Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH:15]4[CH2:19][N:18]([C:30]([C:27]5[CH:28]=[CH:29][O:25][N:26]=5)=[O:31])[CH2:17][CH:16]4[CH2:20]3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 25.8 mg, 0.22 mmol, 1.5 equiv), DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) and HATU (87 mg, 0.22 mmol, 1.5 equiv) were added to anhydrous acetonitrile (2 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 11-2 as a white solid. MS m/z (M+H): calculated=424.2345; observed=424.2353.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C@@H:9]([O:11]C1CCCCO1)[CH3:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C@@H:9]([OH:11])[CH3:10]
Reactant: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@H](O)C(=O)c1ccccc1F
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
(2S)-2'-Fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (25 g) was dissolved in ethanol (200 ml), to which pyridinium p-toluenesulfonate (1.28 g) was added. The reaction solution was stirred at 55° C. for 2.5 hours and then concentrated. The residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=9/1 to 5/1) to give (2S)-2'-fluoro-2-hydroxypropiophenone (16.4 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:29])[CH2:24][C:25]([O:27]C)=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:20])[CH3:19]>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:29])[CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:19])[CH3:20]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NC(=O)CC(=O)O)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Yield: 89.2 %

Procedure:
101 mg of methyl 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methyl-phenyl}amino)-3-oxo-propanoate (Example 4a) are dissolved in 2 ml of ethanol and 1 ml of 1N sodium hydroxide solution, the solution is stirred at room temperature for 1 hour and the solvent is removed in vacuo. The residue is rendered acidic, extracted with ethyl acetate, the extract is dried over sodium sulphate and the solvent is removed in vacuo. 87 mg of 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}amino)-3-oxopropionic acid are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1)([CH3:3])[CH3:2].Br[C:27]1[CH:28]=[C:29]([C:33]2[N:34]([C:38]3[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][CH:41]=[CH:40][C:39]=3[CH:47]([CH3:49])[CH3:48])[CH:35]=[CH:36][N:37]=2)[CH:30]=[CH:31][CH:32]=1.N1C=CC=CC=1C(O)=O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.CS(C)=O>[CH:44]([C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([CH:47]([CH3:49])[CH3:48])[C:38]=1[N:34]1[CH:35]=[CH:36][N:37]=[C:33]1[C:29]1[CH:28]=[CH:27][CH:32]=[C:31]([O:25][C:20]2[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([C:14]3[N:13]([C:5]4[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=4[CH:1]([CH3:2])[CH3:3])[CH:17]=[CH:16][N:15]=3)[CH:19]=2)[CH:30]=1)([CH3:45])[CH3:46]
Reactant: Cc1cc(O)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1
Reactant: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Oc2cccc(-c3nccn3-c3c(C(C)C)cccc3C(C)C)c2)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1
Temperature: 200 °C

Procedure:
To a 300 mL 3-neck round bottom flask was added 3-(1-(2,6-diisopropylphenyl)-1H-imidazol-2-yl)-5-methylphenol (2.5 g, 7.47 mmol), 2-(3-bromophenyl)-1-(2,6-diisopropylphenyl)-1H-imidazole (3.15 g, 8.22 mmol), picolinic acid (1.380 g, 11.21 mmol), copper(I) iodide (0.427 g, 2.242 mmol), potassium phosphate tribasic monohydrate (6.02 g, 26.2 mmol), 100 mL DMSO. Nitrogen was bubbled directly into the mixture and then was heated to 200° C. overnight under nitrogen. The reaction mixture was diluted with ethyl acetate and water and was filtered through Celite. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with 10% LiCl, brine, dried over magnesium sulfate, filtered, and evaporated leaving a residue. The residue was purified by column chromatography eluting with 40 and 50% ethyl acetate/hexane (1.95 g, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:18])=[CH:9][C:10]1[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[C:8]([CH3:18])=[CH:9][C:10]1[S:14][C:13]([C:15]([O:17][C:21]2[CH:29]=[CH:28][C:24]([C:25](=[NH:26])[NH2:27])=[CH:23][CH:22]=2)=[O:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccc(C(=O)O)s1)C(=O)OC(C)(C)C
Reactant: N=C(N)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)s1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
5-(2-(tert-Butoxycarbonyl)-1-propenyl)-2-thiophenecarboxylic acid (0.51 g, 1.89 mmol) and 4-hydroxybenzamidine hydrochloride (0.33 g, 1.89 mmol) were dissolved in pyridine (10 mL), WSC hydrochloride (0.54 g, 2.8 mmol) was added, and the mixture was stirred overnight. The mixture was purified by high performance liquid chromatography and freeze-dried to give the title compound (0.63 g).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@@H:7]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][O:3]1.C1(S(O)(=O)=O)C=CC=CC=1>CO.C(OCC)(=O)C>[N:8]1([C@H:7]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C@H:5]([OH:6])[CH2:4][OH:3])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CC1(C)OC[C@H]([C@@H](c2cccs2)n2ccc3ccccc32)O1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@@H](O)[C@@H](c1cccs1)n1ccc2ccccc21
Reaction time: 6 h
Yield: 84.9 %

