Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:52][C:49]([CH2:50][OH:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:47]=[CH:48][C:49]([CH2:50][OH:51])=[CH:52][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(CO)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(CO)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminobenzyl alcohol as the aniline component. (32%, MS=486.2 (M+H))
Reaction SMILES: [C:1]([N:8]([CH2:13][CH2:14][CH3:15])[O:9][CH2:10][CH:11]=[CH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CCOC(C)=O.[Pd]>[C:1]([N:8]([CH2:13][CH2:14][CH3:15])[O:9][CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C=CCON(CCC)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCON(CCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
N-Boc-N-propyl-O-allylhydroxylamine (6.0 g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5 g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (5.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH:10](C(C)=O)[C:11](OCC)=O>C(O)C.N1C=CC=CC=1>[O:8]1[CH2:11][CH:10]=[N:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]1=2
Reactant: Nc1cnccc1O
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: C1=Nc2cnccc2OC1

Procedure:
The reaction of 3-amino-4-hydroxypyridine with ethyl 2-chloroacetoacetate in a mixture of ethanol and pyridine to give a pyrido[4,3-b][1,4]oxazine is the only example reported for the formation of this ring system [Takahashi, T. and Yoneda, F., Chem. Pharm. Bull (Japan), 1955, 3, 331]. In contrast, several groups have investigated the preparation and evaluation of pyrimido[4,5-b][1,4]oxazines as potential antifolates [Elion, G. B. and Hitchings, G. H., J. Amer. Chem. Soc., 1952, 74, 3877; Dunn, D. L. and Skinner, C. G., J. Org. Chem., 1975, 40, 3713; Lin, S.-C., Holmes, G. P., Dunn, D. L. and Skinner, C. G., J. Med. Chem., 1979, 22, 741; Winchester, M. J., J. Heterocycl. Chem., 1979, 16, 1455; Winchester, M. J., Zappone, L. J., and Skinner, C. G., J. Heterocycl. Chem., 1981, 18, 455]. The formation of pyrimido[4,5-b][1,4]oxazines from polyfunctional pyrimidines (e.g., 2,4,5-triamino-6-hydroxypyrimidine) and alpha-halo carbonyl compounds in a mixture of water and ethanol has been studied in detail by Wood and coworkers [Mirza, J., Pfleiderer, W., Brewer, A. D., Stuart, A., Wood, H. C. S., J. Chem. Soc., C., 1970, 437]. Although these reactants might possibly generate a number of bicyclic ring systems, only dihydropteridines were observed either as a minor or major by-product. Apparently pyrimido[4,5-b][1,4]oxazines are only formed from pyrimidines in which the hydroxy group is conjugated with an electron donating group containing a lone pair of electrons [Mirza, J., Pfleiderer, W., Brewer, A. D., Stuart, A., Wood, H. C. S., J. Chem. Soc., C., 1970, 437; Russell, P. B., Elion, G. B., and Hitchings, G. H., J. Amer. Chem. Soc., 1949, 71, 474].
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([OH:15])=O.S(Cl)(Cl)=O.[OH-].[NH4+:21]>ClCCl>[Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([NH2:21])=[O:15]
Reactant: CCn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCn1nc(C(F)(F)F)c(C(N)=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 22.5 g (91.6 mmol) of 5-chloro-1-ethyl-3-(trifluoromethyl)pyrazole-4-carboxylic acid and 45 mL of thionyl chloride was prepared and heated to reflux with stirring for 3 hours. The slurry became a dark orange solution. The excess thionyl chloride and other volatiles were removed by evaporation under reduced pressure to obtain a dark brown oil. This was taken up in 250 mL of dichloromethane and the resulting solution was cooled to about 0° C. and treated with 100 mL of concentrated ammonium hydroxide, which was added dropwise with stirring and cooling. When the addition was complete, the mixture was allowed to warm to ambient temperature and stir over a 2-hour period. The solids were collected by filtration and washed with water (3×50 mL). The solids that formed in the filtrate due to evaporation of the dichloromethane were collected in the same way. The combined solids were washed with water (2×100 mL) and were then suspended in water for 2 hours, recollected by filtration, and dried in an oven under reduced pressure. The white solid obtained was 18.4 g of the title compound melting at 15°-152° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].[CH:18](O)=[O:19]>O>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH:18]=[O:19]
Reactant: O=CO
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCN(C=O)c1ccc([N+](=O)[O-])cc1

