Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1cccc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 45 °C
Yield: 65.8 %

Procedure:
To a cold (0° C.) solution of 6-chloro-2-picoline (21.4 mL, 196.0 mmol) and ethyl 4-fluorobenzoate (57.5 mL 391.2 mmol) in tetrahydrofuran (311 mL) was added lithium bis(trimethylsilyl)amide (391 mL, 1.0 M in tetrahydrofuran, 391.0 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resultant solution was heated to 45° C. for 15 hours. The mixture was cooled to room temperature and quenched by the addition of water. Ether was added and the organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by recrystallization from ethyl acetate-hexanes to provide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (32.2 g, 66%) as a tinted off-white solid existing as a keto-enol tautomeric mixture. 1H NMR (CDCl3): for the keto tautomer δ 8.11 (m, 2 H), 7.66 (t, 1 H), 7.30–7.25 (m 2 H), 7.17 (t, 2 H), 4.48 (s 2 H), 19F NMR (CDCl3) δ −104.72 (keto), −111.64 (enol); MS m/z 250 (M+1).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)[NH2:2].[C:13](=S)=[S:14].C(N(CC)CC)C.S>N1C=CC=CC=1>[N:1]1[N:2]=[C:13]([SH:14])[N:4]2[N:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=12
Reactant: S=C=S
Reactant: NNc1nncc2ccccc12
Agent: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Sc1nnc2c3ccccc3cnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In pyridine, was dissolved 25 g of 1-hydrazinophthalazine. Thereto, 13 g of carbon disulfide was added dropwise at a temperature of 0° C. The stirring was continued for 30 minutes and then, the temperature of the reaction mixture was raised to 50° C., and the stirring was continued for additional 1 hour. Thereafter, the temperature was lowered to 0° C. again. Upon the addition of excess triethylamine to the resulting solution, hydrogen sulfide gas began to evolve. The temperature of the reaction system was raised and the refluxing was continued for 3 hours. Thereupon, the evolution of the gas ceased, and the reaction system was cooled. Upon cooling, crystals separated out. The crystals were filtered off, and recrystallized from ethanol. Yield 23 g, Melting Point 270°-280° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)=[O:14]>CCCCCC.C1COCC1>[OH:14][CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Nc1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.1 %

Procedure:
Butyllithium, 1.6M in hexane (146 ml) was added dropwise at −78° C. under N2 flow to a solution of 2-bromopyridine (0.1348 mol) in THF (300 ml). The mixture was stirred at −78° C. for 20 minutes. A solution of N-(4-formylphenyl)acetamide (0.1226 mol) in THF (300 ml) was added at −60° C./−70° C. The mixture was stirred at −60° C./−70° C. for 1 hour, then poured out into ice water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (27 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether and 2-propanone. The precipitate was filtered off and dried, yielding 5.09 g (17%) (±)—N-[4-[hydroxy(2-pyridinyl)methyl]phenyl]acetamide (compound 688).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](O)[C:11]3[C:12](=[N:14][N:15]([CH3:17])[CH:16]=3)[N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[C:11]2[C:12](=[N:14][N:15]([CH3:17])[CH:16]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc2c(O)cc(-c3ccc(Cl)cc3)nc2n1
Product: Cn1cc2c(Cl)cc(-c3ccc(Cl)cc3)nc2n1

Procedure:
Following the procedure of Example 2, 37.8 g. of 6-(4-chlorophenyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ol (0.146 mol.) and 165 ml. of phosphorus oxychloride yield 35.1 g. (86%) of 4-chloro-6-(4-chlorophenyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine, recrystallized from ethanol; m.p. 177°-179°.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][N:7]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:8]([NH2:10])=[S:9].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O>>[CH:11]1([N:7]([C:8]2[S:9][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[N:10]=2)[CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Reactant: COC(=O)CCCN(C(N)=S)C1CCCC1
Product: CC(C)c1ccc(-c2csc(N(CCCC(=O)O)C3CCCC3)n2)cc1