Procedure:
1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole (350 mg, 1.12 mmol) was dissolved in methanol (20 mL) and benzenesulfonic acid (17 mg, 0.11 mmol) was added. The mixture was stirred for 6 hours then diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 5% methanol/chloroform) to afford 260 mg (82%) of (2S,3S)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol. HRMS: calcd for C15H15NO2S+H+, 274.08963; found (ESI, [M+H]+), 274.0892.
Reaction SMILES: [I:1][CH:2]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]C(=O)C)=[CH:10][CH:9]=1)[C:3]#[CH:4].C(N)CCC.C(OCC)C.Cl>O1CCOCC1>[I:1][CH:2]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:3]#[CH:4]
Reactant: C#CC(I)OC(=O)Cc1ccc(OC(C)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCN
Solvent: CCOCC
Product: C#CC(I)OC(=O)Cc1ccc(O)cc1

Procedure:
At room temperature, 15 g (0.042 mole) of 4-acetoxyphenylacetic acid iodopropargyl ester (prepared according to B) and 3.1 g (0.042 mole) of n-butylamine was stirred in 15 ml dioxan for 18 hours. The reaction mixture was distributed between diethyl ether and 1N aqueous hydrochloric acid, the ether phase was dried over sodium sulfate and the solvent mixture was distilled off. Ray yield: 14.4 g. After chromatography on silica gel with trichloromethane/petroleum ether (4:1 parts by volume) as the eluent, 8.2 g (62% of the theoretical amount) 4-hydroxyphenylacetic acid iodopropargyl ester (m.p. 73°-77° C.) were obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]5[C:32](C(OCC)=O)=[N:33][N:34]=[C:28]5[CH2:27]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.C1COCC1.CO.[Li+].[OH-]>O>[N:34]1[N:33]=[CH:32][N:29]2[CH2:30][CH2:31][N:26]([C:23]3[N:24]=[CH:25][C:20]([NH:19][C:17]([C:10]4[O:9][C:8]([N:4]5[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]5)=[N:12][C:11]=4[C:13]([F:15])([F:16])[F:14])=[O:18])=[CH:21][CH:22]=3)[CH2:27][C:28]=12
Reactant: CCOC(=O)c1nnc2n1CCN(c1ccc(NC(=O)c3oc(N4CCCC(C)C4)nc3C(F)(F)F)cn1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCn5cnnc5C4)nc3)o2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 217 (64 mg) in 4:1:1 THF:MeOH:H2O (3 mL) was mixed with LiOH (15 mg), and stirred at r.t. overnight. The mixture was concentrated and purified by prep Gilson HPLC to give the decarboxylation product 218 (25 mg as a pale solid). 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.49 (s, 1H), 8.42 (d, 1H, J=2.5 Hz), 7.89 (m, 1H), 7.11 (d, 1H, J=9.1), 4.86 (s, 2H), 4.10 (m, 6H), 3.05 (m, 1H), 2.75 (t, 1H, J=11.7 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.53 (m, 1H), 1.15 (m, 1H), 0.94 (d, 3H, J=6.6 Hz). MS (M+1): 477.3
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:29]=3)[C:23]([O:25]C)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CO.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:29]=3)[C:23]([OH:25])=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure T using methyl 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoate (0.233 g, 0.493 mmol), methanol (2 mL), THF (3 mL), and 1 N aqueous lithium hydroxide (4.9 mL, 4.93 mmol). (Extraction was performed with 20% 2-propanol in chloroform rather than EtOAc). This afforded 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-amino)-5-(4-morpholinyl)benzoic acid as an orange amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72-8.76 (1H, m), 8.13 (1H, m), 8.01-8.06 (1H, m), 7.89 (1H, dt, J=7.8, 1.2 Hz), 7.74-7.82 (1H, m), 7.49-7.56 (2H, m), 7.05 (1H, br. s.), 6.79 (1H, br. s.), 6.65 (1H, br. s.), 3.66-3.75 (4H, m), 3.06-3.11 (4H, m), 2.17 (3H, s). Mass Spectrum (ESI) m/e=459.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](I)[CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].C(CN)O>O.C(O)(=O)C.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(I)c1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: NCCO
Solvent: CC(=O)O
Solvent: CO
Product: Fc1cccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add 1-fluoro-3-iodo-benzene (2.3 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 mL) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 2N ammonia in methanol to give the title compound: mp 69–71° C.; mass spectrum (ion spray): m/z=389.4 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CI.[CH3:15][N:16]([CH:18]=[O:19])C>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:16]1[CH2:15][CH2:5][CH2:4][CH2:3][CH2:2][C:18]1=[O:19]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: O=C1CCCCCN1Cc1ccc2ccccc2c1
Yield: 97 %