Procedure:
1.4 g (6.7 mmol) of 4-(2-dimethylamino-ethylamino)-nitrobenzene (Example 326a) are refluxed for 4 hours in 20 ml of formic acid. Then the solvent is eliminated in vacuo, the residue taken up in water and combined with 2 N sodium hydroxide solution until an alkaline reaction is obtained. The mixture is extracted with ethyl acetate, the combined organic phases are dried over magnesium sulphate and the solvent is eliminated in vacuo. The product is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([CH:22]3[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:30])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:30])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([CH:22]3[CH2:27][CH2:26][C:25]([CH3:28])([CH3:29])[CH2:24][CH2:23]3)[N:17]=2)[CH:14]=1
Reactant: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(F)(F)F)c(F)cc3Cl)[nH]c2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(n2nc(-c3cc(CN)c(F)cc3Cl)[nH]c2=O)CC1
Yield: 89 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-124, 1.0 g), KOH (1.0 g), water (5 mL) and THF (40.0 mL) to afford 0.700 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H][H]>[OH-].[OH-].[Pd+2]>[CH3:23][NH:22][S:19]([CH2:18][C:4]1[CH:5]=[C:6]2[C:10](=[CH:2][CH:3]=1)[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])(=[O:20])=[O:21]
Reactant: [H][H]
Reactant: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 58 %

Procedure:
A solution of (R)-7-bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (193 g) in industrial methylated spirit (950 mL) containing Pearlman's catalyst (47.6 g total) was exposed to hydrogen gas (50 psi). The catalyst was then filtered through an Arbacel pad, washing with hot industrial methylated spirit (2×100 mL) and the combined filtrate and washings evaporated in vacuo to an organic residue. The filtered solids (catalyst+filter aid) were then reslurried in 2N hydrochloric acid (500 mL) then refiltered (through Arbacel)and the filtrand washed with 2N hydrochloric acid (4×250 mL) and water (2×100 mL). The aqueous filtrate and washes were combined with the organic residue and then once washed with ethyl acetate (1000 mL). The aqueous solution was chilled then made basic by addition of 40% aqueous sodium hydroxide solution precipitating the title compound as a pale-yellow solid. This solid was filtered, washed with water (2×100 mL) and dried in vacuo to give the title compound (89.9 g). TLC (methyl iso-butyl ketone/acetic acid/water 2:1:1 Top phase): Rf=0.23. 1H NMR (d6 DMSO) δ10.85 (s, 1H), 7.5 (s, 1H), 7.3 (d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.8 (q, 1H), 4.35 (s, 2H), 3.0 (m, 2H), 2.55-2.4 (d, 3H and m, 2H), 2.35 (s, 3H), 2.1 (m, 1H), 1.7-1.4 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24]CC)=[O:23])=[CH:10]1.[C:27](#[N:29])[CH3:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([NH:29][CH:27]3[CH2:2][CH2:3][NH:9][CH2:10][CH2:28]3)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: CC#N
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(NC3CCNCC3)c(F)cc2c1=O
Reaction time: 2 h
Yield: 74 %

Procedure:
Ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-naphthyridine-3-carboxylate (0.5 g, 1.3 mmole) and (3-N-ethoxycarbonyl)aminopyrrolidine (0.3 g, 1.74 mmole) in acetonitril (5 ml) was stirred at 80° C. for 3 hr and cooled. Solvent was concentrated to dryness and 5% aqueous NaOH (10 ml) was added to reaction mixture and stirred for 2 hr, acidified with conc. HCl solid separated was filtered, dried to furnish the required product. Yield 74%, m.p >320° C., C20H17F3N4O3, m/z 419. (M+1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)[CH2:18][CH2:19][CH2:20][CH3:21])[CH3:17]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCCCC(Br)C(=O)OCC
Product: CCCCC(Nc1ccc2[nH]ncc2c1)C(=O)OCC

