Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:11](=[O:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[C:1]([NH:9][CH:10]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH:11]([OH:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CN(CC(O)C(Cc1c[nH]c2ccccc12)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The product from part (d) is treated with sodium borohydride according to the procedure of Example 1(f) to yield (±)-1-[[[3-(benzoylamino)-4-(1H-indol-3-yl)-2-hydroxybutyl]methylamino]carbonyl]-L-proline.
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]#[C:53][CH2:54][CH2:55][CH2:56][CH2:57][OH:58])=[CH:48][CH:47]=1>>[OH:58][CH2:57][CH2:56][CH2:55][CH2:54][C:53]#[C:52][C:49]1[CH:48]=[CH:47][C:46]([NH:45][C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:51][CH:50]=1
Reactant: Nc1ccc(C#CCCCCO)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 48 in place of 8-aminooctanol. ES/MS calcd. for C37H35N4O6S+ 663.2. Found m/z=663.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=O)[C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[NH2:11][O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+].Cl.[Cl-].[Na+]>CO.O.C(OCC)(=O)C>[C:17]([O:16][C:14]([CH2:13][O:12][N:11]=[C:6]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[C:7]([OH:9])=[O:8])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)C(=O)c1cscn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cscn1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A mixture of 2-(4-thiazolyl)glyoxylic acid (2.3 g) in methanol (23 ml) and t-butyl 2-aminooxyacetate (2.6 g) was stirred for an hour at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate and water and adjusted to pH 7.5 with saturated aqueous solution of sodium bicarbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and the mixture was saturated sodium chloride. The acidic mixture was extracted with ethyl acetate. The extract layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (2.8 g), mp. 136°-139° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCOCc1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1ccccn1
Reaction time: 8 h

Procedure:
A stirred suspension of 2-(2-chloroethoxymethyl)pyridine hydrochloride and sodium azide (9.8 g.) in dry dimethylformamide (103 ml.) is maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate is concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product is basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue is extracted with isopropyl alcohol (3 × 50 ml.). Concentration of the extracts gives 2-(2-azidoethoxymethyl)pyridine. Hydrogenation of the azido compound in isopropyl alcohol over platinum oxide catalyst gives 2-(2-aminoethoxymethyl)pyridine.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:19])[CH:13]=2)[N:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:19])[CH:13]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3ccc(F)cc3nc2OC)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2cc(F)ccc2nc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
To 2-(2,4-dimethoxybenzylamino)-6-fluoro-3-methoxyquinoxaline (2.70 g, 7.86 mmol), 60 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 24 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethanee and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (4:1) mixture and concentration gave 1.27 g of the titled compound (yield, 84%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:17][CH3:18])=[C:8]([CH:10]=[CH:11][C:12]([O:14]CC)=[O:13])[CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:17][CH3:18])=[C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(C(C)=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)=O)cc1C=CC(=O)O

Procedure:
24 g (0.08 mole) of the ester obtained in step (b) are dissolved in 250 ml of methanol and 50 ml of sodium hydroxide at 400 g/l. After the reaction mixture is heated for 2 hours under reflux, it is left to cool then acidified with 5 N hydrochloric acid. The expected product is left to precipitate and, after filtration, is washed with water then with ethanol and finally with isopropyl ether. 13.6 g of the desired product are obtained. m.p.=203° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[OH-].[Li+].[I-].[Na+].[C:12]([C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][Cl:31])[CH2:24][CH2:23]2)[CH:19]=[C:18]([CH:32]2[CH2:34][CH2:33]2)[N:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl>CN(C)C=O.O1CCOCC1>[ClH:31].[C:12]([C:16]1[N:17]=[C:18]([CH:32]2[CH2:33][CH2:34]2)[CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH2:24][CH2:23]2)[N:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cn1nnnc1S
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCCl)CC2)n1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1nnnc1SCCCN1CCN(c2cc(C3CC3)nc(C(C)(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
0.346 g of 1-Methyl-1H-tetrazole-5-thiol (2.98 mmol), 0.071 g of lithium hydroxide (2.98 mmol), and 0.223 g of sodium iodide (1.49 mmol) were stirred in 25 ml of dimethylformamide at 70° C. A solution of 1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidine (2.98 mmol) in 4 ml of dimethylformamide was added slowly within 2 h. After stirring for 2 h at 80° C., the dimethylformamide was evaporated under reduced pressure. The residue was partitioned between 15 ml of aqueous sodium chloride, 15 ml of water and 30 ml of ethyl acetate. The aqueous phase was re-extracted twice with ethyl acetate. The combined ethyl acetate phases were combined and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel using dichloromethane-ethyl acetate (7:3). Fractions containing the product were combined. The solvent was evaporated under reduced pressure. The residue was re-dissolved in 12 ml of ethyl acetate and treated with 2 equivalents of hydrochloric acid in dioxane. The supernatant was removed with a pipette, diisopropyl ether was added, the mixture was stirred, and the solvent was evaporated slowly under reduced pressure to yield 0.9 g of the title compound.
Reaction SMILES: C(OC[C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31]3[NH:32][CH:33]=[C:34]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:35]=3)[C:28](=[O:43])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=O)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C1(OC)C=CC=CC=1>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[CH2:36]([C:34]1[N:35]=[C:31]([NH:30][CH:29]2[C:28](=[O:43])[N:10]3[C:11]([C:12]([OH:14])=[O:13])=[CH:6][CH2:7][S:8][C@H:9]23)[NH:32][CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Nc3nc(Cc4ccccc4)c[nH]3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)C1=CCS[C@@H]2C(Nc3nc(Cc4ccccc4)c[nH]3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diphenylmethyl 3-acetoxymethyl-7-(4-benzylimidazol-2-yl)aminoceph-3-em-4-carboxylate (106 mg.) in a mixture of anisole (0.7 ml.) and TFA (0.4 ml.) was stirred at ambient temperature for 30 minutes and then evaporated to dryness at 25°. The residue was dissolved in the minimum amount of methylene chloride and precipitated with hexane to give 7-(4-benzylimidazol-2-yl)aminoceph-3-em-4-carboxylic acid trifluoroacetate (61 mg.), m.p. 200°-220°, having the following n.m.r. spectrum in d6DMSO: 2.0 (s, 3H); 3.6 (s, 2H); 3.9 (s, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.2 (d, 1H); 5.6 (dd, 1H); 6.8 (s, 1H); 7.3 (s, 5H); 9.3 (d, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:16])#[N:11].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)=[O:16])#[N:11]
Reactant: N#Cc1cccc(C(=O)NCc2ccc(N)cc2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)NCc2ccc(NC(=O)c3ccccc3)cc2)c1

