Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1C(OCC)=O.[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>CN(C=O)C.O>[C:17]1([S:23]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21

Procedure:
To a stirred and cooled (to about 0° C.) solution of ethyl indole-2-carboxylate 10 (1 eq.) in DMF (2 ml/mmol) under N2, was added NaH (60% in oil, 1.2 eq.) portionwise. When gas evolution stopped, benzenesulfonyl chloride (1.2 eq.) was added. The reaction mixture was stirred for about 1 hour (TLC monitoring, eluent dichloromethane); a small amount of water then was added carefully and the DMF was evaporated. The crude residue was dissolved in ethyl acetate and washed with water and brine. After drying and evaporation of the solvents, the compound was purified by chromatography on silica gel (eluent: C6H12/EtOAc 9/1 to 7/3) to give the N-phenylsulfonylindole 62c.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(C(CC)=O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH2:6][C:5]2=[O:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.2 g (131.2 mmol) of 6-hydroxy-2,2-dimethylchroman-4-one were introduced into 350 ml of diethyl ketone with stirring at RT and, after addition of 18.0 g (131 mmol) of powdered potassium carbonate, stirred at 75° C. for 30 min. After cooling to 60° C., 15.7 ml (131 mmol) of benzyl bromide were added dropwise, the mixture was concentrated in vac. after 2 h, the residue was treated with water and the solid was filtered off with suction, 37 g, m.p. 105-107° C.
Reaction SMILES: C(NC(=O)[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C@@H:34]([CH3:47])[C:35](N[C@H](C)CC2C=CC=CC=2)=[O:36])[CH:25]=1)[CH2:11][CH3:12])C1C=CC=CC=1.[OH:49]S(O)(=O)=O>O1CCOCC1>[CH2:11]([NH:10][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([C@@H:34]([CH3:47])[C:35]([OH:36])=[O:49])[CH:25]=1)[CH3:12]
Reactant: O=S(=O)(O)O
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)N[C@H](C)Cc2ccccc2)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1
Solvent: C1COCCO1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)cc(C(F)(F)F)c1

Procedure:
(R)-2-[2′-(3-Benzyl-1-ethyl-ureidomethyl)-5,4′-bis-trifluoromethyl-biphenyl-3-yl]-N—((R)-1-methyl-2-phenyl-ethyl)-propionamide (0.08 g, 0.12 mmol) was treated with 5N aqueous H2SO4 in 1,4-dioxane at 100° C. for 24 hours. The mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Yield: 47.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl) acetamide (0.85 g), 1-(pyridin-4-yl)piperazine (0.64 g) and potassium carbonate (0.81 g) in dimethylformamide (10 ml) was stirred at 60-70° C. for 5 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1)to give a yellow solid(0.6 g). The obtained yellow solid was crystallized from ethyl acetate-methanol to give the title compound (0.37 g) as white crystals, m.p.=164-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[C:4]=1[CH3:12].[CH3:13][O:14]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:6]1[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH:13]=[O:14]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(OC)c(C)c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)c(OC)c(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 1,4-dimethoxy-2,3-dimethylbenzene (100 g, 0.60 mol) and dichloromethyl methyl ether (65 mL, 0.72 mol) in dichloromethane (400 mL) was added dropwise titanium tetrachloride (IV)(100 mL, 0.91 mol) over 30 minutes under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice (1 kg), the organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washes with water and saturated brine, passed through sodium sulfate-silica gel, dried (eluted with hexane-ethyl acetate 5:1) and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 107 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(O[C:14]([S-])=[S:15])C.[K+]>N1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:10][C:14]([SH:15])=[N:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2oc(S)nc2c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of 2-amino-4-methoxy-phenol (20.7 g, 0.15 mol), potassium O-ethylxanthate (26.2 g, 0.16 mol) and anhydrous pyridine was refluxed for two hours before it was cooled to room temperature and ice-cold 1N HCl (600 mL) was added. The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a pale red solid (22.36 g): 1H NMR (CDCl3, 200 MHz): δ=7.20 (m, 1H), 6.78 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]([C:14]1[S:18][C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[C:16]([CH3:23])[CH:15]=1)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CC(=O)CC>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[CH2:31][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([C:14]2[S:18][C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[C:16]([CH3:23])[CH:15]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=1[CH3:13]
Reactant: CC(C)(C)C(=O)CCl
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc(C)c(S(=O)(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)O)s1
Yield: 108.2 %

Procedure:
To a solution of 5-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide (5.1 g, 12.48 mmol) in 2-butanone (50 ml) is added potassium carbonate (2.59 g, 18.72 mmol), and chloropinacolone (3.28 ml, 24.91 mmol). The reaction is refluxed overnight, filtered, and concentrated. The residue is partitioned between EtOAc (400 ml) and 0.2N HCl (100 ml). The organic layer is washed with brine (100 ml), MgSO4 dried, concentrated, and chromatographed (120 g SiO2, 50% EtOAc/Hex) to yield the title compound (6.11 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13].Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13]
Reactant: BrCCOCCBr
Reactant: Nc1cc(Br)c(N)c(C(F)(F)F)c1
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 180 °C
Yield: 63 %

