Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[NH:19][C:18](=O)[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[N:6]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH:8]=2)[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(-c2cccc(Nc3nccc(=O)[nH]3)c2)cs1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(-c2cccc(Nc3nccc(Cl)n3)c2)cs1
Temperature: 25 °C
Yield: 47 %

Procedure:
To 2-(3-(2-methylthiazol-4-yl)phenylamino)pyrimidin-4(3H)-one, 11, (1.0 g, 3.5 mmol) and N,N-dimethyl-aniline (1 mL) is added phosphorus oxychloride (9.5 mL). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and concentrated in vacuo. The residue is neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (5% EtOAc in hexanes) to afford 0.50 g (47% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 2.73 (s, 3H), 6.98 (d, J=5.1 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 8.25 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 10.08 (s, 1H). MS (ESI, pos. ion) m/z: 303 (M+1).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OC(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20](=O)[CH2:19][C:18]=2SC(SC2N=CNN=2)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[CH2:24][C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2S(=O)C1)Sc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=CCS[C@@H]2CC(=O)N12
Reaction time: 0.33 h
Yield: 267.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (1.78 g: 1.69 mMol.) in dimethylformamide (15 ml) at -20° C. is added phosphorus trichloride (0.42 ml: 4.18 mMol.), and the mixture is stirred at the same temperature for 20 minutes. The reaction mixture is poured into two layers of cold aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer is taken, washed with water and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(]-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.59 g) as brown foam. Yield: 91%.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][CH2:7][CH2:6]1)=O.S(O)(O)(=O)=O.[CH3:16][S:17][C:18](=[NH:20])[NH2:19].[OH-].[K+].Cl>CO.O>[CH3:16][S:17][C:18]1[N:20]=[C:3]([OH:2])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[N:19]=1
Reactant: COC(=O)C1CCCC1=O
Reactant: CSC(=N)N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CSc1nc(O)c2c(n1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
46.9 g (330 mmol) of methyl cyclopentanone-2-carboxylate and 53.5 g (192 mmol) of S-methylisothiourea sulfate were successively added to 29.6 g (528 mmol) of KOH in 396 ml of methanol, and the mixture was stirred at room temperature overnight, acidified with 1N hydrochloric acid and diluted with water. The crystals which separated out were filtered off with suction and dried. 20 g of crystals were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([F:36])[C:27]=2[F:37])=[N:23][C:22]=1[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[C:28]([F:36])[C:27]=4[F:37])=[N:23][C:22]=3[CH3:38])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CCl
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 1 a], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 5-chloromethyl-2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazole in the presence of cesium carbonate and potassium iodide to obtain {6-[2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: [OH-].[K+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].CI.[CH3:15]CN(CC)CC>O.C(Cl)Cl>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:15])([CH3:5])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: COc1ccccc1C(C)C
Reaction time: 0.5 h
Yield: 313.4 %

Procedure:
To a stirred 20° C. solution comprised of KOH (1154 g, 4.75 mol), Bu4N+ HSO4− (140 g, 0.41 mol) in H2O (5.6 L) was added commercially available 2-isopropylphenol (590 g, 4.33 mol) in CH2Cl2 (5.6 L). After 30 min, MeI (741 g, 5.22 mol) was added prior to stirring the reaction overnight. After separation of the layers, Et3N (185 mL, 1.3 mol) was added to the CH2Cl2 fraction to destroy the residual MeI. After 15 min, the CH2Cl2 was removed under vacuum and the salts suspended in cyclohexane (4 L) prior to filtration. The cyclohexane filtrate was sequentially washed with 2N HCl followed by 2 brine washes. Concentration under vacuum yielded 2-isopropylanisole (612 g, 94%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:12])[CH:10]=O)=[CH:4][C:3]=1[Cl:13].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29].O.CCCCCC>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:10][NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[OH:12])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)cc(C(=O)C=O)cc1Cl
Reactant: NCCCCCCOCCc1ccccn1
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: O
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1Cl
Reaction time: 8 h
Yield: 11.1 %

