4=[N:11][CH:12]=[C:13]3[NH:42][C:48]2=[O:51])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(=O)O)cnc21
Reactant: O=C([O-])O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1[nH]c(=O)n(C3CCCCC3)c12
Temperature: 100 °C
Yield: 70 %

Procedure:
4-(Cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.713 g, 1.83 mmol) and TEA (0.638 mL, 4.58 mmol) were combined in 1,4-dioxane (14 mL) to give a suspension. The mixture was stirred until the suspension had dissolved. Diphenylphosphoryl azide (0.790 mL, 3.66 mmol) was added and the reaction heated at about 100° C. for about 5 h. DCM (50 mL) and saturated aqueous NaHCO3 (25 mL) were added and the layers separated. The aqueous layer was extracted with DCM (25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (40 g Silicycle™ column) eluting with 20-80% EtOAc in DCM. The solvents were removed under reduced pressure. The material was triturated with heptane and the solid was collected by vacuum filtration and washed with heptane. The solid was dried under vacuum at about 50° C. to a constant weight to give 1-cyclohexyl-6-((2-(trimethylsilyl)ethoxy)methyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.501 g, 70%): LC/MS (Table 2, Method b) Rt=2.78 min.; MS m/z: 387 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][CH3:9])=[CH:4][F:5].[FH:16]>>[F:1][C:2]([F:14])([F:15])[CH:3]([C:6]([F:12])([F:13])[C:7]([F:11])([F:10])[CH2:8][CH3:9])[CH:4]([F:16])[F:5]
Reactant: F
Reactant: CCC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Product: CCC(F)(F)C(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,3,3,4,4-heptafluorohexane may be prepared by fluorinating commercially available 3,4-hexanedione to form 3,3,4,4-tetrafluorohexane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-hexene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-hexene to form 2-trifluoromethyl-1,3,3,4,4-pentafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoro-1-hexene which may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,1,3,3,4,4-heptafluorohexane.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[N+:2]=[N-:3].N[C@@H](CC1C=CC(OC)=CC=1)C[OH:19].COC1C=CC(C[C@@H](C(O)=O)N)=CC=1.O[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]([CH3:53])[C:45]=1[C:54]([OH:56])=O>>[N:1]([CH2:4][C@@H:5]([NH:15][C:54]([C:45]1[N:46]([CH3:53])[C:47]2[C:52]([CH:44]=1)=[C:51]([OH:19])[CH:50]=[CH:49][CH:48]=2)=[O:56])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: Cn1c(C(=O)O)c(O)c2ccccc21
Reactant: COc1ccc(C[C@H](N)CN=[N+]=[N-])cc1
Reactant: COc1ccc(C[C@H](N)CO)cc1
Agent: COc1ccc(C[C@H](N)C(=O)O)cc1
Product: COc1ccc(C[C@@H](CN=[N+]=[N-])NC(=O)c2cc3c(O)cccc3n2C)cc1

Procedure:
From (S)-1-azido-3-(4-methoxyphenyl)-2-propanamine [prepared by an adaptation of a method described by Horwell, et al., J. Med. Chem., 1991, 404–414 from (S)-2-amino-3-(4-methoxyphenyl)-1-propanol (prepared from O-methyl-L-tyrosine by an adaptation of a method described by Sutherland, et al., J Org Chem, 1998, 7764–7769] and 4 hydroxy-1-methyl-1H-indole-2-carboxylic acid the title compound was prepared by a method analogous to that described in Example 13. MS ES (M++H)=380.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH:19]([CH3:25])[C:20](OCC)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C.O1CCCC1.C(OCC)C>[CH:13]1([CH:19]([CH3:25])[C:20](=[O:21])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)C(C)C1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)C1CCCCC1)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
74.5 g. of dimethyl methylphosphonate were dissolved in 514 ml. of tetrahydrofuran and the solution cooled to -60°C. To this solution a solution of butyllithium [prepared from 40.5 g. of butyl bromide and 9.2 g. of lithium] in 240 ml. of diethyl ether was added dropwise. A solution of 39.5 g. of ethyl 2-cyclohexylpropionate in 130 ml. of tetrahydrofuran was added drop-wise and the mixture stirred at the same temperature for two hours and afterwards at 0°C. overnight. The reaction mixture was then neutralised to pH 7 with acetic acid, concentrated under reduced pressure and, after the addition of water to the residue, extracted with diethyl ether. After drying the ethereal extract, the solvent was distilled off and the residue subjected to distillation under reduced pressure to obtain 40 g. (yield 30.2%) of the title compound as a colourless oil, b.p. 140°C./0.2-0.3 mm.Hg. Nuclear magnetic resonance (hereinafter abbreviated to NMR) spectrum (tetrachloromethane): δ = 3.82 (6 H, doublet, 3.18 (2H, doublet), 2.80 - 2.30 (1H, multiplet), 2.1 - 0.65 (14H, multiplet).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](O)[CH:5]=[CH:4][C:3]1=2.[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)#[N:17].[C:26](=[O:29])([O-])[O-].[K+].[K+].O>CC(=O)CC.CN(C)C=O>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:4]2[C:3]3[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=[CH:6][C:5]=2[O:29][C:26]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[C:7]=2[CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: N#Cc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2c1ccc(Oc1ccc3c(c1Cc1ccc(C#N)cc1)C(C)(C)CCC3(C)C)c2Cc1ccc(C#N)cc1
Yield: 101.5 %

Procedure:
40.8 g (0.2 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthol, 30.4 g (0.2 mol) of 4-cyanobenzyl chloride and 80 g (1.2 mol) of anhydrous potassium carbonate in 400 ml of butanone and 300 ml of dimethylformamide were refluxed for 9 h. The mixture was cooled and then poured into 1.5 l of water, and the solid was filtered off with suction and washed with water. Drying resulted in 63 g of the title compound of melting point 149°-150° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:3]=1
Reactant: Cc1cccc(CBr)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.7 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (172 mg, 0.596 mmol) (prepared as in Example 1, step E) in dry N,N-dimethylformamide (3 mL) under an atmosphere of dry nitrogen was added 2-(bromomethyl)-6-methylpyridine (122 mg, 0.656 mmol) and potassium carbonate (165 mg, 1.19 mmol) with magnetic stirring. The mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with water (20 mL) and extracted into ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified using preparative chromatography on silica, eluting with hexane/ethyl acetate (3:1) to give 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (213 mg).