Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1([CH2:6][CH2:7][OH:8])C=CN=C1.C(N(CC)CC)C.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[C:22]1([CH3:23])[CH:24]=[CH:25][C:19]([S:16]([O:8][CH2:7][CH3:6])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: OCCn1ccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A portion of the crude 2-(imidazol-1-yl)ethanol (10 g, 89 mmol) and triethylamine (10.1 g, 100 mmol) were dissolved in methylene chloride (250 ml), tosyl chloride (17.5 g, 92 mmol) was added over 5 minutes as a solid, giving an exotherm to reflux. The reaction was stirred for 30 minutes at ambient temperature then quenched into 250 ml of 1M hydrogen chloride and 250 ml of methylene chloride. The organic phase was washed with brine and dried by passing it through a phase separator paper. Removal of the solvent by evaporation and purification by flash chromatography using methylene chloride/methanol/ammonia (100/10/1) gave 2-(imidazo]-1-yl)ethyl paratoluene sulphonate (10.95 g, 46%, impure). 4-Hydroxy-5-methoxy-2-nitrobenzamide (3 g, 15.3 mmol), (prepared as described for the starting material in Example 23), and 2-(imidazol-1-yl)ethyl paratoluene sulphonate (7 g, impure) were mixed in the presence of potassium carbonate (5 g, 72 mmol) and anhydrous DMF (20 ml) and heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and the DMF was removed by evaporation. The residue was resuspended in methylene chloride/methanol/ammnonia (100/10/1) and silica (15 g) was added. The solvent was removed by evaporation and the resulting powder was placed on the top of a silica gel column and eluted using first methylene chloride and slowly increasing the solvent polarity up to methylene chloride/methanol/ammnonia (100/10/1). Removal of the solvent by evaporation gave 4-(2-(imidazol-1-yl)ethoxy)-5-methoxy-2-nitrobenzaride as a cream solid (2.53 g, 55%).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[F:39][C:36]([F:37])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy} phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.04 (2H, d), 7.92 (2H, d), 7.58 (2H,dd), 7.26 (2H, m), 6.91 (2H, d), 6.79 (2H, d), 4.17 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16][CH3:17])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[OH:19]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16]([CH3:17])=[O:19])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: OO
Reactant: CSc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An amount of 32.6 gm (0.1 mol) of 2-chloro-4-(2,5-dichloro-4-methylmercaptophenoxy)-pyridine, prepared analogously to Example 1, was suspended in 100 ml of glacial acetic acid. The mixture was warmed to 45° to 50° C., and 11 ml (0.11 mol) of 30% H2O2 were added dropwise at such a rate that the internal temperature did not exceed 50° C. The mixture was then stirred for 3 hours at 50° C., after which it was cooled and poured into 300 ml of water. The batch was stirred until crystallization was complete, and the product was recovered by suction filtration, washed with water, dried, and recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:36]=[CH:35][C:21]([CH2:22][NH:23][C:24]([NH:26][NH:27]C(OC(C)(C)C)=O)=[O:25])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:43]>O1CCOCC1>[ClH:43].[ClH:43].[ClH:43].[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:36]=[CH:35][C:21]([CH2:22][NH:23][C:24]([NH:26][NH2:27])=[O:25])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CNC(=O)NNC(=O)OC(C)(C)C)cc3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CNC(=O)NN)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
To a suspension of tert-butyl 2-[(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}benzyl)carbamoyl]hydrazinecarboxylate (121.0 mg, 0.243 mmol) in anhydrous dioxane (1.2 ml) was added 4M hydrogen chloride dioxane solution (1.2 ml). After stirring at room temperature for 5 hrs, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (10 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. This operation was performed 3 times to azeotropically remove hydrogen chloride gas. The residue was suspended in a mixture of ethanol (3 ml) and ethyl acetate (6 ml), filtered, washed with ethyl acetate and dried under reduced pressure to give the title compound (111.0 mg, yield 90.1%) as a slightly yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].C(O)C>CC(C)=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])=[C:2]([OH:1])[CH:3]=1)=[O:6]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 14.7 %

Procedure:
The compound was prepared according to general procedure E with 3,4 dihydroxybenzaldehyde (3.7 mmol) in dry acetone (20 ml), anhydrous K2CO3 (2.3 mmol), and ethylbromoacetate (3.4 mmol) at 0°. The mixture was stirred at room temperature for 20 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate The crude product was purified by silica gel chromatography (eluent dichloromethane). 112 mg of purified compound were obtained (15% yield). 1H NMR (250 MHz, CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 4.28 (q, J=7.1 Hz, 2H), 4.78 (q, J=6.8 Hz, 1H) 6.95 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.55 (s, 1H), 9.86 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 15.2, 63.5, 67.1, 113.9, 117.1, 125.3, 132.8, 148.6, 152.4, 170.8, 193.3
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11](Cl)=[O:12])[CH:2]=[CH2:3].[CH3:14][NH2:15]>CCOCC>[CH3:14][NH:15][C:11]([CH:5]1[CH2:6][CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)=[O:12]
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Reactant: CN
Solvent: CCOCC
Product: C=CCC12C=CC(CC1C(=O)NC)C2
Reaction time: 1 h

