Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH2:26].Cl>C(C#N)(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:26][C:18]1[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=1[F:16]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: CC(=O)C#N
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinazoline (548 mg, 2.4 mmol), 2-fluoro-4-nitro-phenylamine (392 mg, 2.5 mmol), AcCN (10 ml), and conc'd HCl (0.050 ml) was heated to reflux for several hrs. After the reaction mixture was allowed to cool to room temperature, the resulting solids were filtered washed with AcCN and air-dried to give (6,7-dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673 mgs, 80%). 1H-NMR (400 MHz, DMSO): 12.18 (br s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 8.36 (dd, 1H), 8.24 (dd, 1H), 7.91 (dd, 1H), 7.44 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). LC/MS Calcd for [M+H]+ 345.1. found 345.4.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:17]2[O:18][C:19]3[CH:25]=[C:24]([C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O:32][C:33](=[O:36])[CH2:34]Br.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:28]([CH:27]([C:26](=[O:30])[C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:18][C:19]=2[CH:25]=1)[CH2:34][C:33]([OH:36])=[O:32])[CH3:29]
Reactant: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
625.00 μl (313 μmol) potassium bis(trimethylsilyl)amide 0.5M in toluene are placed in 15 ml THF and cooled to −78° C. 75.00 mg (283 μmol) 1-(2-phenyl-benzoxazol-6-yl)-butan-1-one, dissolved in 15 ml THF, are added dropwise to this solution and the mixture is stirred for 15 min at −78° C. Then 55 mg (360 μmol) methylbromoacetate, dissolved in 5 ml THF, are also added dropwise and the mixture is stirred for 30 min at −78° C., then 1N hydrochloric acid is added and the mixture is extracted with diethyl ether. The org. phase is dried on magnesium sulphate and the solv. is eliminated i.V.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Br:12][CH2:13][C:14](=O)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>COCCOCCOC.C1COCC1>[BrH:12].[OH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:13]=[C:14]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[N:1]=2)[CH:6]=1)([CH3:9])[CH3:10]
Reactant: CC(C)(O)c1ccc(N)nc1
Reactant: O=C(CBr)C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: COCCOCCOC
Product: Br
Product: CC(C)(O)c1ccc2nc(C(=O)c3ccccc3)cn2c1
Temperature: 4 °C
Reaction time: 15 h
Yield: 12.6 %

Procedure:
To a solution of 0.2 g of 2-(6-aminopyridin-3-yl)propan-2-ol in 10 mL of diglyme is added a solution of 0.358 g of 3-bromo-1-phenylpropane-1,2-dione in 5 mL of THF. The reaction mixture is stirred for 15 hours at 4° C. and then concentrated to dryness under reduced pressure. The residue is chromatographed on a column of silica, eluting with dichloromethane and then with a 98/2 mixture of dichloromethane and methanol. The fractions containing the expected product are combined and concentrated to dryness to give 60 mg of [6-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridin-2-yl](phenyl)methanone hydrobromide (1:1) in the form of a straw-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.C[Si]([N:46]=[C:47]=[O:48])(C)C>C(Cl)Cl>[NH2:46][C:47]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:48]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3NC(N)=O)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
A solution of 445 mg (0.80 mmol) of N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) in 3 mL of methylene chloride under a nitrogen atmosphere was treated with 4 mL (29.5 mmol) of trimethylsilyl isocyanate. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under vacuum and the residue was passed over silica gel. Elution with ethyl acetate/hexanes (4:1) yielded 211 mg (0.35 mmol, 44%) of product. FAB-MS: calculated for C34H41N5O5 599: found 622 (M+Na). 1H NMR (400 MHz, CDCl3): 1.31 (s, 3H), 1.38 (s, 3H), 1.39 (s, 9H), 1.90 (m, 1H), 2.48 (dd, 2H), 2.60 (m, 2 H), 4.48 (m, 1H), 4.95 (d, 1H), 5.08 (d, 1H), 5.28 (br, s, 1H), 6.66 (br s, 1H), 6.78 (d, 1H), 7.22 (m, 11H), 7.72 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)[CH2:26][C:27]([OH:29])=[O:28].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:18]([O:17][C:15]1[CH:14]=[C:11]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
