Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(I)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Temperature: 15 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
3-Iodophenol (110 g, 0.50 mol, 1 eq) and imidazole (93.6 g, 1.375 mol, 2.75 eq) were placed in a 2000 ml flask with dichloromethane (1150 mL) and cooled in an ice water bath to 15° C. under nitrogen. tert-Butyldimethylchlorosilane (82.9 g, 0.55 mol, 1.1 eq) in dichloromethane (200 mL) was added dropwise through an addition funnel and the reaction mixture was stirred overnight. The reaction solution was washed with 0.5 N sodium hydroxide solution (3×200 mL), water (3×200 mL) and brine (200 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure leaving 166.34 g of crude (3-iodo-phenoxy)-tert-butyl-dimethyl-silane. 1H NMR (300 MHz, CDCl3) δ 7.27 (ddd, J=8.0, 2.0, 1.0 Hz), 7.19 (dd, 1H, J=2.0, 2.0 Hz), 6.92 (dd, 1H, J=8.0, 8.0 Hz), 6.77 (ddd, 1H, J=8.0, 2.0, 1.0 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.CCCCCC.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[S:29][C:28]3=[CH:30][N:31]([CH2:42]O)[C:32](=[O:41])[C:33]([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)=[C:27]3[NH:26][C:25]=2[CH:44]=1>N1C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[S:29][C:28]3=[CH:30][N:31]([CH2:42][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH3:9])[C:32](=[O:41])[C:33]([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)=[C:27]3[NH:26][C:25]=2[CH:44]=1
Reactant: CCCCC(C)C(=O)O
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCC(C)C(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of 1.4 g. of 2-methylhexanoic acid (10.8 mmol.) and 3 ml. of thionyl chloride (41.1 mmol.) in 20 ml. of Skellysolve B was refluxed on a steam bath for five hours. The mixture was then concentrated under reduced pressure and the residue azeotroped twice with 30 ml. of cyclohexane to yield a colorless oil. The oil was then added dropwise to a cold, stirred suspension of 1.2 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (3.1 mmol.) in 20 ml. of pyridine. After stirring for 35 minutes, the reaction mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in formation of a yellow solid, which was collected, washed with water, air-dried, then purified using flash chromatography on silica gel, employing a mixture of 2% ethyl acetate: 98% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(2-methyl-1-oxohexyloxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow crystalline solid (1.17 g; 76% yield) having the structural formula, ##STR19## a melting point in the range of 140°-146° C. and the following elemental analysis:
Reaction SMILES: [Se]=[O:2].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1)=[O:5]>O1CCOCC1>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH:3]=[O:2])=[CH:7][C:8]=1[F:14]
Reactant: O=[Se]
Reactant: COc1ccc(C(C)=O)cc1F
Solvent: C1COCCO1
Product: COc1ccc(C(=O)C=O)cc1F
Reaction time: 8 h

