Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]=[C:3]([CH3:6])[CH:4]=O.[CH3:7][C:8]1([CH3:16])[CH2:15][C:13](=O)[CH2:12][C:10](=[O:11])[CH2:9]1.C(N(CC)CC)C>Cl.C([O-])(=O)C.[NH4+]>[CH3:6][C:3]1[CH:2]=[N:1][C:13]2[CH2:15][C:8]([CH3:7])([CH3:16])[CH2:9][C:10](=[O:11])[C:12]=2[CH:4]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(C=O)=CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: Cc1cnc2c(c1)C(=O)CC(C)(C)C2
Temperature: 120 °C
Reaction time: 20 h
Yield: 41.2 %

Procedure:
A mixture of 3-amino-2-methylacrolein (8.5 g., 0.1 mol.) and dimedone (14 g., 0.1 mol.) was treated with triethylamine (5 ml.) and ammonium acetate (0.1 g.) and heated in an oil bath at 120° C with stirring for 20 hours. The cooled reaction mixture was diluted with 2N HCl (50 ml.) and extracted with ethyl acetate (2 × 50 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 10.0 with sodium carbonate and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were dried (MgSO4 and the solvent removed to give a residual oil which was distilled to give the title compound as a colourless oil (7.8 g., 40%) b.p. 80°/0.2 mm Hg. (RT = 2 min. 2% OV17, T=150°).
Reaction SMILES: [C:1]([C:3]1[C:21]([NH:22][S:23](=[O:26])(=[O:25])[NH2:24])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14])#[N:2].[OH-].[Na+].CC(O)=O>CCO.O>[NH2:2][C:1]1[C:3]2[C:4]([O:5][CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][N:8]3[C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=[CH:20][C:21]=2[NH:22][S:23](=[O:25])(=[O:26])[N:24]=1
Reactant: CCNC(=O)N1CCCCC1COc1cccc(NS(N)(=O)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCNC(=O)N1CCCCC1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a solution of 2-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)-N-ethylpiperidine-1-carboxamide (Example 26a, 0.6 g, 1.57 mmol) in EtOH (10 mL) was added NaOH 2M (1.57 mL, 1.57 mmol) and the reaction mixture was heated at 100° C. for 2 h. The solution was then evaporated to dryness. The residue was diluted with water (7.0 mL), and 10% AcOH (3.5 mL, 3.5 mmol) was added at 0° C. to provide a white precipitate which was filtered and washed with cold water and further purified by Biotage purification system (120 g Silicycle column, DCM:THF=4:1 as eluent) to give the title compound (0.318 g, 53%). MS 382 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH2:14][CH:15]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:27]([CH2:26][CH:15]([CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 7 h
Yield: 62.8 %

Procedure:
8 ml of trifluoroacetic acid are added, at 0° C., to a solution of 2 g (5.6 mmol) of phenylmethyl 1,1-dimethylethyl 2-(phenylmethyl)-1,4-butanedioate in 16 ml of dichloromethane. After 7 h at room temperature, the mixture is evaporated to dryness and the residue is recrystallized from cyclohexane. 1.05 g of a white product are obtained.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH:8]([CH3:16])[CH2:7]1)=O)C.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.CC(O)=O>[Br:24][C:14]1[S:15][C:9]2[CH:8]([CH3:16])[CH2:7][NH:6][CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCc2ccsc2C(C)C1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC1CNCCc2cc(Br)sc21
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The product of step f) was dissolved in 2 mL of 1:1 CHCl3/HOAc and treated with NBS (62 mg, 0.35 mmol). After stirring for 10 minutes, the reaction was concentrated to dryness and filtered through a pad of silica gel, eluting with EtOAc. The eluent was concentrated and the residue was treated with 2 mL each EtOH and 40% aqueous KOH. After heating for 14 hours at 100° C., the reaction was diluted with water and extracted 2× into DCM. The title compound was purified by preparative HPLC-MS. The two enantiomers were separated using a Chiralpak® AD-RH® 20×250 mm column from Chiral Technologies (10 mL/min MeOH mobile phase) to give enantiomer 1 (rt=11.6 minutes) and enantiomer 2 (rt=13.6 minutes) of the title compound. 