Procedure:
4-{Cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-butyric acid was prepared according to general procedure B using 4-(1-cyclopentyl-thioureido)-butyric acid methyl ester (70 mg, 0.3 mmol) and 2-bromo-4′-isopropylacetophenone (80.0 mg, 0.3 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the ester, which was hydrolyzed following general procedure T. LCMS m/z: 374 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][S:2]([O:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(OCCCc2ccc(OCc3ccccc3C(=O)O)cc2)cc1
Yield: 23.8 %

Procedure:
Methyl 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]methyl}benzoate (0.38 g, 0.81 mmol) was dissolved in a mixture of THF/water (7/1, 4 ml) and lithium hydroxide (9.3 mg, 0.39 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 88 mg of 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]-methyl}benzoic acid (yield 23.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][CH:35]=[CH:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2cccc2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 31 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), pyrrole (0.42 g) and dimethylformamide (25 ml), the title compound (0.60 g) was obtained as an amorphous solid, MS, m/z: 388.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(CCCl)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloropropiophenone (25.2 g) was dissolved in abs. ethanol (200 ml), NaBH4 (2.2 g) was slowly added and the mixture stirred overnight at R.T. The mixture was filtered and the filtrate evaporated to dryness. H2O was added and the solution extracted with ether, the ether phase dried (MgSO4) and evaporated. The resulting oil purified on silicagel CH2Cl2 as eluent giving 3-chloro-1-phenyl-1-propanol (compound 14), identified by 1H NMR.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:33])([CH3:32])[CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:8]=1[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[OH:4][CH2:3][CH2:2][O:5][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:33])([CH3:32])[CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:8]=1[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1
Reactant: OCCO
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)COC3CCCCO3)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)COC4CCCCO4)cc3)ncnc2OCCO)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Sodium (35.65 g) is gradually added to ethylene glycol (1.3 liter) at 23-75° C., and thereto is added N-[6-chloro-5-(4-methylphenyl)pyrimidin-4-yl]-4-[2-(2-tetrahydropyranyloxy)-1,1-dimethylethyl]benzenesulfonamide (160 g) at 4° C. The mixture is stirred at 100° C. for 16 hours, and allowed to cool to room temperature. The reaction mixture is poured into a mixture of a saturated aqueous ammonium chloride solution and ethyl acetate under ice-cooling, and the mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, and the organic layer is dried over anhydrous sodium sulfate and activated carbon. The solid materials are removed by filtration through a Celite pad, and the filtrate is concentrated under reduced pressure. The residue is crystallized from ethyl acetate-diisopropyl ether to give N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)-pyrimidin-4-yl]-4-[2-(2-tetrahydropyranyloxy)-1,1-dimethyl-ethyl]benzenesulfonamide (80.26 g) as colorless crystals. In addition, the mother liquor is concentrated, and the resultant is recrystallized from ethyl acetate-diisopropyl ether to give the crystals of the above compound (73.1 g).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:16]=3)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.CCOCC>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:22]([C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:13]([C:9]4[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][C:10]=4[CH3:12])[NH:14]3)=[CH:19][CH:18]=2)=[O:34])=[CH:25][CH:26]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(CCC(=O)O)cc(C)c1-c1cc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1
Temperature: 50 °C

Procedure:
A mixture of 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-indol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester and 1N NaOH (500 μL) in THF (5 mL) was heated at 50° C. for 18 h. The mixture was cooled and was neutralized with one equivalent of 1N HCl and partitioned between water and ethyl acetate. The ethyl acetate layer was dried, filtered, and the solvent removed under reduced pressure to leave an oil, which was twice taken up in ether and solvent removed under reduced pressure to give 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-indol-2-yl]-3,5-dimethylphenyl}-propionic acid. 1H NMR (Acetonitrile-d3, 400 MHz): δ 9.62 (s, 1H), 8.72 (s, 1H), 8.04 (s, 1H), 7.63 (m, 4H), 7.40 (d, J=8.7 Hz, 2H), 7.03 (s, 2H), 6.40 (s, 1H), 2.87 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.11 (s, 6H), 1.32 (s, 9H). MS (m/z) 469.3 (M+1); Retention time=1.50 min (Method 10).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C(O)C>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:20][C:2]=2[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(=S)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1sc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 68.2 %