Procedure:
4-Amino-3,5-dichloro-α-oxobenzeneacetaldehyde (0.56 g) and 6-[2-(2-pyridinyl)ethoxy]hexanamine (0.40 g) were dissolved in benzene (10 ml) and heated under reflux for 1 h using a Dean-Stark water trap. The solution was cooled, evaporated in vacuo and the residue dissolved in methanol (10 ml). Sodium borohydride (0.38 g) was added portionwise at 0°-5° over 0.5 h with stirring. The solution was allowed to stand overnight then evaporated in vacuo. The residue was partitioned between water (50 ml) containing 2N sodium carbonate (4 ml) and ethyl acetate (60 ml). The organic phase was dried, evaporated in vacuo and the residue purified by FCC eluting with System C (90:10:1) to afford a gum. Trituration with hexane gave the title compound (85 mg) as a colourless powder m.p. 93°-96°, t.l.c. (System A 39:10:1) Rf 0.44.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH:28]([N:30]1[CH2:34][CH:33]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[O:32][C:31]1=[O:44])[CH3:29])(C(C)(C)C)(C)C.[Cl-].[Na+]>O1CCCC1>[Cl:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[O:36][CH2:35][CH:33]1[O:32][C:31](=[O:44])[N:30]([CH:28]([CH3:29])[CH2:27][OH:26])[CH2:34]1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
1.2 ml of a 26% w/v solution of tetrabutyl ammonium fluoride in tetrahydrofuran were added, whilst ice-cooling, to a solution of 152 mg of 3-(2-t-butyldimethylsilyloxy-1-methylethyl)-5-(3-chlorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 11) in 1 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 hours. At the end of this time, a saturated aqueous solution of sodium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of ethyl acetate and ethanol ranging from 1:0 to 20:1 by volume as the eluent, to give 97 mg of the title compound, whose physico-chemical properties were the same as those of the product of Preparation 5(a).
Reaction SMILES: [C:1]([CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH:21]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[OH:32])([CH3:23])[CH3:22]>CC(=O)CC>[CH:21]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[O:32][CH2:3][C:1]#[N:2])([CH3:23])[CH3:22]
Reactant: COc1ccc(O)c(C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(OCC#N)c(C(C)C)c1
Reaction time: 96 h

Procedure:
A stirred slurry of toluene-4-sulfonic acid cyanomethyl ester (13.0 kg), potassium carbonate (13.0 kg) and 2-isopropyl-4-methoxyphenol (9.57 Kg) in 79.7 kg of 2-butanone was heated to 55-60 degrees C. for 4 days, then heated to reflux for 18 hours. The resultant slurry was cooled and filtered to remove solids. The filtrate was concentrated under reduced pressure and the residue was redissolved in toluene. The toluene solution was extracted with 1N KOH, and the organic phase was concentrated by distillation to give 20.6 g of a 1:1 (by weight) solution of (2-Isopropyl-4-methoxy-phenoxy)-acetonitrile in toluene, which was used directly in the next step. An aliquot (96.7 g) of this solution was concentrated to dryness to give 50.9 g of crude (2-Isopropyl-4-methoxy-phenoxy)-acetonitrile, projecting to a yield of 10.9 kg in the bulk solution: MS (M+H)=206; 1H nmr (CDCl3) delta: 1.25 (d, J=6.9 Hz), 3.31 (septet, 1H, J=6.9 Hz), 3.82 (s, 3H), 4.76 (s, 2H), 6.73 (dd, 1H, J=8.8 Hz, 3.1 Hz), 6.87 (d, 1H, J=3.1 Hz), 6.91 (d, 1H, J=8.8 Hz)
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>C(Cl)(=O)C(Cl)=O.ClCCl.C1COCC1>[N:12]1([CH2:11][C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
3-Carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate (128 mg, 0.44 mmol) was dissolved in a mixture of oxalyl chloride (0.6 mL) and dichloromethane (3.4 mL). The reaction mixture was stirred for 30 min at ambient temperature and the solvent was evaporated. The residue was dissolved in a mixture of dichloromethane (2.5 mL) and anhydrous TBF (2.5 mL) and added to a mixture of 3-chloro4-fluoro-aniline (17 mg, 0.12 mmol) and N,N-(diisopropyl)aminomethylpolystyrene resin (140 mg, Argonaut Technologies, Inc) in anhydrous THF (3 mL). The mixture was shaken overnight. The resin was filtered off, the solvents were evaporated and the crude product was purified on a preparative LC/MS (XTerra Cs column 19×100mm, 0.1 M aqueous NH4Ac/CH3CN). The pooled fractions were lyophilized to afford 7.2 mg (20%) of the title compound. Calculated for C15H11ClFN3O m/z: 303.7, found 304.7 [M+H]+. 1H NMR (400 M, MeOD) δ ppm 5.2 (s, 2H), 7.2 (t, J=9.1 Hz, 1H), 7.3 (m, 2H), 7.5 (m, 1H), 7.5 (d, J=7.1 Hz, 1H), 7.7 (d, J=7.1 Hz, 1H), 7.8 (dd, J=6.6, 2.5 Hz, 1H), 8.2 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:23][CH2:24][CH2:25][O:26][CH3:27].C(Cl)(=O)C([Cl:31])=O>C1COCC1.CN(C=O)C>[Cl:31][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=2)[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOc1cc2c(=O)[nH]c(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cc2c(Cl)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Yield: 67.9 %

