Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[OH:2][CH2:3][CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1
Reactant: COC(=O)CC1COc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCCC1COc2ccccc2O1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
At room temperature and while stirring, a solution of 15.61 g (75 mmol) of 2-methoxycarbonylmethylbenzo-1,4-dioxan in 120 ml of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 2.85 g (75 mmol) of lithium aluminium hydride in 120 ml of absolute diethyl ether. The reaction mixture is stirred for a further 2 hours at room temperature. It is then carefully decomposed with 2.85 ml of water, 2.85 ml of sodium hydroxide solution (15% strength) and 8.55 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The solution is washed thoroughly with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 12.37 g (91.6%) of 2-(2-hydroxyethyl)-benzo-1,4-dioxan are obtained in the form of a colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:51][CH2:52][C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@H:54]1[OH:59]>ClCCl.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:4]2[C:9]([C:10]([NH:51][CH2:52][C@@H:53]3[CH2:58][CH2:57][CH2:56][CH2:55][C@H:54]3[OH:59])=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: NC[C@@H]1CCCC[C@H]1O
Reactant: Cc1cc(N2CCOCC2)nc(C2CC2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)nc(C2CC2)c1C(=O)NC[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized according to the methods described in sections a) to d) of example X1) (0.15 g, 0.57 mmol) in dichloromethane (10 ml) are added N-ethyl-diisopropylamine (0.24 ml, 1.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.13 g, 0.69 mmol), and 1-hydroxybenzotriazole hydrate (0.015 g, 0.11 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0° C., before (1R,2S)-2-(aminomethyl)cyclohexanol (0.07 g, 0.57 mmol) is added and stirring is continued for 3 days. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-N-[[(1S,2R)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X2) (0.21 g, 0.56 mmol, 98%). [M+H]+374.2.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][CH:3]2[S:9][CH:10]=[CH:11][CH:2]12.[Br-:12].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:12][CH2:7][C:6]([C:5]1[S:1][CH:2]2[CH:11]=[CH:10][S:9][CH:3]2[CH:4]=1)=[O:8]
Reactant: CC(=O)C1=CC2SC=CC2S1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)C1=CC2SC=CC2S1
Reaction time: 1 h

Procedure:
1-(3a,6a-Dihydro-thieno[3,2-b]thiophen-2-yl)-ethanone (453 mg, 2.48 mmol) was dissolved in THF (12 mL) and phenyltrimethylammonium tribromide (932 mg, 2.48 mmol) was added. After stirring for 1 h, the suspension was filtered over CELITE. The filtrate was diluted with diethyl ether, then washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated to afford the title compound which was carried on without purification.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:19])C.[O:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)=[CH:24][N:23]=[CH:22]1>>[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]([S:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]3[O:21][CH:22]=[N:23][CH:24]=3)=[CH:31][CH:30]=1)=[C:7]([CH3:19])[N:6]2[CH2:5][C:4]([OH:3])=[O:20])(=[O:18])[CH3:17]
Reactant: CCOC(=O)Cn1c(C)cc2c(NC(C)=O)cccc21
Reactant: Sc1ccc(-c2cnco2)cc1
Product: CC(=O)Nc1cccc2c1c(Sc1ccc(-c3cnco3)cc1)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of example 3 using (4-acetylamino-2-methyl-indol-1-yl)-acetic acid ethyl ester and the product of example 2 step (i).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:25][CH:26]=1>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:25][CH:26]=1)[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2coc(-c3ccccc3)n2)c1)C(=O)O
Yield: 80 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-phenyl-oxazole, the title compound was obtained in 80% yield as a brown oil. MS: (M+H)+ 391.1.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:7](=[O:8])[C:4]3[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=3)[CH:32]=[CH:31][C:29]=2[N:30]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(C)cc5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-4-methylbenzamide was prepared from p-toluoyl chloride (17.5 mg, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 44 mg, 93 μmol, 82%). LC/ESI-MS: m/z=472 [M+H]+; m/z=470 [M−H]−; R′, =3.32 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.Cl.C1(C2N=NC(CN)=CC=2)C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:14]3[S:13][CH:17]=[CH:16][N:15]=3)=[CH:25][CH:24]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccc(-c2nccs2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: NCc1ccc(-c2ccccc2)nn1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccc(F)cc1
Yield: 85.5 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 4-fluorobenzenesulfonyl chloride (278 mg, 1.42 mmol) in place of 3-pyridylsulfonyl chloride, and using 4-(thiazol-2-yl)benzylamine hydrochloride (364 mg, 1.38 mmol) obtained in Reference Example 4-(d) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (411 mg) as a slightly yellow solid. (Yield: 85%)
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:6].Cl>COCCOC>[C:16]([N:15]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([O:13][CH3:14])[CH:9]=2)[C:5](=[O:6])[CH2:4]1)(=[O:18])[CH3:17]
Reactant: COc1ccc(C(=O)CCl)c(NC(C)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(c1)N(C(C)=O)CC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 3.97 g, 99.3 mmol) in DME (75 mL) was added an ice-cold solution of N-[2-(chloroacetyl)-5-methoxyphenyl]acetamide (12.00 g, 49.7 mmol) (Example 11) in DME (165 mL) at 0° C. The mixture was stirred under argon for 15 minutes, then 2 N HCl (75 mL) solution was added slowly. The mixture was extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to yield a solid. The crude material was purified on silica gel eluting with EtOAc/hexane (1:1) and then EtOAc to give a reddish solid (7.87 g, 77%) with minor impurities: LC/MS m/z 206 (M+H)+; 1H NMR (400 MHz, DMSO-d6) 7.94 (d, 1H), 7.59 (d, 1H), 6.80 (dd, 1H), 4.51 (s, 2H), 3.85 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]([CH3:27])[CH3:26])=[O:18])C)(C)(C)C>ClCCl>[CH3:26][N:25]([CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17](=[O:18])[C@H:16]([NH:14][CH3:13])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:27]
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.9 %