Procedure:
A mixture of 2-bromo-4′-chloropropiophenone (45.0 g), thiobenzamide (24.7 g), sodium acetate (14.8 g) and ethanol (400 mL) was stirred with heating under reflux for 3 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 4-(4-chlorophenyl)-5-methyl-2-phenylthiazole (35.1 g, 68%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90–91° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[CH2:18][OH:19])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([O:23]CC)=[O:22].C(O)C.[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[CH2:18][OH:19])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cc2c(=O)c3cc(C(C)CO)ccc3oc2nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CO)c1ccc2oc3nc(N)c(C(=O)O)cc3c(=O)c2c1
Temperature: 50 °C
Yield: 87.6 %

Procedure:
A mixture of ethyl 2-amino-7-(2-hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (480 mg), ethanol (40 ml), water (5 ml) and 1N sodium hydroxide (5 ml) was heated at 50° C. for 80 minutes, which was then concentrated. The concentrate was dissolved in water, which was made acid with 10% hydrochloric acid. Resulting precipitates were collected by filtration, washed with water, and recrystallized from dimethylformamide-ethanol-water to yield colorless crystals (386 mg) of 2-amino-7-(2-hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano-[2,3-b]pyridine-3-carboxylic acid, m.p. >300° C.
Reaction SMILES: C[O-].[Na+].Br[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=1.[CH2:21]([SH:24])[CH2:22][CH3:23].O>CO>[CH2:21]([S:24][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=1)[CH2:22][CH3:23]
Reactant: CCCS
Reactant: FC(F)(F)c1ccncc1-c1ncc(CBr)o1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCSCc1cnc(-c2cnccc2C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium methoxide (130 μl, 30% in methanol) was added to a solution of 5-bromomethyl-2-(4-trifluoromethyl-3-pyridyl)-oxazole (160 mg) and n-propanethiol (60 μl), in methanol (7 ml), and the mixture was stirred at room temperature for 4 hours. Water (50 ml) was then added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. This gave the desired product in pure form as a pale yellow oil.
Reaction SMILES: C([O:8][N:9]([CH2:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([O:35]CC3C=CC=CC=3)[C:32]([NH2:34])=[O:33])=[CH:26][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([NH2:12])=[O:11])C1C=CC=CC=1.[H][H]>CN(C)C=O.C(O)C.[C].[Pd]>[OH:35][N:31]([CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]2[CH:43]=[CH:44][C:14]([CH2:13][N:9]([OH:8])[C:10]([NH2:12])=[O:11])=[CH:15][CH:16]=2)=[CH:25][CH:26]=1)[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)N(Cc1ccc(OCCCCOc2ccc(CN(OCc3ccccc3)C(N)=O)cc2)cc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: NC(=O)N(O)Cc1ccc(OCCCCOc2ccc(CN(O)C(N)=O)cc2)cc1
Yield: 62 %

Procedure:
1,4-Bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane (1.94 g) was dissolved in 45 ml of dimethylformamide-ethanol (8:1), mixed with 0.29 g of 10% palladium carbon and then the mixture was stirred for 22 hours at room temperature in an atmosphere of hydrogen. The catalyst was removed by filtration using Celite, and the solvent was evaporated under a reduced pressure to obtain 0.84 g of 1,4-bis[4-[(1-hydroxyureido)methyl]phenoxy]butane.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:30]([O:29][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][C:6]([OH:37])=[O:5])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[S:16]1(=[O:28])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(=O)O)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of 3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (420 mg, 0.77 mmol) in 6 mL of TFA/methylene chloride (1:1) is stirred at RT for 20 min. The solvent is removed under reduced pressure. Methylene chloride is added and removed (4×) to give the title compound as an oil: (M−1)−=489.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:18]1C=CC=C[CH:19]=1>C(O)C.S(=O)(=O)(O)O>[CH2:18]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=1)[CH3:19]
Reactant: c1ccccc1
Reactant: O=C(O)c1ccccc1Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1