3.18 g. of 3,5-dibenzyloxy-benzaldehyde [L.A. Svensson, Kem. Tidskr., 87, 289 (1975)] and 1.6 g. of malonic acid are stirred in a mixture of 8 ml. of pyridine and 0.1 ml. of piperidine for 3 hours at 100° C. 25 ml. of 15% hydrochloric acid are then added, whereafter the product is filtered by suction, washed with water and dried. The crude product is crystallized from 150 ml. of methanol and 3 g. of 3-(3,5-dibenzyloxy-phenyl)-propenoic acid melting at 154°-156° C. are obtained. The product is suspended in 250 ml. of abs. ether, 0.90 g. of lithium aluminum hydride is added and the mixture is heated under stirring for 5 hours. After cooling the excess hydride is decomposed by acetone and acidified with 100 ml. of 10% hydrochloric acid. The two layers are separated and the aqueous layer is shaken out with ether again, the combined organic layer is washed with water, dried on magnesium sulphate and evaporated. 2.88 g. of 3-(3,5-dibenzyloxy-phenyl)-1propanol are obtained, m.p.: after recrystallization from n-hexane: 48°-50° C. 5.47 g. of the above alcohol are dissolved in 30 ml. of abs. pyridine and 2.26 g. (1.5 ml., 0.020 mole) of methane sulfonic acid chloride are added and the mixture is poured after 30 minutes to a mixture of 300 g of ice and 75 ml. of cc. HCl. The product is extracted with 125 ml. of dichloromethane and the organic layer is washed with 2×20 ml. of saturated hydrochloric acid solution, dried above magnesium sulphate and evaporated. 6.2 g. of 3-(3,5-dibenzyloxy-phenyl)-1-methanesulfonyloxy-propane are obtained, from which 2.60 g. are heated for 15 minutes with 20 ml. of 1 N sodium methylate and the solution is poured to 220 ml. of 1% hydrochloric acid solution. The product is extracted with dichloromethane, the extract is dried and evaporated. The residue (1.9 g.) is subjected to column chromatography and as eluants benzene and methyl ethyl ketone solvents are used. 1.30 g. of 1-(3,5-dibenzyloxy-phenyl)-3-methoxy-propane are obtaned as colorless oil,
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[C:12](Cl)=[N:11][N:10]=1.[CH2:26]([OH:28])[CH3:27]>>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12]([O:28][CH2:26][CH3:27])=[N:11][N:10]=[C:9]2[NH:8][CH2:7][C:6]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:4]([Cl:3])[CH:5]=1
Reactant: CCO
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(Cl)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOc1nnc(NCc2ccc(OC)c(Cl)c2)c2cc(Cl)ccc12
Temperature: 150 °C

Procedure:
A solution of 120 mg of 60% oily sodium hydride in 20 ml of ethanol was added to 1.0 g of 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazine prepared in Example 27. The obtained mixture was heated at 150° C. in a sealed tube overnight, cooled and concentrated in a vacuum. The residue was dissolved in ethyl acetate. The obtained solution was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was subjected to silica gel column chromatography and eluted with dichloromethane/methanol (50:1) to give 0.9 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)C.[OH-].[Li+]>C1COCC1.CO.O>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[O:21][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
(2,4-Difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.3 gm, 2.98 mmol) was dissolved in THF (5 ml) and methanol (0.5 ml). To this was added a solution of lithium hydroxide (0.62 gm, 14.90 mmol) in water (5 ml) and stirred for 18 hours at 25° C. Organic solvents were evaporated from the reaction mixture and aqueous layer was acidified with 1N HCl, precipitated product was filtered off and residue was washed with water. Solid product was dried under vacuum to provide (2,4-difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid (1 gm).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3C=CC=[CH:19][CH:18]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].CC1N=C(N2CCN(CCC)C2=O)SC=1C(OCC)=O>>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[C:13]2=[O:23])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Product: CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Yield: 94 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-propylimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 94% yield: 1H NMR (300 MHz, DMSO-d6) δ 3.98-3.89 (m, 2H), 3.57-3.44 (m, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.45 (s, 3H), 1.54-1.42 (m, 2H), 0.79 (t, J=7.2 Hz, 3H); MS (ES+) m/z 270.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[NH:12][C:11]([CH2:13]O)=[N:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[SH:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[NH:12][C:11]([CH2:13][S:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[NH2:16])=[N:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(Cl)ccc1S
Reactant: CC(C)(C)OC(=O)Nc1nnc(CO)[nH]1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2N)[nH]1

Procedure:
A solution of tert-butyl(5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)carbamate (190 mg, 0.888 mmol), 2-amino-4-chlorobenzenethiol (213 mg, 1.332 mmol), PPh3 (466 mg, 1.776 mmol) and di-tert-butylazodicarboxylate (409 mg, 1.776 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 2 days. The solvent was then removed and the crude residues was loaded on silica gel column to get the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[S:13][C:14]([CH2:26][CH3:27])=[CH:15][C:16]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]([CH3:28])=[N:9][N:8]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[S:13][C:14]([CH2:26][CH3:27])=[CH:15][C:16]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]([CH3:28])=[N:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CCl)s1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Four grams of thionyl chloride is added dropwise to a solution of 10 g of 3-hydroxymethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole in 50 ml of dioxane. The mixture is stirred at 70° - 80°C for 2 hours. The reaction mixture is poured into 200 ml of water and made alkaline with potassium carbonate. The oil liberated is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is treated with ligroin containing 5% ethyl acetate to cause crystallization. The crystals are collected by suction filtration and recrystallized from ligroin containing 5% ethyl acetate to give 9.3 g of 3-chloromethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole as colorless pillars melting at 109° - 110°C.
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11])#[N:4].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br>CN(C)C=O>[CH2:12]([O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[C:3]#[N:4])[CH:14]1[O:16][CH2:15]1
Reactant: BrCC1CO1
Reactant: N#C[C@@H]1CCCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1CCCCC1OCC1CO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 60 mg, 1.59 mmol) was added to a solution of trans-2-cyano-cyclohexanol in N,N-dimethylformamide (2.0 mL) and stirred for 10 minutes at room temperature. Epibromohydrin (0.22 g, 1.59 mmol) was then added and the reaction stirred for an additional 3 hours. The solution was partitioned between diethyl ether/water, and the layers separated. The ether layer was washed with water (3×100 mL) and dried over magnesium sulfate and evaporated to give 0.17 g of 2-cyanocyclohexyl glycidyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:23][CH2:24]Br>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11]3=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]3[CH2:24][CH2:23]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2nc3ccccc3[nH]2)cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCn3c2nc2ccccc23)cc1
Reaction time: 0.08 h
Yield: 5.7 %

Procedure:
A mixture of N-(4-nitrophenyl)-1H-benzimidazol-2-amine (1.00 g) in DMF (20 mL) at ambient temperature was treated with a 60% dispersion of sodium hydride in mineral oil (393 mg) then stirred for 5 min. The mixture was treated with a solution of 1,2-dibromoethane (738 mg) in DMF (1 mL) then stirred at ambient temperature for 1 h. After this time, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (80 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with 5% aqueous lithium chloride (2×50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:1 ethyl acetate/heptane) to afford 1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (63 mg) as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=1)=[O:10].Cl.O1CCOCC1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CCCCCCCBr)Nc1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(8-bromooctanoyl)amino]benzoate (0.61 g, 1.5 mmol, as prepared in Intermediate 35) in dichloromethane (2 ml) was added a 4M solution of HCl in 1,4-dioxane (4 ml, about 10 equivalents), and the mixture was left to stand at ambient temperature for 18 hours. The mixture was evaporated to dryness and the residue was co-evaporated with dichloromethane (20 ml) to give the title compound as a white solid (0.51 g). LCMS showed MH+=342/344 (Br isotope pattern); TRET=3.34 min. NMR (d6-DMSO) suggested that the material was again about 75% pure and that the impurity from the previous reaction (Intermediate 35) was still present. The mixture was used without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[C:6]([F:14])[CH:5]=1.CC(C[AlH]CC(C)C)C.CCCCCC.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C1COCC1>[F:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([F:14])[C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])c(F)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(CO)cc1F
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3,5-difluoro-4-nitro-benzoic acid methyl ester (10.95 g, 50 mmol) in THF (250 mL) was added at 0-5° C. under argon a 1M DIBAL solution in hexane (165 mL, 165 mmol) within 1.5 h. The reaction mixture was stirred for 2.5 h at 0-5° C. before it was added to 200 mL cold 1M aq. potassium tartrate solution under ice-cooling. After stirring the reaction mixture for 0.5 h at 25° C. the aqueous phase was extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to provide the title compound as a yellow solid: TLC (hexane-EtOAc 1.1) Rf=0.35; HPLC RtA=1.31 min; 1H NMR (400 MHz, CDCl3): δ 7.12 (d, 2H), 4.77 (s, 2H).
