Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cc2)CC1
Yield: 75 %

Procedure:
A solution of tert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 1.1, 36 g, 101.05 mmol, 1.00 equiv), Pd(PPh3)4 (11.7 g, 10.12 mmol, 0.05 equiv), and Zn(CN)2 (17.9 g, 152.44 mmol, 1.51 equiv) in DMF (400 mL) under nitrogen was stirred overnight at 80° C. After reaching ambient temperature, the reaction was then quenched by the addition of 600 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×300 mL of ethyl acetate. The combined organic layers were washed with 1×200 mL of potassium carbonate (aq., sat.) followed by 1×200 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:5) as eluent to yield 23 g (75%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH2:16])=[O:10])=[CH:4][C:3]=1[CH3:17].BrC1C=CC(N)=CC=1C.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][CH2:36][C:29]2[C:30]3[C:35](=[N:34][CH:33]=[CH:32][CH:31]=3)[NH:27][CH:28]=2)=[O:10])=[CH:4][C:3]=1[CH3:17]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: Cc1cc(NC(=O)c2sccc2N)ccc1Br
Agent: Cc1cc(N)ccc1Br
Product: Cc1cc(NC(=O)c2sccc2NCc2c[nH]c3ncccc23)ccc1Br

Procedure:
EXAMPLE 9 was prepared according to the procedure described in EXAMPLE 5 using N-(4-bromo-3-methylphenyl) 3-aminothiophene-2-carboxamide (prepared as described in EXAMPLE 1, part 1, using 4-bromo-3-methylaniline instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (EXAMPLE 8, part 1) instead of 2-(N-methylcarbamoyl)pyridine-4-carboxaldehyde. MS (ES+): 441, 443 [MH+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=O)[N:13]=[N:12]1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([NH:20][C:21]2[C:22](=[O:34])[N:23]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[N:24]([CH3:27])[C:25]=2[CH3:26])=[O:19])[N:13]=[N:12]1
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(C2CC2)cc1Cl
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(C2CC2)cc1Cl
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
1-(2-Chloro-4-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (15 g, 54.0 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A)(11.30 g, 54.0 mmol) were slurried in EtOAc (150 mL). The reaction mixture was cooled to 10° C. and triethylamine (18.82 mL, 135 mmol) was added dropwise, followed by dropwise addition of T3P (50% w/w in EtOAc) (47.7 mL, 81 mmol) over 15 mins, maintaining a temperature <10° C. The reaction mixture was allowed to warm to RT and stirred for 2.5 hrs. The resulting mixture was quenched with sat. sodium bicarbonate (aq) (150 ml). The layers were separated and the organic layer was washed with sat. sodium bicarbonate (aq) (50 ml), water (150 ml) and brine (150 ml). The organic extracts were dried over MgSO4 and charcoal. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The crude material was slurried in ethyl acetate (335 ml) and heated to reflux with stirring. The hot mixture was filtered and the filtrate was seeded and at left to stand at room temperature overnight. The resulting crystalline solid was collected by filtration and dried under reduced pressure at 40° C. over 2 days to yield the title compound.
Reaction SMILES: Br[CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.N1C=CN=C1C(C(C(C1NC=CN=1)=O)=O)=O.O>C(#N)C>[CH3:5][C:4]([C:3]([CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[N:17]1[CH:18]=[N:19][CH:20]=[CH:21]1)=[O:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=C(C(=O)c1ncc[nH]1)C(=O)c1ncc[nH]1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1

Procedure:
The antigingivitis agent utilized in present invention is 1-imidazoyl-(p-chlorophenoxy)3-3-dimethyl 2-butanone having the structural formula: ##STR2## which is prepared by reacting 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone with imidazole dissolved in acetonitrile as disclosed in U.S. Pat. Nos. 3,812,142 and 3,903,287, which is made a part of this specification. This imidazoyl ketone is a water insoluble crystalline powder having a melting point of 94.5°-97.8° C. which may be obtained from the Bayer Company as Climbazole. Due to the water insolubility of this imidazole compound, it must first be solubilized in a nonionic compound prior to the addition of ionic materials in an aqueous medium.
Reaction SMILES: B.CSC.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[O:17][CH2:16][C:15](=O)[N:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1.CO.Cl>O1CCCC1>[ClH:5].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[O:17][CH2:16][CH2:15][N:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)N1CC(c2cccc(Cl)c2)OCC1=O
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)N1CCOC(c2cccc(Cl)c2)C1
Yield: 117.2 %