Procedure:
A mixture of 560.0 g of 2-(4-bromophenoxy)benzoic acid in 1940 ml of absolute benzene, 218 ml of absolute ethanol and 32.6 ml of concentrated sulphuric acid is boiled under reflux for 32 hours, the water that forms being removed in a water separator. The reaction mixture is cooled to 10° and, with the addition of ice, is washed with 1000 ml of water, 500 ml of a 2N aqueous sodium carbonate solution and then once more with 1000 ml of water. The organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation at 40° at a pressure of 11 mm Hg. The residue is distilled in a high vacuum and yields the 2-(4-bromophenoxy)benzoic acid ethyl ester. Boiling point 140°-150°/0.05 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]([CH3:25])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: Clc1ccc2cc(-c3cncc(OCc4ccccc4)c3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(-c2cncc(OCc3ccccc3)c2)cc2ccc(Cl)cc21
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1H-indole (Example 98, 0.435 g, 1.29 mmol), dimethyl carbonate (0.328 mL, 3.89 mmol), potassium carbonate (0.098 g, 0.714 mmol) and DMF (3 mL). The reaction mixture is stirred at 150° C. overnight. It is then cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo, to give a residue which is purified by flash chromatography (heptane-ethyl acetate, 1:1) to afford 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.70 (s, 3H), 5.31 (s, 2H), 6.67 (d, J=0.8 Hz, 1H), 7.10 (dd, J=8.3, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.41-7.47 (m, 2H), 7.49-7.55 (m, 3H), 7.57 (d, J=8.3 Hz, 1H), 7.64 (dd, J=2.5, 1.8 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H); HRMS (ESI) m/z 349.1108 [(M+H)+ Calcd for C21H18ClN2O: 349.1108].
Reaction SMILES: C([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:26][CH3:27])[C:14]([CH2:23][CH:24]=[CH2:25])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH4+:8].[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([CH2:23][CH2:24][CH3:25])[C:13]([O:26][CH3:27])=[C:12]2[C:17]=1[C:18](=[O:19])[NH:8][S:9]2(=[O:10])=[O:11])[CH3:22]
Reactant: C=CCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(Cc1ccccc1)C2=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)NC2=O
Yield: 201.6 %

Procedure:
By the method of part D of Example 45 2-benzyl-4-ethoxy-6-allyl-7-methoxysaccharin (2.35 g) was simultaneously debenzylated and hydrogenated with ammonium formate (1.51 g) and palladium on carbon (10%, 1.25 g) in methanol (70-100 mL) affording 4-ethoxy-6-propyl-7-methoxysaccharin ammonium salt (1.94 g), phenylthiomethylation of which with chloromethyl phenyl sulfide (0.95 g) in dimethylformamide and purification of the product (a yellow oil, 2.67 g) by column chromatography on silica gel using dichloromethane-hexane (80:20) as eluant afforded 2-phenylthiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin, 0.85 g, 34% yield.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[N:11]=[C:10]([NH:12][C:13]3[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2nc(Nc3cccc(Cl)c3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above-prepared (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (155 mg, 0.6 mmol) and 3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed in tert-butanol (3 mL) over 20 h. The mixture is concentrated in vacuo and the residue is suspended in EtOH/H2O (1 mL/3 mL). K2CO3 (83 mg, 0.6 mmol) is added and the suspension is stirred for 2 h at room temperature. The solid that forms is collected and dried under vacuum to give the product [2-(3-chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.