Procedure:
With cooling, 9.8 g of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are added dropwise to 50 ml of a 40% aqueous methylamine solution. After 1 hour at 20° C., 100 ml of ether are added. The organic phase is separated, and working up is effected as described in Example 4, affording 8.0 g (84% of theory) of a yellow liquid. For the purpose of characterisation, a sample is distilled in a bulb tube; nD20 =1.5160; η25 =420 mPas.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[OH-]>O1CCCC1.O>[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([NH2:3])=[O:27])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CNC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to a solution of 4.6 g of 3-benzyloxycarbonylamino-2,2-di(methyl)propanol obtained in Reference Example (2a) (19.4 mmol) in a mixed solvent of carbon tetrachloride (40 ml), acetonitrile and water (40 ml), and the mixture was stirred at room temperature for 16 hours. 11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for three days. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 3.16 g of crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid. 3.0 g of 1,1′-carbonylbis-1H-imidazole (18.5 mmol) was added to a solution of 3.1 g of the crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid obtained above (12.3 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for one hour. 20 ml of a 28% ammonia aqueous solution (914 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with a 1 M hydrochloric acid aqueous solution and brine and dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate/n-hexane=2/1-3/1) to obtain 2.54 g of the title compound (yield: 54%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][C:13]#[N:14])[C:4]=2[CH:3]=C1.C([OH:17])C>>[CH:3]([C:4]1[C:5]([OH:1])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]#[N:14])=[O:17]
Reactant: CCO
Reactant: N#CCCOc1cccc2occc12
Product: N#CCCOc1cccc(O)c1C=O

Procedure:
3-(4-Benzofuranyloxy)propionitrile (0.935 g, 8 μM) was dissolved in absolute ethanol (225 ml) and ozonised in an analogous manner to that described in example 5(B) to give 3-(2-formyl-3-hydroxyphenoxy)propionitrile which was recrystallised from ethyl acetate/petrol, m.p. 84°-86° C. (Found: C, 62.56; H, 4.79; N, 6.99. C10H9NO3 requires C, 62.38; H, 4.71; N, 7.33%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]([CH3:22])([CH3:21])[CH:14]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[N:30]([Si](C)(C)C)=[C:31]=[O:32]>ClCCl>[CH3:21][C:15]1([CH3:22])[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH2:1][N:2]([C:31]([NH2:30])=[O:32])[CH2:3][CH2:4]3)=[O:12])=[CH:14]1
Reactant: CC1(C)C=C(C(=O)c2ccc3c(c2)CCNC3)C(C)(C)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C=C(C(=O)c2ccc3c(c2)CCN(C(N)=O)C3)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of the product of Example 10j (59 mg, 0.2 mmol) in dichloromethane (5 mL) was added triethylamine (110 mg, 1.0 mmol) and isocyanatotrimethylsilane (94 mg, 0.8 mmol) and stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (47 mg, Yield: 69%). Mp=78.6-79.7° C.; Rf 0.3 (10:1 dichloromethane/methanol); 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H), 5.79 (s, 1H), 4.63 (s, 2H), 4.52 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H), 1.59 (s, 4H), 1.24 (s, 6H), 1.06 (s, 6H) ppm; Mass spectrum (ESI +ve) m/z 341 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH3:20][O:21][C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)=[O:23]>>[CH3:20][O:21][C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:13]2[C:14]3[C:2]([CH3:1])=[C:3]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:4]=[CH:5][C:6]=3[C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:26][CH:25]=1)=[O:23]
Reactant: COC(=O)Cc1ccc2c([nH]c3ccccc32)c1C
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)Cc1ccc2c3ccccc3n(Cc3ccc(C(=O)OC)cc3)c2c1C

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using methyl (1-methylcarbazol-2-yl)acetate and 4-methoxycarbonylbenzyl bromide as starting materials, the title compound was obtained as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Br)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:36]2[CH:35]=[CH:34][C:33]([F:32])=[C:38]([F:39])[CH:37]=2)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(F)c(F)c3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 90 °C
Yield: 99.8 %