Procedure:
Borane-methyl sulphide (0.5 ml) was added dropwise, under nitrogen, to a stirred solution of 2-[3-chlorophenyl]-4-[1,1-dimethylethyl]-5-oxo-morpholine (0.85g) in dry tetrahydrofuran (40 ml). The mixture was heated under reflux for 2 h., cooled, treated with methanol (5 ml) and heated for 1 hr. The resulting solution was cooled, treated with hydrogen chloride and evaporated to give 2-[3-chlorophenyl]-4-[1,1-dimethylethyl]morpholine hydrochloride as a white solid (0.54g), m.p. 223-8° C. (ethyl acetate).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[N:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>C(N(CC)CC)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([S:2]([C:5]3[CH:6]=[CH:7][C:8]([C:9]([N:38]4[CH2:39][CH2:40][N:35]([C:32]5[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=5)[CH2:36][CH2:37]4)=[O:11])=[CH:12][CH:13]=3)(=[O:3])=[O:4])[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(S(=O)(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
4-(Chlorosulphonyl)benzoic acid (0.75 g) was added to a solution of 1-(3-chlorophenyl)piperazine dihydrochloride (0.90 g) in triethylamine (2.4 ml) and dichloromethane (50 ml). The reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The resulting solid was suspended in N,N-dimethylformamide (50 ml) and carbonyl diimidazole (0.55 g) was added. The reaction mixture was stirred for one hour at room temperature then 1-(4-pyridyl)piperazine (0.55 g, 3.4 mmol) was added. The reaction mixture was stirred for three hours, then concentrated in vacuo. The resulting solid was separated between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer was washed with aqueous saturated sodium bicarbonate solution (100 ml) then dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting yellow oil was subjected to chromatography (SiO2: 10%-12% MeOH/EtOAc) to yield 1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine as a white solid (300.1 mg);
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[C:25]([F:28])[C:24]([C:29]([F:32])([F:31])[F:30])=[C:23]([F:33])[C:22]=2[F:34])[N:19]=[CH:18][CH:17]=1)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:22]([F:34])=[C:23]([F:33])[C:24]([C:29]([F:32])([F:31])[F:30])=[C:25]([F:28])[C:26]=2[F:27])[N:19]=[CH:18][C:17]=1[N+:8]([O-:11])=[O:9])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reaction time: 4 h
Yield: 94 %

Procedure:
12.5 ml (0.13 mol) of acetic anhydride and 4.5 ml (0.105 mol) of 98 percent strength nitric acid are added in succession to 34.1 g (0.10 mol) of 5-acetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 85 ml of glacial acetic acid at about 15° C. The temperature is allowed to rise slowly to 25° C. and the mixture is subsequently stirred for 4 hours. The reaction solution is then poured onto 250 ml of water. The precipitate is filtered off, washed neutral and dried in vacuo. 36.3 g (94% of theory) of 5-acetamido-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 138° C.-140° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[C:5]([CH:6]=O)=[CH:4][C:3]=1[CH:11]=O.O=[C:14]([CH3:18])[C:15]([OH:17])=[O:16].[OH-:19].[Na+].N>O.C(O)C>[N:10]1[C:8]2[C:5](=[CH:4][C:3]3[CH:11]=[CH:18][C:14]([C:15]([OH:16])=[O:19])=[N:1][C:2]=3[CH:9]=2)[CH:6]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: [OH-]
Reactant: CC(=O)C(=O)O
Reactant: Nc1cc(N)c(C=O)cc1C=O
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2cc3ccc(C(=O)O)nc3cc2n1
Temperature: 80 °C