1H NMR (CD3OD) δ 6.92 (s, 1H), 3.48-3.34 (m, 3H), 3.17-2.99 (m, 4H), 1.44 (d, J=7.2 Hz, 3H); MS: ESI (positive): 246, 248 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](O)=[O:16])[C:10](=[O:18])[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(OC(Cl)=O)C(C)C.Cl.[NH2:50][CH2:51][C:52]([NH:54][C@H:55]([C:63]([NH:65][CH3:66])=[O:64])[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:53]>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:50][CH2:51][C:52]([NH:54][C@H:55]([C:63]([NH:65][CH3:66])=[O:64])[CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:53])=[O:16])[C:10](=[O:18])[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][CH:21]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1Cc1ccc(OCc2ccccc2)cc1
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of piperazinone acetic acid 5a (0.45 g, 1.0×10-3 mole) and dry THF (3 ml) at -10° C. under argon is added in turn Et3N (0.16 ml, 1.1×10-3 mole) and isobutylchloroformate (0.15 ml, 1.1×10-3 mole). After stirring 10 minutes at -10° C., a freshly neutralized solution of glycyl-L-phenylalanine methyl amide 9a hydrochloride (0.30 g, 1.1×10-3 mole), Et3N (0.28 ml, 2.0×10-3 mole), THF (3 ml), and H2O (1.5 ml) is added in one portion. The cooling bath is then removed and the reaction allowed to warm to room temperature. After stirring overnight the reaction is quenched into 0.5 M aqueous HCl. The aqueous mixture is extracted with Et2O (2 times) and CH2Cl2 (2 times). The ethereal extracts are combined and washed with saturated aqueous NaHCO3 as are the CH2Cl2 extracts. The ethereal and CH2Cl2 extracts are then combined and dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate give 10a which is purified by chromatography, and the structure corroborated by NMR. NMR (CDCl3) δ1.26 (S, 9, t-boc), 2.64 (d, 3, methylamide), 3.08, 3.90 (m, 12, methylenes), 4.68 (m, 2, C3 -H and phenylala-CH), 4.98 (S, 2, benzyloxy methylene), 6.6-7.8 (m, 17, aromatic and amide NH's).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[OH:30])[CH:25]=O)[CH3:20].[Cl-].[NH4+].Cl>O1CCCC1>[CH2:19]([O:21][C:22]1[CH:23]=[C:24](/[CH:25]=[C:3](\[CH2:2][CH3:1])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:27]=[CH:28][C:29]=1[OH:30])[CH3:20]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccc(O)c(OCC)c1)CC
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A solution of 11.8 g (46 mmol) of triethyl 2-phosphonobutyrate in 20 mL of tetrahydrofuran is added to a mixture of 1.8 g (46 mmol) of sodium hydride in 20 mL of tetrahydrofuran at 0° C. The reaction medium is stirred for 15 minutes. A solution of 3.4 g (20 mmol) of 3-ethoxy-4-hydroxybenzaldehyde prepared as in Example 32a in 20 mL of tetrahydrofuran is then added to the reaction mixture and the reaction medium is stirred at room temperature for 3 days. The reaction medium is then poured into saturated ammonium chloride solution, acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the residue (12.5 g) is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 3.7 g (71%) of ethyl 2-[1-(3-ethoxy-4-hydroxyphenyl)meth-(E)-ylidene]butyrate are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:19][C:16]1[CH:17]=[CH:18][C:10]2[CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:12](=[O:13])[C:11]=2[CH:15]=1
Reactant: O=C(O)c1cc(F)ccc1CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2cc(F)ccc2CCc2ccc(F)cc21
Yield: 85 %

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]-5-fluorobenzoic acid (2.02 g, 7.71 mmol, 1 equiv) and oxalyl chloride (1.37 g, 10.8 mmol, 1.4 equiv) in CH2Cl2 (20 mL) was refluxed for 30 min. The resulting solution was then added to a stirring suspension of aluminum chloride (1.44 g, 10.8 mmol, 1.4 equiv) in CH2Cl2 (50 mL). This mixture was refluxed for 1 h. The reaction mixture was then washed with 1N HCL (3×20 mL), aq. satd. NaCl (1×50 mL), and H2O (1×50 mL). The organic layer was dried (anhyd. Na2SO4) and rotary evaporated to provide 1.6 g of a light-orange-colored semisolid. This material was chromatographed (3:1 hexane/CHCl3) through silica gel (150 mm×25-mm dia.). Evaporation of the combined fractions containing product provided 0.93 g (49%) of the desired product as a light-yellow shiny solid.