Procedure:
Selenium oxide (4.953 g) is heated to dissolve in 100 ml aqueous dioxane (95:5 dioxane: H2O). The 3-fluoro-4-methoxyacetophenone (5.00 g) is added to the mixture. The resulting mixture is refluxed overnight then coiled. The precipitated selenium metal is filtered. The filtrate is concentrated in vacuo to give a brown thick gum. It is recrystallized from -~200 ml hot H2O, filtered hot and allowed to stand at RT overnight. The precipitated pale pink flake are filtered, washed with H2O and let air dried to give 1-methoxy-2-fluoro-4-glyoxyloylbenzene, which is used directly in the next step.
Reaction SMILES: [Li].[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[O:7][CH2:6][CH2:5][O:4]1.O1CCC[CH2:15]1.C[Li]>C(OCC)C>[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:15])[O:4][CH2:5][CH2:6][O:7]1
Reactant: CC1(CCCC(=O)O)OCCO1
Reactant: C1CCOC1
Agent: [Li]
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
348 Mg. of the lithium salt of the ketal acid, 4-(2-methyl-1,3-dioxolan-2-yl)butanoic acid was dissolved in 5 ml. anhydrous tetrahydrofuran. The solution was cooled to 0° C and 1.25 ml. of a 1.6 molar solution of methyllithium in diethylether was added dropwise over a period of one hour while stirring under a nitrogen atmosphere. The solution was allowed to rise approximately to 20° C and kept at this temperature over a period of two hours. The reaction mixture was added to crushed ice and the organic solvents were removed in vacuo. The residue was extracted with ether, the extract was washed with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated in vacuo to give crude 5-(2-methyl-1,3-dioxolan-2-yl)-2pentanone.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][CH:14]([SH:16])[CH3:15].C(N(CC)CC)C.O>CN(C=O)C>[CH:14]([S:16][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])([CH3:15])[CH3:13]
Reactant: CC(C)S
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (2.5 g, 15.6 mmol) in DMF (50 mL) were added 2-propane thiol (1.74 mL, 18.6 mmol) and triethylamine (4.8 mL, 34.4 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was poured into water (250 mL) and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (2×) and brine, then dried over MgSO4 and concentrated to yield 2.98 g (86%) of 15A as a yellow oil which solidified upon standing.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH2:2]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=1)[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cccc(-c2ccccc2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and phenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol, and water. The compound was purified by flash chromatography on silica gel and eluted with 3%-10% 3.5N methanolic ammonia/chloroform mixtures. Evaporation of solvent gave the title compound as a colourless solid; MS (ES+) 307 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)[C:16]([CH3:18])=[CH2:17].N>CS(C)=O>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:17]([C:16]([CH3:18])=[CH2:15])=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: C=C(C)C(=O)O
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: N
Solvent: CS(C)=O
Product: C=C(C)c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Temperature: 0 °C

Procedure:
3.0 g. (15.7 mmole) 5,6-diamino-3,3-dimethylindolin-2-one and 1.37 g. (15.9 mmole) methacrylic acid are heated for 30 minutes at 200° C. in 28 g. polyphosphoric acid. Thereafter, the reaction mixture is mixed with 40 ml. ice water. The brown suspension obtained is adjusted, while cooling with ice, to pH 8 with 45 ml. concentrated aqueous ammonia solution. The substance is filtered off with suction and washed with a little water. There are obtained 3.74 g. of crude product which are dissolved in 5 ml. dimethyl sulphoxide, diluted with 15 ml. methanol and purified over a silica gel column (7.50 g. gel; elution agent: dichloromethane/methanol 10:1 v/v). There is obtained 0.6 g. (14% of theory) of the title compound; m.p. 270°-273° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=3[CH:20](O)[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC4C=CC=CC=4)[CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=3[CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: OC(c1cccc(OCc2ccccc2)c1)c1ccccc1-c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cccc(Cc2ccccc2-c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 29.1 %