Procedure:
2-Bromo-6-trifluoromethyl-benzene-1,4-diamine (2.21 g), bis-(2-bromoethyl)ether (1.30 mL) and N,N-diisopropyl-ethylamine (4.64 mL) were mixed in N,N-dimethylformamide (19 mL) and heated to 180° C. for 30 minutes in a sealed microwave process vial. Saturated aqueous bicarbonate (100 mL) was added and the crude mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 1.78 g (63%) of the title compound as a yellow solid. LC-MS (m/z) 326 (MH+); tR=2.54, (UV, ELSD) 83%, 75%. 1H NMR (500 MHz, DMSO-d6): 2.99 (m, 4H), 3.70 (m, 4H), 5.00 (s, 2H), 7.00 (d, 1H), 7.38 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(OCC2CO2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
In 120 ml of anhydrous N,N-dimethylformamide was dissolved 25.9 g of benzyl 4-hydroxybenzoate and 12.7 ml of epibromohydrin. To the solution was added 23.6 g of anhydrous potassium carbonate, and the mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 24.5 g of the title compound as an oil (yield 76%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[O:9]=O>O>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:9])=[O:1]
Reactant: O=CCCCCCO
Reactant: O=O
Solvent: O
Product: O=C(O)CCCCCO
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
5.28 Grams (45 mmols) of 6-hydroxyhexanal was charged to a 100 milliliter Schlenk flask and dissolved in 45 milliliters of deionized water by heating to 85-95° C. in a water bath. The resulting solution was charged to the Parr autoclave, placed under 1500 psi O2 and heated to 120° C. Samples were taken every 30 minutes throughout the reaction. After 1.5 hours, reaction conversion was 92% and 6-hydroxycaproic acid was formed in 92% selectivity.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[C-:32]#[N:33].[Na+]>CN1CCCC1=O>[CH3:21][C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2]([C:32]#[N:33])=[N:7][C:6]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: [C-]#N
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C#N)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 150 °C
Yield: 29.4 %

Procedure:
A well stirred suspension of 0.30 g (0.66 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) and 0.098 g (2.0 mmol) of sodium cyanide in 5.0 ml of 1-methyl-pyrrolidin-2-one was heated for 16 hours at 150° C. After cooling down to RT, the reaction mixture was poured into crashed ice/NaCl-solution (sat. in H2O) and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.086 g (29%) of 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile as light yellow solid. MS: 443.4 (MH+); and 0.045 g (15%) of 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid amide as light yellow solid. MS: 461.4 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:36][C:30]1[CH:29]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:63]([C@H:61]3[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]3)=[O:64])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:27]=[C:26]([F:25])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (64.1 mg, 0.17 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.15 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (32.8 mg, 0.15 mmol) and DIEA (0.030 mL, 0.17 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the precipitate was collected by filtration, and washed with water to give tert-butyl 2-(trans-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (60.0 mg, 0.102 mmol, 66.6%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]3[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[CH:16][C:8]=23)[CH:6]=1.C([Li])CCC.[C:36]1(=[O:40])[CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:13][C:12]1[C:7]([N:5]2[CH:6]=[C:2]([C:36]3([OH:40])[CH2:39][CH2:38][CH2:37]3)[CH:3]=[N:4]2)=[C:8]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]2=[N:10][CH:11]=1
Reactant: Cn1cc(-c2cc3c(-n4cc(Br)cn4)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(-c2cc3c(-n4cc(C5(O)CCC5)cn4)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Reaction time: 0.03 h

Procedure:
A −78° C. solution of Example 113F (75 mgs, 0.148 mmol) in tetrahydrofuran (2.1 mL) was treated with n-butyllithium (2.45 M in hexanes, 0.121 mL, 0.295 mmol) dropwise over 3 minutes, and the reaction was stirred for 2 minutes. Cyclobutanone (0.022 mL, 0.295 mmol) was added, and the reaction was stirred for 1 hour at −78° C. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 4% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 499.2 [M+H]+.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O>[OH:11][C:8]1[CH:9]=[CH:10][C:2]([I:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: [I-]
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(O)ccc1I
Reaction time: 8 h