Procedure:
To 4,6-diaminoisophthalaldehyde (1,64 g) and 2-oxopropionic acid (1.94 g), ethyl alcohol (40 cc) was added and 2N sodium hydroxide solution (12.8 cc) was added with stirring at 80° C. and allowed to react for 4 hours. Then, 2-oxopropionic acid (0.41 g) and 2N sodium hydroxide solution (3 cc) were added and refluxed for 2 hours. After the addition of 2N aqueous ammonia (50 cc) and water (130 cc) and heating and filtration, charcoal was added with stirring. Refiltration and pH adjustment to 4-5 by 0.6N hydrochloric acid and 0.3N acetic acid a5 70°-80° C. gave solid which is hard to dissolve.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[ClH:1].[Cl:25][C:23]1[CH:22]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:28][CH2:27]2)[CH:20]=[C:19]([Cl:18])[CH:24]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cc(Cl)cc(Cl)c3)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3,5-dichlorophenyl)-piperazine.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[N:14][N:15]=[C:8]1[CH:7]=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:26].[Na+]>[Ru](=O)=O>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[CH:11][C:10]([N:9]2[CH:13]=[N:14][N:15]=[C:8]2[CH3:7])=[C:5]([CH:4]=1)[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:26]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: FC(F)(F)c1ccc2c(c1)c(-c1ccccc1Cl)cc1nncn12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-(trifluoromethyl)-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-(trifluoromethyl)-2'-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1)([O-])=O.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:12]1([O:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OC2CCCC2)nc1
Temperature: 80 °C

Procedure:
A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 ml) was heated at 80° C. for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyloxy-5-nitropyridine) was hydrogenated by method B. This resulted in the product with the molecular weight of 178.24 (C10H14N20); MS (ESI): 179 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:20]([NH2:21])=[C:19]([CH3:25])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OCC)(=O)C>C1COCC1>[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:20]([NH:21][C:2]2[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=2)=[C:19]([CH3:25])[CH:18]=1
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Reactant: Cc1cc(Br)cc(C)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(COC)n1cc(Cl)nc(Nc2c(C)cc(Br)cc2C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
To (+/−)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (300 mg) and 4-bromo-2,6-dimethylaniline (238 mg) in THF (anhydrous, 9.4 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0 M/THF, 2.6 mL). The mixture was stirred at 0° C. for 10 minutes. Ethyl acetate (100 mL) was added and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4 and concentrated and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. The product was then crystallized from ethyl acetate/hexane to afford the title compound (419 mg). Elemental analysis calcd. for C17H21N3O2BrCl: C, 49.23; H, 5.10; N, 10.13. Found: C, 49.33; H, 5.05; N, 10.09.
Reaction SMILES: [CH:1]1([C:7]2[C:11]([CH2:12][C:13]3[CH:20]=[CH:19]C(C#N)=[CH:15][CH:14]=3)=[CH:10][N:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:32].[K+].[CH2:34]([OH:36])[CH3:35]>O>[CH:1]1([C:7]2[C:11]([CH2:12][C:13]3[CH:20]=[CH:19][C:35]([C:34]([OH:32])=[O:36])=[CH:15][CH:14]=3)=[CH:10][N:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: N#Cc1ccc(Cc2cn(-c3ccc(OC(F)(F)F)cc3)nc2C2CCCCC2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(Cc2cn(-c3ccc(OC(F)(F)F)cc3)nc2C2CCCCC2)cc1
Reaction time: 17 h

Procedure:
To a hot solution of 0.63 g 4-({3-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methyl)benzonitrile From Step A above in 20 mL ethanol and 6 mL water was added 0.96 g potassium hydroxide. The resulting solution was refluxed under nitrogen for one day. HPLC showed some amide intermediate remaining. Add 1.05 g potassium hydroxide in 2 mL water and 4 mL ethanol. Reflux continued for another 17 hours. The solvents were removed under reduced pressure. The residue was re-suspended in 5 mL water and acidified with 18.0 mL 2 N HCl. The resulting solid was filtered, washed with water, and dried to give the title compound as a white solid. 1H NMR (CD3OD, 500 MHz) δ 7.93˜7.95 (m, 2H), 7.91 (s, 1H), 7.75˜7.79 (m, 2H), 7.32˜7.36 (m, 4H), 3.95 (s, 2H), 2.60 (tt, J=3.2 & 11.8 Hz, 1H), 1.68˜1.81 (m, 5H), 1.51˜1.60 (m, 2H), 1.22˜1.36 (m, 3H). LC-MS: 2.51 min. (M+H=445.2).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11](Br)[CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14]>C1COCC1.CCCCCC>[O:4]=[C:3]([CH2:5][CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (225 μL, 2.1 mmol) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension, prewashed with hexane) (100 mg, 2.1 mmol) in anhydrous THF (5 mL) at 0° C. under an Argon atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6M solution (1.3 mL, 2.1 mmol) of n-butylithium in hexane over 2 minutes. The yellow solution was stirred 15 min at 0° C. and then treated dropwise with farnesyl bromide (545 μL, 2.0 mmol). The cloudy orange solution was stirred at 20° C. for 11/2 hours and then quenched by dropwise addition of saturated aqueous NH4Cl solution. The resulting mixture was diluted with ethyl acetate and washed with water, dried, filtered and evaporated to give the crude product which was used in the next step without purification.
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][NH2:15]>C(O)C>[CH2:12]([P:1](=[O:2])([O-:5])[O-:8])[CH3:13].[CH3:10][O:11][CH2:12][CH2:13][CH2:14][NH3+:15].[CH3:10][O:11][CH2:12][CH2:13][CH2:14][NH3+:15]
Reactant: COCCCN
Reactant: CCOP([O-])OCC
Solvent: O
Solvent: CCO
Product: CCP(=O)([O-])[O-]
Product: COCCC[NH3+]
Yield: 94.3 %