Procedure:
A solution of 2-(4,5-diphenyl-2-oxazolyl)-3'-benzyloxybenzhydrol (650 mg) in ethyl acetate (3 ml), methanol (3 ml), and 10% hydrogen chloride in methanol (0.3 ml) was stirred in the presence of 10% palladium on carbon--water (50/50 wt. % ) (400 mg) and hydrogen at atmospheric pressure at room temperature for 10 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed (toluene--ethyl acetate) over silica gel to afford 3-[[2-(4,5-diphenyl-2-oxazolyl)phenyl]methyl]phenol (150 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2([C:18]([OH:20])=[O:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[C:4]([CH:23]=[C:24]([CH3:26])[CH3:25])[CH:3]=1>C(O)(=O)C.[Pd]>[CH2:23]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)=[O:7])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)=Cc1cc(C)ccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(CC(C)C)c1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a solution of 2-[4-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (510 mg, 1.45 mmol) in glacial acetic acid (65 mL) under N2 is added Pd/C (10% Pd, 138 mg, 10 mol %). The reaction is hydrogenated at 60 psi H2 and 90° C. overnight. The reaction is cooled to RT and filtered through Celite, washing the filter cake with water (2×15 mL) and MeOH (2×15 mL); the filtrate is concentrated in vacuo. The residue is dissolved in water (75 mL) and extracted with EtOAc (2×30 mL). The combined organic layers are washed with a 5% NaHCO3 solution (3×20 mL), water (20 mL) and brine (20 mL) then dried over anhydrous Na2SO4. The organic layer is concentrated in vacuo to give product (280) as white solid (350 mg, 69%).
Reaction SMILES: Cl.[CH2:2]([O:6][CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:4][CH3:5].[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:8](=[O:10])[CH2:7][O:6][CH2:2][CH2:3][CH2:4][CH3:5])[C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CCCCOCC(=O)O
Agent: Cl
Product: CCCCOCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 30.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-butoxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 38, (2S,4R)-4-benzyl-1-(2-butoxyacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (9.1 mg, 30.1%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.56 (m, 2H), 7.27 (m, 2H), 7.19 (m, 5H), 6.96 (m, 4H), 4.47 (t, 1H), 4.03 (t, 1H), 3.60 (m, 1H), 3.42 (m, 2H), 3.29 (m, 2H), 2.65 (m, 3H), 1.89 (m, 2H), 1.35 (m, 4H), 0.85 (t, 3H). MS (EI) for C30H33FN2O4: 505.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.Cl.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C-:25]#[N:26].[K+]>O>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:18]3([C:25]#[N:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: [C-]#N
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.1 %

Procedure:
To a stirred suspension of 4-(2-keto-1-benzimidazolinyl)piperidine (500 mg, 2.3 mmol) in 2N HCl(1.15 ml, 2.3 mmol) and water(0.5 ml) was added cyclohexanone(0.24 ml, 2.3 mmol) at 0° C. To this mixture was added a solution of KCN(156 mg, 2.4 mmol) in water(0.3 ml) all at once at room temperature. After 17 h stirring at room temperature, the precipitated white solid was collected by filtration, washed with water, and dried under vacuum at 50° C. for 1 h to afford 605 mg of white powder. As this included small amount of starting material amine, this was purified by column chromatography(silica gel: 130 g, CH2Cl2MeOH:30/1 to 20/1) to give 293 mg(39.3%) of white powder, mp199-201° C.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[N:33]([CH3:34])[C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][N:33]1[C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]=[C:29]1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cn1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (460 mg), 2-chloromethyl-1-methyl-1H-benzimidazole (250 mg), potassium carbonate (360 mg) and N,N-dimethylformamide (15 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (550 mg, yield: 85%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.C(O)(=[O:14])C.C(OCC)(=O)C.OO>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:14])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: CC(=O)O
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1cc(Br)cnc1F
Temperature: 35 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of 1.36 g (6.18 mM) of 5-bromo-2-fluoro-3-pyridineboronic acid in a mixture of 9.5 ml of ethanol, 2.3 ml of acetic acid and 1.3 ml of ethyl acetate is prepared. 2.2 ml of 30% hydrogen peroxide are added to the solution. The reaction mixture is stirred at a temperature of 35° C. for 3 hours and then cooled and extracted with ethyl ether. The organic phases are washed with a solution of ferrous ammonium sulfate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solid residue is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (9/1; v/v) as the eluent to give the desired product in the form of a white solid with a yield of 62%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)[CH2:48][CH3:49].C(N(CC)CC)C>CN(C=O)C>[F:43][C:41]1[CH:42]=[C:37]([CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=1)[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH2:47][CH2:48][CH3:49])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reactant: CCCc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.25 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.16 g), 2-propylthiazole-4-carboxylic acid (example 56, step c) (0.09 g) and triethylamine (0.29 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the mixture evaporated to give the subtitled compound as a clear gum. Yield 0.14 g.
Reaction SMILES: [C-:1]#[N:2].[K+].FC(F)(F)S(O[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:19])[C:11]=1[CH3:20])(=O)=O.S([O-])(O)(=O)=O.[K+].O>O1CCCC1>[CH3:20][C:11]1[C:12]([CH3:19])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[C:1]#[N:2]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Reactant: [C-]#N
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C#N)ccc([N+](=O)[O-])c1C
Reaction time: 10 h
Yield: 91 %