Procedure:
Suspension of 2-amino-5-hydroxybenzoic acid (5.0 g, 32.7 mmol) in deionized water (100 mL) was mixed with 60 mL of concentrated sulfuric acid, which was added dropwise, resulting in a clear solution, which was held at 4° C. overnight, yielding suspension of white crystals. The suspension, while still cold, was mixed with 20 mL of an aqueous solution of sodium nitrite (2.4 g, 34.8 mmol). The resulting yellow-orange solution was mixed with 20 mL of an aqueous solution of potassium iodide (7.4 g, 44.6 mmol), which was added dropwise. The resulting mixture, dark-brown in color, was kept at 90° C. for 1 h and then was kept at 4° C. overnight affording dark red to brown crystals, which were filtered off and redissolved in 100 mL of deionized boiling water. Activated charcoal (7 g) was added to the hot solution, which was held at 90° C. for 1 h. The slurry, while hot, was filtered off using filter paper (retention, 10 μm) and the supernatant was kept at 4° C. resulting in faintly orange crystals, which were filtered off and dried in a desiccator at r.t. C7H5IO3, found (calc): C, 31.51 (31.84); H, 2.14 (1.91); I, 47.31 (48.07). 1H NMR (400 MHz, DMSO-d6): δ 5.1 (s, 1H, OH), 6.81, 7.38, 7.71 (H3, H5, H2, 1H each, in aromatic ring), 11 (s, 1 H, COOH). Yield, 3.2 g (37 mol %).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cscn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 48.7 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.045 g, 0.11 mmol), EtOH (2.6 mL) and DMF (0.35 mL), p-anisaldehyde (0.017 g, 0.12 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.33 mL, 0.33 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v 96:4) to give the title compound as a white solid (0.026 g, 49%); 1H-NMR (500 Mz, DMSO-d6): δ 2.64-2.72 (m, 4H, piperazine N(CH2)2), 3.61-3.70 (m, 4H, piperazine N(CH2)2), 3.77 (br s, 2H, NCH2), 3.84 (s, 3H, OMe), 7.10 (d; J=9.0 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.14 (d, J=7.0 Hz, 2H, ArH, C6H4), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.33 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.07 min—485/487 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 485.0759, calculated for C21H22BrN6OS (M+H)+: 485.0742.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH2:6][C@@H:7]([CH3:17])[N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH:10]=1)=O.[C:18](=[S:21])([S-:20])[NH2:19].[NH4+]>CO.C(N)(=S)C1C=CN=CC=1>[SH:21][C:18]1[S:20][CH:2]=[C:3]([C:5]2[CH2:6][C@@H:7]([CH3:17])[N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH:10]=2)[N:19]=1
Reactant: NC(=S)[S-]
Reactant: C=CCOC(=O)N1CC=C(C(=O)CCl)C[C@H]1C
Agent: NC(=S)c1ccncc1
Agent: [NH4+]
Solvent: CO
Product: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of allyl (2R)-4-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (0.255 g, 1.0 mmol) in methanol (5 ml) were added at 0–5° C. thioisonicotinamide (5 mg) and ammonium dithiocarbamate (0.22 g, 2.0 mmol). The reaction mixture was raised to room temperature, stirred for 15 minutes and then stirred at 55–60° C. for 1.5 hour. The solvent was removed in vacuo and to the residue was added aqueous 1N NaOH solution to make the solution alkaline. To the solution were added ethyl acetate and hexane, and the mixture was separated with a separating funnel. The aqueous layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give allyl (2R)-4-(2-mercapto-1,3-thiazol-4-yl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (170 mg, 59%).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][CH2:35][CH3:36])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28](=[O:33])[C:29]([O:31]C)=[O:30])=[CH:18][CH:17]=2)[C:9]=1[C:10]1[NH:14][N:13]=[N:12][N:11]=1)([CH3:4])[CH3:3].O.[OH-].[Li+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][CH2:35][CH3:36])[N:8]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28](=[O:33])[C:29]([OH:31])=[O:30])=[CH:20][CH:21]=2)[C:9]=1[C:10]1[NH:14][N:13]=[N:12][N:11]=1)([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(-c2nnn[nH]2)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(-c2nnn[nH]2)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Yield: 54.3 %

Procedure:
Following a procedure similar to that described in Example 1(b), but using 180 mg of methyl {4'-[4-(1-hydroxy-1-methylethyl)-2-propyl-5-(tetrazol-5-yl)imidazol-1-ylmethyl]biphenyl-2-yl}glyoxylate [prepared as described in step (b) above] and 77 mg of lithium hydroxide monohydrate, 95 mg of the title compound, melting at 169°-170°C., were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[C:14]([F:38])[C:13]=2[F:39])=[CH:8][CH:7]=1)=[O:5])C.FC1C(F)=C(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC=1C1C=CC(C(O)=O)=CC=1>>[F:39][C:13]1[C:14]([F:38])=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:31])([F:29])[F:30])[CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Agent: O=C(O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Yield: 88 %

Procedure:
2′,3′-Difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid (14B) was prepared from 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid ethyl ester (13B) as described in the preparation 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid (14 A) yielding 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid (14B) as a white solid (88%).