Procedure:
Following the procedure described in Example 122, step 1, but substituting respectively 2-bromomethylnaphthalene for methyl iodide, and DMF for THF, the title compound 217 was obtained in 97% yield. MS (ESI)=254 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([O:24][C:25](=[O:34])[NH:26][CH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:34])[NH:26][CH:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=3)[CH:9]=2)[CH2:31][CH2:32]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.8 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 0.9 g (3.52 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g, 3.52 mmol) were used to afford 0.6 g of the required product. 1H NMR (DMSO-d6): 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.15 (1H, m), 3.7 (1H, m), 6.62 (1H, s), 6.76 (1H, d), 7.04 (1H, s), 7.16 (3H, m), 7.86 (2H, m), 8.2 (1H, d), 10.0 (1H, s).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14])=[C:2]=[O:3].[CH2:15]([CH:17]([NH:20][OH:21])[CH2:18][CH3:19])[CH3:16]>ClCCl>[OH:21][N:20]([CH:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[C:2](=[O:3])[NH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:20]([CH:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[OH:21])=[O:14]
Reactant: CCC(CC)NO
Reactant: O=C=NCCCCCCCCN=C=O
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)NCCCCCCCCNC(=O)N(O)C(CC)CC
Yield: 91.9 %

Procedure:
The same general procedure as reported in Example 16 was followed. 1,8-Diisocyanatooctane (3.9 ml, 20 mmol), N-(1-ethylpropyl)hydroxylamine (4.3 g, 42 mmol), and dichloromethane (200 ml) were combined to provide 7.4 g of the desired product as a white powder: MP: 89.0-90.0° C. ; 1H NMR (500 MHz, DMSO): δ 8.65 (s, 2H), 6.71 (t, J=5.9 Hz, 2H), 3.78 (m, 2H), 3.01 (q, J=6.7 Hz, 4H), 1.49-1.21 (m, 20H), 0.79 (t, J=7.5 Hz, 12H); 13C NMR (125 MHz, DMSO): δ 161.2, 60.1, 39.3, 29.9, 28.9, 26.3, 24.5, 11.1; IR (KBr): 3444, 3128, 2962, 2933, 2856, 1628, 1537, 1473, 1358, 1319, 1271, 1165, 1140, 1105, 1070, 1039, 927, 839, 779, 748 cm-1 ; MS (FAB): m/e 403.3277 (403.3284 calc'd for C20H43N4O4, M+H), 300; Anal. calc'd for C20H42N4O4 : C, 59.67; H, 10.51; N, 13.92. Found: C, 59.71; H, 10.65; N, 13.92.
Reaction SMILES: Br[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][O:14][C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][N:10]=2.[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Pd]>[O:14]1[C:5]2[C:6]3[C:11]([C:2]([B:15]([OH:19])[OH:16])=[CH:3][CH:4]=2)=[N:10][CH:9]=[CH:8][C:7]=3[CH2:12][CH2:13]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1ccc2c3c(ccnc13)CCO2
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: OB(O)c1ccc2c3c(ccnc13)CCO2
Temperature: 95 °C
Yield: 30.1 %