Procedure:
To a suspension of 7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4(3H)-one (1.65 g, 4.46 mmol) in anhydrous THF (30 mL) was added oxalyl chloride (1.3 mL, 14.7 mmol) and 2 drops of DMF. The mixture was refluxed for 2 h, upon which the mixture was concentrated in vacuo, taken up in CHCl3 (100 mL) and washed with sat. NaHCO3 (3×50 mL), water (2×50 mL) and brine (1×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline (1.18 g, 3.03 mmol, 68%). HPLC retention time 9.55 mins.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([C:28]1[CH:33]=[C:32](CO)[CH:31]=[CH:30][N:29]=1)(=[O:27])[NH2:26]>C(Cl)Cl>[Br:24][CH2:20][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([C:25](=[O:27])[NH2:26])[CH:33]=1
Reactant: BrC(Br)(Br)Br
Reactant: NC(=O)c1cc(CO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NC(=O)c1cc(CBr)ccn1

Procedure:
Triphenylphospine (200 mg, 0.76 mmol) and carbon tetrabromide (273 mg, 0.82 mmol) were added to a solution of 2-carbamoyl-4-(hydroxymethyl)pyridine (101 mg, 0.66 mmol, Reference compound No. 13-1) in methylene chloride (3 mL), then the mixture was stirred at room temperature for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 4-bromomethyl-2-carbamoylpyridine. Triethylamine (134 μL, 0.96 mmol) was added dropwise to a solution of this bromo-intermediate and N-(3,5-dimethylphenyl)-2-thiopyridone-3-carboxamide (103 mg, 0.40 mmol, Reference compound No. 18-1) in N,N-dimethylformamide (1 mL) at room temperature, then the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate (50 mL), then the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (100 mL) and brine (50 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 40 mg of the target compound as a white solid. (Yield 16%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>CN(C)C=O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[CH2:9][O:14][C:11](=[O:13])[CH3:12]
Reactant: BrCc1c(Br)cccc1Br
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 70 °C
Yield: 61.1 %

Procedure:
To 1,3-Dibromo-2-bromomethyl-benzene (3.35 g, 10.2 mmol) was added potassium acetate (4.00 g, 40.8 mmol) and 25 mL N,N-dimethylformamide. This was heated at 70° C. for 20 minutes. The resulting mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% ethyl acetate hexanes) to yield Acetic acid 2,6-dibromo-benzyl ester (1.92 g, 6.23 mmol). 1HNMR (300 MHz, CDCl3) δ 2.12 (s, 3H), 5.42 (s, 2H), 7.08 (t, J=8 Hz, 1H), and 7.58 (d, J=8 Hz, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[N:13]([CH3:14])[CH:12]([CH3:15])[CH2:11][C:10]([CH3:16])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1CC(C)=CC(C)N1C)C1C=CC=CC=1.N>O.Br.C(O)(=O)C>[CH3:14][N:13]1[CH:12]([CH3:15])[CH2:11][C:10]2([CH3:16])[CH2:9][CH:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=12
Reactant: CC1=CC(Cc2ccccc2)N(C)C(C)C1
Agent: Br
Agent: CC1=CC(C)N(C)C(Cc2ccccc2)C1
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: CC1CC2(C)CC(Cc3ccccc32)N1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 6-benzyl-1,2,4-trimethyl-1,2,3,6-tetrahydro-pyridine and 2-benzyl-1,4,6-trimethyl-1,2,3,6-tetrahydropyridine (from Example LV, 11.7 g) is combined with 48% HBr in water (30 mL) and 33% HBr in acetic acid (20 mL). The mixture is heated to reflux temperature and stirred at this temperature for 4 d. After cooling to ambient temperature, aqueous ammonia (32%, 45 mL) is carefully added and the resulting mixture is extracted with Et2O (3×50 mL). The combined organic extracts are extracted with 2 M hydrochloric acid (3×50 mL), the combined aqueous extracts are basified using 32% aqueous ammonia (20 mL), and the basic aqueous phase is extracted with Et2O (3×50 mL). The combined organic extracts are dried (MgSO4), the solvent is removed, and the residue is purified by chromatography on silica gel (EtOAc/MeOH/NH395:5.0.5->75:25:2.5). The title compound obtained thereafter is dissolved in iPrOH and treated with HCl in iPrOH to precipitate the HCl salt of the title compound from the iPrOH solution.
Reaction SMILES: CO[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16]OC)[CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C([Li])CCC.[I:24]I.[Cl-].[NH4+]>C1COCC1.CCCCCC>[I:24][C:13]1[C:12]([O:15][CH3:16])=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([O:4][CH3:3])=[CH:6][CH:7]=[CH:8]2
Reactant: II
Reactant: COCOc1ccc2cccc(OCOC)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cccc(OC)c2c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
1.2 g of 1,7-bis-methoxymethoxy-naphthalene are dissolved in 9 ml of THF and cooled to -78°. 3.13 ml of a 1.6M n-butyl-lithium solution in hexane are added dropwise thereto and the mixture is stirred at room temperature overnight. Subsequently, it is again cooled to -78° and a solution of 1.25 g of iodine in 3.4 ml of THF is added dropwise. The mixture is warmed to room temperature and 10 ml of saturated ammonium chloride solution are added. The organic solvents are evaporated on a rotary evaporator and the residue is extracted three times with ether. After drying and evaporation the residue is chromatographed on silica gel with ethylene chloride. 0.72 g of 8-iodo-1,7-bis-methoxy-naphthalene is thus isolated. Yield: 40%. Mass spectrum: peaks inter alia at 374 (M+, 87%), 171 (40%), 45 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](S(CC)(=O)=O)=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([NH:28][CH2:27][CH2:26][CH2:25][CH:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CN1CCC(CCCN)CC1
Reactant: CCOC(=O)c1cnc(S(=O)(=O)CC)nc1C
Solvent: CCO
Product: CCOC(=O)c1cnc(NCCCC2CCN(C)CC2)nc1C
Temperature: 100 °C