Procedure:
Potassium cyanide (2.26 g, 34.7 mmol) was added to a solution of 2,3-dimethyl-4-nitrophenyl trifluoromethane-sulfonate (5.20 g, 17.4 mmol) in tetrahydrofuran (21 ml) at room temperature, followed by deaeration. After tetrakistriphenylphosphine (1.00 g, 0.865 mmol) was added thereto, deaeration was conducted again and then the reaction was carried out under reflux conditions for 10 hours. A 0.5M-aqueous potassium hydrogensulfate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and distilled to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: n-hexane/chloroform) to obtain 2,3-dimethyl-4-nitrobenzonitrile (2.79 g, 90.9%).
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[C:18]1([N:24]2[C:3]3[CH:4]=[CH:5][Se:1][C:2]=3[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=3)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc[se]2)cc1
Reactant: NNc1ccccc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)cc1

Procedure:
Compound 63 (5.86 g, 0.02 mole), phenylhydrazine 8 (4.36 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 66. Yield: 1.93 g (25.3%); white crystals;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].Cl.[Al+3].[Cl-].[Cl-].[Cl-]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(Br)cc1O
Reaction time: 2 h

Procedure:
3-Bromo-phenol (10.0 g, 57.8 mmol) was dissolved in 10 ml of pyridine and 10 ml of acetic anhydride and stirred overnight at RT. The mixture was then poured into water, and 1 M HCl was added until reaching a neutral pH value. Extraction with AcOEt furnished a crude product, which was treated with AlCl3 (13.25 g, 100 mmol) at 140° C. After 2 h, the mixture was poured into water and extracted with diethyl ether. The crude residue was purified by column chromatography (eluent: hexane/AcOEt 70:30) to give 1-(4-bromo-2-hydroxy-phenyl)-ethanone (10.1 g) as a red solid.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])=[O:5].[OH-].[Na+].[CH2:22](O)[CH3:23].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O>[CH2:26]([O:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH2:18][CH2:2][CH2:3][CH2:4][CH2:22][CH3:23])=[O:10])=[O:5])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCO
Reactant: Cc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCOC(=O)c1cccc(C(=O)c2ccc(C)cc2OCCCCCC)c1

Procedure:
mixture of 3-(2-hydroxy-4-methylbenzoyl)benzoic acid (2.97 g), 2N sodium hydroxide (12.8 ml), and ethanol (25 ml) is heated under reflux for 15 minutes. Then, 1-bromohexane (4.21 g) is added to the cooled solution and the resulting mixture refluxed for 48 hours. The cooled mixture is diluted with water (100 ml) and extracted with ether (3×75 ml). The ether extracts are dried over magnesium sulfate and concentrated in vacuo to yield hexyl 3-(2-n-hexyloxy-4-methylbenzoyl)benzoate (4.56 g) as a dark brown oil. This ester is mixed with 2N sodium hydroxide (6.4 ml) and refluxed for 4 hours. The cooled reaction mixture is diluted with water (50 ml), washed with ether (25 ml) and acidified to pH 2.0 with concentrated hydrochloric acid. The product is extracted with ether (3×35 ml) and the combined extracts dried over magnesium sulfate, filtered, and concentrated in vacuo. The product is then dissolved in 2N sodium hydroxide (2.95 ml) and water is added to brink the total volume to 10 ml. This sodium salt is chromatographed on a Water's Prep 500A/LC System using the reverse phase prep pack-500/C18 column (water:acetone; 80:20). The fraction containing the major component is acidified to pH 2.0 with concentrated hydrochloric acid and extracted with ether (3×100 ml). The combined ether extracts are dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is recrystallized from heptane to yield 3-(2-n-hexyloxy-4-methylbenzoyl)benzoic acid (1.50 g), m.p. 118° C.