Procedure:
A mixture of 13.81 g. of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 8.91 g. (0.1 moles) of 3-methoxypropyl amine and 30 ml. of ethanol as described in Example 1. 18.8 g. of 3-methoxypropyl-ammoniumethyl phosphonate are obtained. Yield: 94.3%. nD30 =1,4440
Reaction SMILES: [Br:1][C:2]1[N:10](C(OC(C)(C)C)=O)[C:9]2[C:4](=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[C:3]=1[CH2:20][C:21]([O:23]CC)=[O:22].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccc(OC)nc12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2[nH]c(Br)c(CC(=O)O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
tert-Butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (380 mg, 0.9 mmol) was dissolved in 12 mL of THF/MeOH/H2O (3/2/1) and to it was added LiOH.H2O (116 mg, 2.7 mmol). The reaction mixture was allowed to stir at ambient temperature for 3 hours and then purified by RP HPLC eluting with acetonitrile/water to afford 220 mg of 2-(2-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. Dissolved 200 mg of the above acid (0.7 mmol) and (S)-methyl 3-(3-allylphenyl)-2-aminopropanoate hydrochloride (197 mg, 0.77 mmol) in 5 mL of DMF and to it was added N,N-diisopropylethylamine (366 μL, 2.1 mmol). The reaction mixture was cooled down to 0° C. and to it was added HATU (319 mg, 8.4 mmol), and then it was allowed to stir at ambient temperature for 20 minutes. The reaction mixture was purified by RP HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford 210 mg (0.43 mmol) of (S)-methyl 3-(3-allylphenyl)-2-(2-(2-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamido)propanoate which was dissolved in 5 mL of CH2Cl2 and cooled down to 0° C. To it were added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol), di-tert-butyl carbonate (113 mg, 0.86 mmol) and 4-dimethylaminopyridine (5.2 mg, 0.04 mmol). The resulting mixture was allowed to stir for 5 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to dryness. It was purified by silica gel chromatography eluting with EtOAc/hexanes) to afford 230 mg of (S)-tert-butyl 3-(2-(3-(3-allylphenyl)-1-methoxy-1-oxopropan-2-ylamino)-2-oxoethyl)-2-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate MS (m/z): 586.0 [M+H]+; HPLC retention time 4.86 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([O:11][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(F)c1I
Temperature: 60 °C
Yield: 74.2 %

Procedure:
1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (13 g, 41 mmol) was dissolved in DMF (41.3 mL). Methyl iodide (3.9 mL, 62 mmol) was added followed by potassium carbonate (11 g, 83 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature, diluted with ether, washed with water, dried over MgSO4, concentrated. The residue was purified on silica gel (eluting with 0 to 10% EtOAc in hexanes) to give the desired product (10 g, 70%). LCMS calculated for C9H8ClFIO2 (M+H)+: m/z=328.9. found: 328.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: CCCCCCCCCC(I)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 865 mg of diiododecane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethyl acetate 4:1). The product is obtained as an oil. C34H40F2INO3 (675) MS (ESI): M+−18