Procedure:
A mixture of 2-ethanesulfonyl-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (0.30 g, 1.18 mmol) and 3-(1-methyl-piperidin-4-yl)-propylamine (0.18 mg, 1.10 mmol) in EtOH (3 mL) was heated in a sealed tube at 100° C. for 6 h. The mixture was concentrated and purified by FCC to give 200 mg (53%). 1H NMR (CDCl3): 8.88-8.72 (m, 1H), 5.60-5.44 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.52-3.39 (m, 2H), 2.91-2.77 (m, 2H), 2.64 (s, 3H), 2.26 (s, 3H), 1.94-1.85 (m, 2H), 1.72-1.57 (m, 4H), 1.41-1.20 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:30])=[C:13]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28]C)=[O:27])([CH2:20][C:21]([O:23]C)=[O:22])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>[Cl-].[Na+].O.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:30])=[C:13]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([OH:28])=[O:27])([CH2:20][C:21]([OH:23])=[O:22])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1(CC(=O)OC)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1(CC(=O)O)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Yield: 86.3 %

Procedure:
A mixture of dimethyl 2,2′-(3-(5-(benzyloxy)-2-bromophenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (12.0 g), THF (120 mL), methanol (120 mL), and a 1 M aqueous sodium hydroxide solution (120 mL) was stirred at room temperature for 3 hours. The reaction mixture was rendered acidic using 6 M hydrochloric acid at 0 C, and brine was added thereto, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (9.75 g).
Reaction SMILES: [SH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl>C(O)(=O)C>[C:12]([S:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(=O)O)c1S
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Sc1c(C)cccc1C(=O)O

Procedure:
2-Mercapto-3-methylbenzoic acid (9.0 g, 54 mmol), acetic anhydride (6.5 g, 63 mmol) and glacial acetic acid (25 ml) were refluxed 1 hour, then poured into dilute hydrochloric acid. The product was filtered and recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:11]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(-c2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of the product from step D (6.8 g, 21.7 mmol) in 50 mL of N,N-dimethylformamide was added cesium carbonate (10.6 g, 32.6 mmol) and the resultant mixture stirred at ambient temperature for 15 min. Methyl 4-(bromo-methyl)benzoate (5.46 g, 23.9 mmol) was added and stirring continued for 3 h. The reaction mixture was diluted with ethyl acetate and the organic layer washed successively with six portions of water and one portion of brine then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 5% ethyl acetate/hexanes) to give the title compound as a light tan solid. 1H NMR (500 MHz, CDCl3) δ; 8.03 (d, J=8.4 Hz, 2H); 7.75 (d, J=1.8 Hz, 2H); 7.35 (m, 3H); 7.12 (s, 1H); 5.88 (s, 2H); 3.94 (s, 3H); 1.57 (s, 9H).