Procedure:
At 0° C., trifluoroacetic acid (8 ml) was added to a solution of N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl}-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester (2.26 g, 5.80 mmol) in dichloromethane (8 ml). The reaction mixture was stirred for 20 min at 20 0° C. The solvent was removed in vacuo. Dichloromethane (70 ml) was added, and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.24 g of (2R)-1-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-methylamino-3-phenylpropan-1-one.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15]O)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:21]1[C:29]2[N:28]=[C:27]([Cl:30])[N:26](CC=C)[C:25]=2[C:24](=[O:34])[NH:23][C:22]1=[O:35])[CH2:18][CH2:19][CH3:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH2:17]([N:21]1[C:29]2[N:28]=[C:27]([Cl:30])[NH:26][C:25]=2[C:24](=[O:34])[N:23]([CH2:15][CH2:14][CH2:13][C:10]2[N:9]=[C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)[C:22]1=[O:35])[CH2:18][CH2:19][CH3:20]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: OCCCc1noc(Cc2ccccc2)n1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Yield: 63.4 %

Procedure:
A solution of 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (594 mg, 2.7 mmol) in THF (25 ml) was treated with 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (700 mg, 2.48 mmol) and PPh3 (779 mg, 2.97 mmol) under nitrogen. DBAD (684 mg, 2.97 mmol) was added in one portion and the reaction left to react for 60 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. MeOH was added to the residue and then passed down an aminopropyl column with the product eluting with 2-4% AcOH/MeOH. Product fractions were combined and concentrated. The off-white residue was recrystallised from EtOAc:cyclohexane (1:1), giving the title compound as a white solid (696 mg, 63%).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][N:37]([CH3:38])[C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(C)(O)C(=O)O
Product: C[C@H](CN(C)C(=O)C(C)(C)O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 28 %

Procedure:
The procedure described in Example 1 was repeated using 2-hydroxy-iso-butyric acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a white solid in 28% yield; NMR spectrum (DMSO-d6 373K) 1.25 (s, 3H), 1.27 (s, 3H), 1.43 (d, 3H), 3.26 (s, 3H), 3.54 (m, 1H), 4.16 (dd, 1H), 5.16 (m, 1H), 5.28 (s, 2H), 7.23 (m, 2H), 7.34 (m, 2H), 7.58 (m, 2H), 7.69 (t, 1H), 7.83 (dt, 1H), 8.07 (d, 1H), 8.46 (s, 1H), 8.58 (d, 1H), 9.88 (s, 1H); Mass spectrum MH+ 536.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl.[Cl-].[Na+].O>[CH:4]([C:3]1[C:6]([CH3:17])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24])=[O:5]
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (8.70 g, 36.8 mmol) and pyridine (14.56 g, 184.1 mmol) in dichloromethane (40 mL) was slowly added Tf2O (15.58 g, 55.2 mol) at −10 to 0° C. The mixture was stirred at 0° C. for 3 hours. The mixture was diluted with cold brine and extracted with 50% EtOAc/hexane. The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane=1:4) to give pure product (9.48 g, 69.3%). 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 6.86-7.03 (m, 2H), 5.53 (t, J=2.93 Hz, 1H), 3.79 (m, 1 H), 3.55-3.71 (m, 1H), 2.65 (s, 3H), 1.84-2.05 (m, 3 H), 1.51-1.78 (m, 3 H). MS (ESI) m/z=369 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH3:15]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An oven dried two neck flask was charged with 5 ml DMF and NaH (66 mg, 60% in oil, 1.65 mmol). The mixture was cooled down to 0° C., followed by dropwise addition of 4-hydroxy indole (200 mg, 1.5 mmol) in 5 ml DMF over 10 second. After stirring for 30 min under N2, bromoethane in 2 ml DMF was added dropwise, and the reaction was allowed to warm to rt. with continued stirring for 2 hr. Removal of the solvent in vacuo, followed by aqueous work up afforded crude 4-ethoxyindole which was purified by prep. HPLC to afford 201 mg (83%) of pure 4-ethxyindole; HPLC retention time, 1.190 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:11][C:12](=[O:14])[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[F-].[Cs+].[C:17]([Si](C)(C)C)([F:20])([F:19])[F:18]>C(#N)C.C(OCC)C>[F:18][C:17]([F:20])([F:19])[C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:13][C:12]([OH:11])=[O:14]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1C=C(c2ccc(F)cc2)C(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(O)C=C(C(=O)C(F)(F)F)c1ccc(F)cc1
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-fluorophenylmaleic anhydride (1.42 g, 7.39 mmol) (prepared by procedures similar to those described in Dean, W. D.; Bum, D. M. J. Org. Chem. 1993, 58, 7916-7917), in acetonitrile (15 ml) at 0° C. (ice/water/sodium chloride bath—temperature of the bath −10° C.), was added CsF (1.1 g, 7.39 mmol), followed by the drop-wise addition of CF3SiMe3 (1 ml, 7.39 mmol), under nitrogen. The reaction mixture was stirred for 1 h, and then diluted with diethyl ether and extracted with 2M sodium hydroxide (200 ml). The organic layer was removed and the aqueous layer acidified to pH=1 by the addition of conc. hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer removed, dried (Na2SO4), and the solvent evaporated in vacuo to yield D5 (1.4 g, 72%) as a mixture of isomers. C11H6F4O3 requires 262 Found 261 (M-H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.C(N(CC)CC)C>[CH3:15][S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:18])=[O:17]
Reactant: OCCOCCc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCc1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 100 %