Procedure:
2-(1H-Indazol-5-ylamino)-hexanoic acid ethyl ester was prepared from 1H-indazol-5-ylamine and ethyl 2-bromohexanoate similarly to the method described in Example 3, step 1 above, (6.81 g, 24.8 mmol, 65%) as a beige solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]([CH3:13])[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5].[CH2:17]1COC[CH2:18]1>>[CH3:13][N:10]1[C:9]2[CH:14]=[CH:15][C:6]([C:4](=[O:5])[CH2:17][CH3:18])=[CH:7][C:8]=2[N:12]=[CH:11]1
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2C
Reactant: C1CCOC1
Product: CCC(=O)c1ccc2c(c1)ncn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of N-methoxy-N,1-dimethyl-1H-benzo[d]imidazole-5-carboxamide (900 mg, 1.0 eq) in 30 mL anhydrous THF was added 3 M EtBrMg (9 mL, 6.0 eq) slowly at 0° C. The reaction was stirred at rt overnight, quenched with sat NH4Cl (aq), and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (730 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.04 (J=8.4 Hz, 1.6 Hz, 1H), 7.95 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.10 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][CH:14]([C:25]([NH2:27])=[O:26])[NH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:13]1[CH:14]([C:25]([NH2:27])=[O:26])[CH2:15][C:16]2[CH:21]=[C:20]3[O:22][CH2:23][O:24][C:19]3=[CH:18][C:17]=2[C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[N:12]1)(=[O:31])[CH3:30]
Reactant: Cc1cc(C2=NNC(C(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1C(N)=O)OCO3
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
3.68 g (10.0 millimoles) of (±)-7,8-dihydro-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carboxylic acid-amide are suspended in 30 ml of acetic anhydride and stirred at room temperature for 48 hours. The reaction mixture is cooled with icecold water, the precipitated product is filtered and washed with 20 ml of diethyl ether. Thus 3.32 g of the desired compound are obtained, yield 81%, mp.: 157–161° C.
Reaction SMILES: [H-].[Na+].CC(C)([O-])C.[K+].[C:9](=[O:14])([O:12][CH3:13])OC.[CH2:15]1[C:19]2([CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[CH2:18][CH2:17][CH2:16]1>O1CCCC1.C(OCC)(=O)C.O.C(O)(=O)C>[CH3:13][O:12][C:9]([CH:21]1[CH2:22][CH2:23][CH2:24][C:19]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:20]1=[O:25])=[O:14]
Reactant: COC(=O)OC
Reactant: O=C1CCCCC12CCCC2
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1CCCC2(CCCC2)C1=O

Procedure:
To a suspension of 60% sodium hydride (4.59 g) and potassium tert-butoxide (1.52 g) in tetrahydrofuran (100 mL) was added dimethyl carbonate (7.89 mL) under argon atmosphere at 85° C. To this mixture was added dropwise a solution of spiro[4.5]decan-6-one (8.74 g) obtained in the same manner as in Step 1 in tetrahydrofuran (70 mL) over 1.5 hours. The reaction mixture was heated under reflux for 3 hours. After ice-cooling, to the reaction mixture were added successively acetic acid (7.3 mL), water (85 mL) and ethyl acetate (175 mL), followed by separation of the organic layer. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:100 to 1:90) to give 6-oxo-spiro[4.5]decane-7-carboxylic acid methyl ester (9.99 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH:14]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:15]([F:18])([F:17])[F:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8](N)=[CH:7][CH:6]=2.N([O-])=O.[Na+].NC(N)=O.[I-:33].[K+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>Cl.O>[Cl:1][C:2]1[C:3]([O:13][CH:14]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:15]([F:18])([F:17])[F:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([I:33])=[CH:7][CH:6]=2
Reactant: [I-]
Reactant: Nc1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(Cl)nc2c1
Agent: Cl
Agent: NC(N)=O
Agent: O=C([O-])O
Solvent: O
Product: FC(F)(F)C(Oc1nc2ccc(I)cc2nc1Cl)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
In 2.0 mol/L hydrochloric acid (50.0 mL) was dissolved 3-chloro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy) quinoxaline-6-amine (2.00 g, 5.64 mmol) obtained in Step 3 and the mixture was cooled to 0° C. Sodium nitrite (506 mg, 7.33 mmol) was added and the mixture was stirred at 0° C. for 10 minutes. Urea (508 mg, 8.46 mmol) was added to the reaction mixture and the mixture was stirred at 0° C. for 10 minutes. Potassium iodide (2.34 g, 14.1 mmol) dissolved in water (10.0 mL) was slowly added and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/2) to give Compound A47 (868 mg, 33% yield).
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:21][CH3:22])[NH:7][C:8]=3[C:9](Cl)=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])[O-].[K+].[K+]>CO.[C].[Pd]>[NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:21][CH3:22])[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: COc1ccccc1-c1[nH]c2c(Cl)ccc3c2c1CCC3N
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1ccccc1-c1[nH]c2cccc3c2c1CCC3N
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A portion (1.45 g) of the compound obtained in Example 183 was dissolved in methanol (50 ml) and 1N hydrochloric acid (50 ml) and to the solution was added 10% palladium-carbon (1.45 g). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was neutralized with potassium carbonate, the catalyst and the inorganic salt were filtered off and washed with methylene chloride. The filtrate and the washed liquid were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was crystallized from ether to yield 0.93 g (72%) of the titled compound as a pale yellow powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[C:2]=1[CH:13]=[O:14].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:15]1([CH:13]([C:2]2[C:3]([CH:11]([OH:12])[C:1]3[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[OH:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc2ccccc2cc1C=O
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)c1cc2ccccc2cc1C(O)c1ccccc1
Yield: 86.6 %