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](O)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:6][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:25]1[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][CH:26]=1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(C(O)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C(NC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
A mixture of 140.14 g Z-Gln-OH (0.5 mole) and 274.4 g 4-methyltriphenylcarbinol (1 mole) in 1.5 l acetic acid and 93.4 ml acetic anhydride (1 mole) is stirred at room temperature for 7 minutes. Upon addition of 2.5 ml concentrated sulfuric acid the temperature is raised to 50° C.; a clear, yellow solution results after 15 minutes. After 21/2 hrs the solution is allowed to cool and poured into 5 l ice-cold water. The precipitate formed is filtered off, washed thoroughly with water and dissolved in 1 l ethylacetate. The resulting solution is washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to an oil (400 ml) which crystallized on addition of diisopropylether.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1)=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]3[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=3[CH:13]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)NC(=O)CO3)CC1
Yield: 93.8 %

Procedure:
A mixture of 6-formyl-4H-benzo[1,4]oxazin-3-one (1.91 g, 10.8 mmol) and 1-(tert-butoxycarbonyl)piperazine (2.0 g, 10.8 mmol) in 1,2-dichloroethane (120 mL), was cooled in an ice-bath, and treated portionwise with sodium triacetoxyborohydride (3.43 g, 16.2 mmol) over 0.3 h, with stirring under argon. The resulting mixture was stirred at room temperature for 4 h, then partitioned between dichloromethane (100 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo to give the title compound (3.52 g, 94%) as a yellow oil.
Reaction SMILES: [N+:1]1([O-:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:23])[CH:17]=[CH:16][C:15]([S:18]([O:21]C)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:23])[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH3:12][O:11][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: [O-][n+]1cccc2ccccc21
Product: CO[n+]1cccc2ccccc21
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
N-Methoxyquinolinium p-toluenesulfonate was prepared by mixing quinoline-N-oxide and an equimolar amount of methyl p-toluenesulfonate and heating the mixture at 95°C for 5 hours. The crude product was recrystallized from a mixture of methanol and ethyl acetate. By this procedure N-methoxyquinolinium p-toluenesulfonate was obtained. The salt had the following features in the NMR:
Reaction SMILES: C(CC(C)(C)C)(C)C.C([O:12]C(C)C)(C)C.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24]C(O)=O)=[C:19]([N+:28]([O-])=O)[CH:18]=1.Cl>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]2[S:23][C:24](=[O:12])[NH:28][C:19]=2[CH:18]=1
Reactant: CC(C)OC(C)C
Reactant: Cc1ccc(SCC(=O)O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)CC(C)(C)C
Product: Cc1ccc2sc(=O)[nH]c2c1
Yield: 74 %

Procedure:
Analogous to Example 2(a), 2-acetyl-5-methyl-2-(3H)-benzothiazolone, m.p. 86°-88° C. (from isooctane/diisopropyl ether), was prepared with a yield of 51% of theory, starting from [(4-methyl-2-nitrophenyl)thio]-acetic acid. This intermediate was subsequently treated with 5 N hydrochloric acid analogous to Example 2(b). 5-Methyl-2(3H)-benzothiazolone was obtained with a yield of 74% of theory; m.p. 178°-180° C. (from ethanol/water 1:1).