Procedure:
7-bromo-2.3-dihydropyrano[4.3.2-de]quinoline (0.170 g; 0.680 mmol), bis(pinacolato)diboron (0.207 g; 0.816 mmol), anhydrous potassium acetate (0.133 g; 1.36 mmol) and bis(tricyclohexylphosphine)palladium(0) (0.045 g; 0.068 mmol) in anhydrous 1.4-dioxane (3.1 mL) were mixed in a tube, purged with argon and sealed. After heating at 95° C. for 16 h, the mixture was cooled at room temperature, concentrated under reduced pressure and store at 3° C. for 21 h. The brown residue was dissolved in acetonitrile, filtered, and the dark brown solution was concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.044 g (25%) of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccccc1CCl
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccccc3F)c2c1

Procedure:
The titled compound (22 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-fluorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCC>C1(C)C=CC=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.45 g, 0.76 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.25 g, 0.84 mmol), tetrakis(triphenyl-phosphine)palladium (0.053 g, 0.046 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) as a light brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8]>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(S(=O)(=O)NCCCCO)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1-c1ccc(S(=O)(=O)NCCCCO)cc1
Reaction time: 4 h

Procedure:
2′-Nitrobiphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide (0.5 g) was dissolved in methanol (50 mL). 10% Pd/C (0.5 g) was added and the mixture stirred under hydrogen for 4 hours. The mixture was filtered through celite and evaporated to a brown oil. Column chromatography gave a clear oil, crystallised from ether/petrol to give a white powder. δC (DMSO, 62.9 MHz): 25.9, 29.6, 42.6, 60.3, 115.6, 116.8, 124.1, 126.8, 128.8, 129.3, 129.9, 138.6, 143.8 and 145.2.
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].S(=O)(=O)([OH:16])N>O.CC(C)=O>[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]([OH:16])=[O:9]
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccccc1F
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Sodium chlorite (1.45 g, 16.11 mmol) in 2 mL water was added at 0° C. to 2-fluoro-benzaldehyde (0.5 g, 4.03 mmol) in 5 mL acetone. After 5 minutes, sulphamic acid (1.17 gm, 12.086 mmol) was added and the resulting mixture was stirred at 0° C. for 20 minutes. Water was then added, and the resulting precipitate was filtered under reduced pressure. The aqueous layer was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 2-fluorobenzoic acid in 86% yield.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])[O:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:17][CH:15]([F:16])[C:12]1[O:13][CH:14]=[C:9]([OH:8])[C:10](=[O:18])[CH:11]=1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1cc(C(F)F)occ1O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To an ice-salt cooled, clear solution of 5-benzyloxy-2-difluoromethyl-pyran-4-one (252 mg, 1 mmol) in CH2Cl2 (4 mL) was added dropwise a solution of 1.0 M BBr3 in CH2Cl2 (1 mL, 1 mmol) diluted with CH2Cl2 (1 mL). After 10 min, TLC analysis of the reaction mixture using a mixture of CH2Cl2 and MeOH (20/1, v/v) as eluant indicated consumption of the starting material. The reaction mixture was quenched with MeOH (5 mL), and evaporated to dryness. The residual oil was taken up in ethyl acetate (30 mL), and the organic layer was washed with brine (2×10 mL), dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was triturated with ether, and was then collected by suction filtration. The title compound was obtained as an off-white solid (80 mg, 50% yield). The purity (peak area percent is 97.3%) of this material was analysed by HPLC Method 1 as described above.