Procedure:
9-Benzyloxy-6-[(2-bromophenyl)methyl]-2-isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione (169) (150 mg, 0.311 mmol) and 3,4-difluorphenylboronic acid (56.5 mg, 0.358 mmol) were suspended in a mixture of toluene/ethanol (10 ml/1 ml), treated at room temperature under argon with tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.4 μmol) and 2M sodium carbonate solution (342 μl, 684 μmol) and the reaction mixture was then heated at 90° C. for 7 h. The reaction was quenched with water and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 25 g silica gel with methanol/dichloromethane (gradient: 0 to 10% methanol). All fractions containing product were combined and concentrated to afford 9-benzyloxy-6-[[2-(3,4-difluorophenyl)phenyl]methyl]-2-isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione (160 mg) as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]([OH:37])[CH2:6][C:7]2[N:8]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=[CH:10][N:11]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
Butyllithium (1.6M in hexanes) (4.24 mL, 6.78 mmol) was added dropwise to 2-methyl-1-trityl-1H-imidazole (Intermediate 85) (2.0 g, 6.16 mmol) in THF (30 mL) cooled to −78° C. over a period of 20 minutes under nitrogen. The resulting dark red solution was stirred at −78° C. for 30 minutes then a solution of 4-Chlorobenzaldehyde (0.867 g, 6.16 mmol) in THF (10 mL) added dropwise. The reaction was allowed to warm slowly to 0° C. then quenched with saturated NH4Cl (50 mL) and extracted with TBME (2×). The combined extracts were washed with brine, dried over MgSO4, concentrated by evaporation then purified by flash silica chromatography, elution gradient 20 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanol (1.810 g, 63.1%) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]=[C:39]=[O:40])[CH:33]=1>C1COCC1>[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=2)=[O:40])=[C:3]([F:24])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A 0° C. solution of Example A5 (200 mg 0.58 mmol) and pyridine (68 mg, 0.87 mmol) in THF (20 mL) was treated with 1-fluoro-3-isocyanato-benzene (80 mg, 0.58 mmol), warmed to RT and stirred for 3 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea (193 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.87-7.49 (br. s, 1H), 7.59 (d, J=10.8 Hz, 1H), 7.48 (d, J=11.6 Hz, 1H), 7.33 (m, 1H), 7.08 (m, 1H), 6.83 (m, 1H), 6.44 (s, 1H), 4.18 (m, 2H), 2.94 (s, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI): m/z 484.1 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1C=CC=C[CH:3]=1.[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH:10]1[CH2:19][OH:20]>>[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH:10]1[CH2:19][O:20][CH2:3][CH:2]1[O:8][CH2:1]1
Reactant: OCC1COc2ccccc2O1
Reactant: OCc1ccccc1
Product: c1ccc2c(c1)OCC(COCC1CO1)O2

Procedure:
In a similar manner to Example (1a), with benzyl alcohol replaced by (1,4-benzodioxan-2-yl)methanol, 1-[(1,4-benzodioxan-2-yl)methoxy]-2,3-epoxypropane is obtained. The latter derivative, when condensed according to Example (1b) with 2-aminoethyl hydrogen sulfate, leads to the derivative of formula: ##STR26## Empirical formula: C18H23NO8Molecular mass: 381.38
Reaction SMILES: [N-]=C=O.[N-]=C=O.C1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-])=O.NC1C=CC=CC=1.C=O>C1C=CC=CC=1>[CH2:13]=[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]1[NH:20][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: C=O
Agent: [N-]=C=O
Solvent: Nc1ccccc1
Solvent: c1ccccc1
Product: C=C1C=CC=CC1Nc1ccccc1

Procedure:
The invention relates to a process for preparation and distillative workup of diphenylmethane diisocyanate, referred to hereinafter as MDI for short, proceeding from a benzene-comprising feed stream, in which benzene is nitrated to nitrobenzene which is hydrogenated to aniline, aniline is reacted with formaldehyde to give methylenediphenylamine (MDA) and MDA is phosgenated to MDI. In this process, not the pure products but at first product mixtures are obtained in each process step, which are purified before further processing.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:1]1([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 83 %

Procedure:
A solution of phenyl acetic acid (27.2 g.), benzyl alcohol (21.6 g.) and p-toluenesulfonic acid (380 mg.) in 100 ml. of toluene was heated under reflux under a Dean-Stark trap until the theoretical (3.6 ml.) quantity of water had been collected. On cooling, the solution was washed with dilute NaHCO3 and saturated NaCl and solvent was removed in vacuo.. The resulting oil was distilled at 125°-129° (0.4 torr)1 to give pure benzyl phenylacetate, 37.7 g. (83% yield). ##STR230##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.C([N:36]1[CH2:40][CH2:39][NH:38][C:37]1=[O:41])(=O)C>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:40][CH2:39][NH:38][C:37]5=[O:41])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 60.8 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (223 mg) described in Preparation Example 240 and 1-acetylimidazolidin-2-one (83 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (137 mg) was obtained.