Procedure:
The 2-[2-(2,4-difluorophenyl)ethoxy]ethanol obtained according to the preceding paragraph was dissolved in 40 ml of dichloromethane containing 1.13 g of triethylamine and the solution was treated with 1.28 g of methanesulfonyl chloride. After stirring for 15 minutes, the solution was washed well with water, the organic layer was separated, dried over sodium sulfate, filtered and evaporated to give 3.12 g (100%) of 2-[2-(2,4-difluorophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[S:19](N)([NH2:22])(=[O:21])=[O:20]>O1CCOCC1>[NH2:22][S:19]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([N:3]([CH3:11])[CH3:2])=[O:10])(=[O:21])=[O:20]
Reactant: NS(N)(=O)=O
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1CCCN1S(N)(=O)=O

Procedure:
To a solution of the subtitle product of step ii) (3.70 g) in dioxane (50 ml) was added triethylamine (2.02 g) and sulfamide (9.96 g). The mixture was heated at reflux for 3 days before the reaction mixture was cooled, filtered and washed with methanol (50 ml). The solvent was evaporated and the residue purified by column chromatography (2% methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.70 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8](CC3C=CC(OC)=CC=3)[C:7](=[O:21])[C:6]=2[C:22]=1[CH3:23]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:21])[C:6]=2[C:22]=1[CH3:23]
Reactant: COc1ccc(CN2CCOc3ccc(Br)c(C)c3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc2c1C(=O)NCCO2
Yield: 63.3 %

Procedure:
A mixture of 7-bromo-4-(4-methoxybenzyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (130c, 2.8 g, 7.4 mmol) in TFA (30 mL) was refluxed for 14 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 3/1) to give 7-bromo-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (7-bromo-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (130d, 1.2 g, 63%) as a brown solid.
Reaction SMILES: [C:1](OC)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC1C=CC(C)=CC=1>CO>[C:2]1([CH3:1])[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: CO
Solvent: Cc1ccc(C)cc1
Product: COC(=O)c1ccc(C)cc1

Procedure:
U.S. Pat. No. 4,126,755 and the corresponding German Offenlegungsschrift P2244662.4 disclose a method of producing dimethyl terephthalate from high-boiling tarry residues resulting from the combined oxidation of p-xylene and methyl p-toluate with air, esterification of the resulting acids with methanol and after-treatment of the esterification reaction product, which comprises treating the high-boiling residues with methanol at a temperature above 250° C., and thereafter separating the resulting dimethyl terephthalate in accordance with conventional separation techniques.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH3:21])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:6][CH:5]=1.Cl>C(O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH3:21])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1oc(C)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reaction time: 0.5 h

Procedure:
2N Sodium hydroxide (5 ml) was added to a solution of methyl 4-(4-chlorophenyl)-2-methyloxazole-5-propionate (1.4 g) in ethanol (10 ml) and the mixture was allowed to stand at room temperature for 30 minute, diluted with water and adjusted to pH 2 with hydrochloric acid. The resulting crystalline precipitate was collected by filtration and recrystallized from ethanol to give crystals of 4-(4-chlorophenyl)-2-methyloxazole-5-propionic acid, yield 1.17 g (88.6%), m.p. 211°-212° C. The IR and NMR spectra of this compound were in complete agreement with those of the compound obtained in Example 5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Product: Cc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1

Procedure:
Prepared from (4′-methyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C4) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a white solid (125 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: OCc1ccc(O)cc1
Product: Oc1ccc(Cn2ccnc2)cc1

Procedure:
In a manner analogous to that described in the second paragraph of Example 13, from 4-hydroxybenzyl alcohol and imidazole, 4-[(1-imidazolyl)methyl]phenol was obtained.