Procedure:
2,3-Naphthalenedicarboxaldehyde (10.0 g) in dry tetrahydrofuran (100ml) was added to phenylmagnesium bromide [derived from bromobenzene (53 g) and magnesium (8 g)] in dry tetrahydrofuran (500 ml) over 1 hr. and the solution was refluxed for a further 3 hr. On cooling, water (500 ml) was added and the ethereal layer was decanted. The aqueous slurry was washed with ether (4 × 500 ml) and the combined ethereal extracts were dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography on silica gel and recrystallised from dichloromethane/petroleum ether (b.p. 40°-60°) to yield two isomers of 2,3-bis(1-phenyl-1-hydroxymethyl)naphthalene (III) (8.0 g. m.p. 145° and 3.0 g, m.p. 164°).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:31])=[O:30]
Reactant: CC(C)CCCC(C)CCCC(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 22.8 g (100 mmol) of 3,7,11-trimethyldodecanol and 9.48 g (120 mmol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 20.96 g (110 mmol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling (1 to 2° C.). After the dropwise addition, the resultant was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated to obtain 41.6 g of crude 3,7,11-trimethyldodecyl tosylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].C[O-].[Na+].Cl>CN(C=O)C.O.CO>[C:12]([C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)([OH:14])=[O:13]
Reactant: O=C1OCc2ccccc21
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Temperature: 130 °C
Reaction time: 6.5 h
Yield: 82.8 %

Procedure:
A solution of 4-hydroxyphenylacetic acid (90.0 g, 0.58 mol; assay >98%) and phthalide (85.07 g, 0.63 mol) in DMF (323 g) was heated to an internal temperature of 130° C. The pressure was reduced to 800 mbar and sodium methoxide (224.6 g, 1.25 mol, assay: 30% methanolic solution) was added slowly to the mixture maintaining the internal temperature above 100° C. During the addition methanol was distilled off, and after the addition the distillation was continued under normal pressure until the internal temperature increased to 130° C. again (260 g distillate). After stirring at this temperature for 6.5 h, phthalide (8.5 g, 0.06 mol) was added and the mixture was stirred overnight (16 h). Afterwards the mixture was cooled to 100° C. and hydrolyzed with water (1040 g). After cooling to <10° C., the pH of the mixture was adjusted to pH 1 with hydrochloric acid (163.5 g, 1.43 mol; assay: 32%). The product was filtered off, washed with water (700 g) and dried under vacuum for 15 hours at 60° C. to give crude 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 174.6 g, 0.48 mol, 82.1%; HPLC assay: 78.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)NCCc2ccccc2)cc1
Solvent: CCO
Product: Nc1ccc(CS(=O)(=O)NCCc2ccccc2)cc1
Yield: 94.6 %

Procedure:
By a procedure similar to that described in example 9(b) the product of stage (a) (7.0 g) was hydrogenated in ethanol to give the title compound as a white solid (6.0 g), m.p. 123°-125° (from ethanol).
Reaction SMILES: C[O:2][C:3]([CH:5]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[OH-].[Na+]>CO.O>[C:3]([CH:5]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[CH2:6][CH2:7][CH2:8][CH3:9])([OH:4])=[O:2]
Reactant: CCCCC(Oc1ccccc1C(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(Oc1ccccc1C(=O)O)C(=O)O
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
13.0 g of methyl 2-(1-methoxycarbonylpentoxy)benzoate were dissolved in methanol in a 250 ml flask, and a solution of 9.1 g of sodium hydroxide in 40 ml of water was added. The reaction mixture was stirred at 40° C. for one hour, during which a precipitate formed. This was dissolved after cooling to room temperature by adding further methanol and sodium hydroxide solution. The reaction mixture was washed with dichloromethane, and the aqueous phase was subsequently adjusted to pH 0 with concentrated hydrochloric acid while cooling in ice. A colourless solid precipitated during this and was filtered off and dried. 10.1 g (87% of theory) of 2-(1-carboxypentoxy)benzoic acid were obtained in this way.