Procedure:
A solution of 0.6 g (4.2 mmol) of benzoylchloride in 10 ml of methylene chloride is added dropwise to a solution of 1 g (4 mmol) of 3-cyano-N-(4-amino-benzyl)-benzamide and 0.6 g (6 mmol) of triethylamine in 30 ml of methylene chloride at ambient temperature. After 8 hours at ambient temperature the product which has crystallised out is dissolved in methylene chloride and methanol. After extraction with water the combined organic extracts are dried and evaporated down.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[O:14][CH2:15][CH2:16][OH:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[O:14][CH2:15][CH2:16][O:17][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 68.7 %

Procedure:
A mixture of 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethanol (8.2 g, 24 mmol), p-toluenesulfonyl chloride (9.39 g, 49.3 mmol) and triethylamine (19 mL, 140 mmol) in methylene chloride (85 mL) was stirred at ambient temperature under nitrogen for 4.5 hours. It then was solvent evaporated and partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 63° C. for 30 minutes. The residue was purified by flash chromatography with 100% chloroform and 5% methanol in chloroform. It was dried in vacuo at 65° C. for 20 minutes to yield toluene-4-sulfonic acid 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethyl ester as a yellow solid (8.1 g, 69%); Mass spectrum (−EI, [M−H]−) m/z 490. 1HNMR (300 MHz, DMSO-d6): δ7.99 (d, 1H, J=9.02 Hz), 7.67-7.75 (m, 3H), 7.54-7.62 (m, 4H), 7.43 (d, 2H, J=7.93 Hz), 7.00 (dd, 1H, J=9.15 Hz and 2.80 Hz), 6.78 (d, 1H, J=2.81 Hz), 5.09 (s, 2H), 4.29-4.31 (m, 2H), 4.13-4.15 (m, 2H), 2.37 ppm (s, 3H). Elemental Analysis for C22H21NO8S 0.40 mol H2O: Calcd: C, 52.98; H, 4.41; N, 2.81; Found: C, 52.67; H, 4.26; N, 2.61.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH:14]C(C)(C)C)=[S:11].Cl>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH2:14])=[S:11]
Reactant: Cc1cccc(C)c1NC(=S)NC(=O)NC(C)(C)C
Agent: Cl
Product: Cc1cccc(C)c1NC(=S)NC(N)=O

Procedure:
A mixture of 25.6 g. (0.1 mole) of 1-(2,6-dimethylphenyl)-3-(t-butylcarbamyl)thiourea and 200 ml. of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, the solid filtered and washed with 10 ml. of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain 1-(2,6-dimethylphenyl-3-carbamylthiourea.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:22]=1[CH3:38].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:22]=3[CH3:38])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (157 mg, 0.594 mmol; described herein), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (162 mg, 0.59 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (150 μL, 0.59 mmol), and NMP (590 μL, 7.1 mmol), and heating in a microwave at 160° for 3 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.70 (1H, d, J=4.7 Hz), 7.98 (1H, d, J=8.2 Hz), 7.87-7.93 (2H, m), 7.83 (1H, d, J=11.7 Hz), 7.55-7.65 (2H, m), 7.38 (1H, m), 7.13-7.24 (1H, m), 6.46 (1H, d, J=2.7 Hz), 3.88-4.03 (4H, m), 3.77-3.88 (4H, m), 3.01-3.28 (4H, br. s.), 3.04-3.14 (4H, m), 2.23 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [OH-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[C:8]=1[C:9]([O:11]CCF)=[O:10].OC1C=CC=C(O)C=1C(O)=O.BrCCF.Cl>C(O)C>[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(OCCF)c1c(OCCF)cccc1OCCF
Agent: Cl
Agent: FCCBr
Agent: O=C(O)c1c(O)cccc1O
Solvent: CCO
Product: O=C(O)c1c(OCCF)cccc1OCCF
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
To a stirred solution of 3.0 grams (0.075 mole) of sodium hydroxide in 150 ml of ethanol was added 11.3 grams (0.039 mole) of 2-fluoroethyl 2,6-di(2-fluoroethoxy)benzoate (prepared by the method of Step A of Example 13 from 2,6-dihydroxybenzoic acid and three equivalents of 1-bromo-2-fluoroethane). The reaction mixture was stirred at room temperature for approximately 48 hours. The reaction mixture was filtered, and the filter cake was saved. The filtrate was evaporated under reduced pressure leaving a residue. The filter cake and residue were added to 200 ml of an aqueous, 10% hydrochloric acid solution. The resultant mixture was stirred at room temperature and was extracted with several portions of methylene chloride. The extracts were combined and dried over anhydrous magnesium sulfate. The dried organic phase was filtered, and the filtrate was evaporated under reduced pressure to yield 4.9 grams of 2,6-di(2-fluoroethoxy)benzoic acid as a solid, mp 57°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH:26]([F:28])[F:27])=[CH:13][CH:12]=1)=[O:10].[C:30](Cl)(=[O:32])[CH3:31].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:30](=[O:32])[CH3:31])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH:26]([F:27])[F:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (70 mg, 0.159 mmol) (intermediate 2) was treated with acetyl chloride (22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (0.5 ml) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2.0 h. THF was evaporated and the residue was washed with saturated sodium bicarbonate solution 5% HCl and water. The solid obtained was purified by silica gel column chromatography using 10% acetone-chloroform as eluent to obtain 25 mg of N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 234° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[O:18][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A solution of 3-benzyloxy-4-nitrophenol (EP application 095121) (6.3 g, 25.7 mmol), t-butyldimethychlorosilane (5.81 g, 38.6 mmol), imidazole (3.5 g, 51.4 mmol), and dimethylaminopyridine (2-3 mg) in DMF (20 mL) is stirred 18 h. The solution is poured into EtOAc and extracted once with water and five times with brine. The organic phase is dried, filtered, and concentrated to afford the title compound: 1H NMR (CDCl3δ 7.73 (d, J=9.1 Hz, 1H), 7.21 (m, 5H), 6.31 (d, J=2.5 Hz, 1H), 6.26 (dd, J=8.8, 2.5 Hz, 1H), 5.02 (s, 2H), 0.78 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21]O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:28]1[C:24](=[O:34])[C:25]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:26]2[C:27]1=[O:29]
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
In the manner given in Example 17, 3.47 g. (20.0 mmol) of 2',5-dichloro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with 3.24 g. (22.0 mmol) of phthalimide and 5.76 g. (22.0 mmol) of triphenylphosphine suspended in 200 ml. of cold (0°-5°) tetrahydrofuran and finally with 3.83 g. (22.0 mmol) of diethyl azodicarboxylate, added slowly over three-fourths hour. After overnight stirring, the resulting solid is filtered and crystallized to afford 2',5-dichloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.CS(C)=O.Cl>CO.C(OCC)(=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:24][CH2:23][C:22]4[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccc(OC)cc3)c3ccccc3nc21
Temperature: 0 °C
Reaction time: 48 h
Yield: 86.8 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (10 g, 0.043 mol), 4-methoxybenzylamine (13.0 g, 0.095 mol) and DMSO (75 ml) is heated at reflux overnight and then is allowed to stand for about 2 days. The reaction mixture is poured into ice water, and the resulting gum is treated with ethyl acetate. The product that oils out of the ethyl acetate is separated and then is dissolved in CH2Cl2. The CH2Cl2 layer is washed with water, then brine and then is dried over MgSO4 and evaporated under reduced pressure. The residue is dissolved in CH2Cl2 and purified by column chromatography on silica gel eluting with CH2Cl2 to afford the product as the free base. The free base is dissolved in methanol, and then is treated with methanolic HCl. A precipitate forms which is collected by filtration, washed with ether and dried in vacuo at 50° C. to afford 12.4 g of 1-ethyl-N-(4-methoxy phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.HCl.1/2 H2O, m.p. 179°-180° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=C(O)C=[CH:27][CH:28]=1.S(=O)(=O)(O)O.P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:19]3[C:18](=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[O:17][C:15](=[O:16])[CH:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1cn(Cc2ccccc2)cn1
Agent: O=S(=O)(O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3cn(Cc4ccccc4)cn3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1 mmol of ethyl 3-(1-benzyl-1H-imidazol-4-yl)-3-oxopropionate and 1 mmol of 3-methoxyphenol [150-19-6] is admixed dropwise at 0° C. with 0.5 ml of concentrated sulphuric acid. 0.25 ml of phosphoryl chloride is added and the reaction mixture is stirred at room temperature for 17 hours. It is poured into a 1:1 mixture of ice and saturated, aqueous sodium hydrogen carbonate solution and extracted with chloroform (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.