Reaction SMILES: Cl.[C:2]([NH2:8])(=[NH:7])[CH2:3][CH2:4][CH2:5][CH3:6].C[O-].[Na+].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>CO>[CH2:3]([C:2]1[NH:8][C:15](=[O:14])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][N:7]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1ncc(C(=O)OCC)c(=O)[nH]1
Reaction time: 2 h

Procedure:
To a solution of 2.0 g valeramidine hydrochloride and 750 mg sodium methoxide in 50 mL methanol was added 3.2 g diethyl ethoxymethylenemalonate (Aldrich) at room temperature. After 2 hours, an additional 850 mg sodium methoxide was added and the mixture was allowed to stir overnight. Solvent was removed in vacuo and the remaining material was partitioned between saturated aqueous ammonium chloride solution and ether. The organic layer was removed and the aqueous layer was extracted twice more with ether. The combined organic material was dried over MgSO4, was stripped of solvent in vacuo, and then was Still flash chromatographed in 3% MeOH in CH2Cl2 to give the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ8.73 (s, 1H), 4.37 (4 line m, 2H), 2.77 (3 line m, 2H) 1.80 (m, 2H), 1.41 (m, 2H) 1.38 (3 line m, 3H), 0.96 (3 line m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:28])[C:17]=1[C:18](Cl)=[O:19]>[N+](C)([O-])=O>[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:28])[C:17]=1[C:18]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([I:1])[CH:3]=2)[NH:8][CH:9]=1)=[O:19]
Reactant: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: Ic1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=C(c1c(F)ccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(I)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
In a reaction vial, 5-iodo-1H-pyrrolo[2,3-b]pyridine (43, 1.00 g, 4.10 mmol) is mixed with 22 mL of nitromethane and aluminum trichloride (3.28 g, 24.6 mmol) is added. The reaction is stirred at room temperature for 1 hour and 2,6-difluoro-3-nitro-benzoyl chloride (44, 1.36 g, 6.15 mmol) is added. The reaction is heated at 45° C. for 93 hours, then quenched with addition of methanol. The resulting precipitate is collected by filtration to provide the desired compound (45, 1.06 g).
Reaction SMILES: [O:1]1[CH2:5]C[CH2:3][CH2:2]1.[CH3:6][C:7]1[NH:8][C:9]([CH3:38])=[C:10]([C:30]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])=[O:31])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:12]=1[C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])=[O:14].[H-].[Na+].ClCOCC>O.C(O)(=O)C>[CH2:2]([O:1][CH2:5][N:8]1[C:7]([CH3:6])=[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])=[O:14])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]([C:30]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])=[O:31])=[C:9]1[CH3:38])[CH3:3]
Reactant: CCOCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCC)C1c1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOCCOC(=O)C1=C(C)N(COCC)C(C)=C(C(=O)OCCOCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml. of anhydrous tetrahydrofuran was dissolved 10 g. of bis(2-ethoxyethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4 -dihydropyridine-3,5-dicarboxylate and then the solution was added dropwise to 10 ml. of an anhydrous tetrahydrofuran suspension of 1.2 g. of a 50% oil dispersion of sodium hydride under stirring. After stirring the mixture further for 30 minutes at room temperature, the mixture was cooled to -10° C., 5 ml. of anhydrous tetrahydrofuran solution of 2.5 g. of chloromethoxyethane was added thereto over a period of 15 minutes, the temperature of the system was elevated gradually up to 0° C. over a period of about 15 minutes, and then the mixture was maintained at 0° C. for 15 minutes. The reaction product was cooled again to -10° C. and 2 ml. of acetic acid was added to the product. After stopping the cooling, 100 ml. of water was added to the product and then the product was extracted three times each time with 30 ml. of ether. The ether extracts were combined, dried over anhydrous sodium sulfate and then ether was distilled away. By recrystallizing the residue from 20:1 hexane-ethanol mixed solvent, 8.6 g. of colorless plate crystals of bis(2-ethoxyethyl) N-ethoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate melting at 63°-63.5° C. were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].CCOCC>C(#N)C>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C1OCc2ccccc21
Solvent: CC#N
Solvent: CCOCC
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Temperature: 20 °C
Yield: 10.2 %

Procedure:
To prepare compound I-24 identified above, 38.3 g of p-nitrophenylhydrazine and 33 g of phthalide were heated in acetonitrile for 3 hours at 70°-80° C. After cooling to 20° C., the solid product was stirred together with ether and then the product was collected by filtration and washed with ether to obtain 7.2 g of 1-(2'-hydroxymethylbenzoyl)-2-(p-nitrophenyl)hydrazine.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:23](C1C(N[C@@H]2C3C(=CC=CC=3)CC[C@H]2O)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:23][C@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3CC[C@H]2O)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2c3ccccc3CC[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (trans)-1-[(3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.30 (m, 6H), 1.95 (m, 1H), 2.25 (m, 1H), 2.64 (dd, J=7.5, 15.1 Hz, 2H), 2.84 (dd, J=7.6, 15.2 Hz, 2H), 2.94 (m, 2H), 4.03 (m, 1H), 4.74 (d, J=6.7 Hz, 1H), 5.08 (s, 1H) 5.16 (dd, J=6.7, 7.2 Hz, 1H), 7.2 (m, 1H), 7.28 (m, 2H), 7.35 (m, 1H); MS (EI) m/z (rel. intensity) 375 (M+, 9), 359 (68), 357 (67), 230 (45), 146 (35), 129 (69), 128 (56), 118 (55), 117 (99), 115 (68), 91 (45). HRMS (FAB) calcd for C18H22BrN3O+H 376.1025, found 376.1029. Anal. Calcd for C18H22BrN3O: C, 57.45; H, 5.89; N, 11.17; Br, 21.23. Found: C, 57.61; H, 5.88; N, 10.70.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1.BrCC1C=CC=C(F)C=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:13]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2ccc(Br)cc2)c1

Procedure:
3-Nitro-phenol was reacted with 1-bromo-4-bromomethyl-benzene according to the procedure from Example 199A substituting 1-bromo-4-bromomethyl-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[C:24]3[C:23](=[N:25]O)[CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][C:17]=2[CH3:27])=[CH:11][CH:10]=1.[I-].[Na+]>C(O)(=O)C.C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:25][C:5](=[O:7])[CH3:6])[NH:18][C:17]=2[CH3:27])=[CH:13][CH:14]=1
Reactant: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=NO)CCC2
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1cccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c12
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
Acetic anhydride (1.1 mL, 11.6 mmol) was added to a stirred slurry of N-[-3-(4-chlorophenylsulfanyl)-2-methyl-4,5,6,7-tetrahydro-1H-indol-4-ylidene]hydroxylamine (3.0 g, 9.8 mmol) in a mixture of acetic acid (15 mL) and xylene (15 mL) at r.t. in reaction flask 1 (mildly exothermic addition) then the mixture was held with stirring for 45 mins. Meanwhile, reaction flask 2 was charged with acetic acid (7.5 mL), xylene (7.5 mL), acetic anhydride (1.1 mL, 11.6 mmol), and sodium iodide (70 mg, 0.47 mmol) and the mixture was heated to 110° C. with stirring. The contents of reaction flask 1 were transferred to reaction is flask 2 in aliquots over a period of 2 h, whilst maintaining the reaction temperature at 110° C. Reaction flask 1 was rinsed with a mixture of xylene (2 mL) and acetic acid (2 mL) which was transferred to reaction flask 2. Subsequently, the reaction mixture was maintained at 110° C. for a further 3 h then allowed to cool to r.t. and held overnight. The reaction mixture was evaporated to dryness in vacuo to leave a dark brown solid residue. This was purified by chromatography on silica gel, eluting with dichloromethane/ethyl acetate to provide the title compound as an off-white solid; 2.74 g (85%); purity 95.6 area % by HPLC; m/z: 331/333 (MH+); 1H-NMR: 11.84 (1H, s), 9.45 (1H, s), 7.45 (1H, d, J=7.7 Hz), 7.29 (2H, d, J=8.3 Hz), 7.17 (1H, d, J=8.0 Hz), 7.04 (1H, t, J=7.9 Hz), 6.98 (2H, d, J=8.2 Hz), 2.40 (3H, s), 1.84 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[OH:21])=[O:13])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[OH:21])=[O:13])[N+:5]([O-:30])=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c2ccccc2n1
Solvent: ClCCl
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (0.20 g, 0.57 mmol) in 3.0 mL CH2Cl2 at room temperature was added 3-chloroperbenzoic acid (0.20 g, 1.15 mmol). The reaction mixture was stirred at room temperature for 18 h. Additional 3-chloroperbenzoic acid (0.20 g, 1.15 mmol) was added to reaction mixture and was stirred at room temperature for an additional 18 h. The reaction mixture was concentrated, and the resultant residue was subjected to silica gel chromatography eluting with 0-75% ethyl acetate in hexanes to afford 4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide 1-oxide that gave a mass ion (ES+) of 367.1 for (81Br) for M+H+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].BrBr.C(=O)([O-])O.[Na+:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[O:6]=[C:5]1[O:7][CH2:3][C:2]([C:1]([O-:9])=[O:8])=[CH:4]1.[Na+:16]
Reactant: C=C(CC(=O)O)C(=O)O
Agent: BrBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C1C=C(C(=O)[O-])CO1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a solution of itaconic acid (26.0 g) in water (35 ml) was added dropwise bromine (10.3 ml) at room temperature while keeping a temperature of the reaction solution below 45° C., and then the mixture was stirred at 30° C. for 15 minutes. To this reaction solution was added portionwise sodium hydrogen carbonate (33.6 g), and then the mixture was heated to 55° C. To this reaction solution was added dropwise a solution of sodium carbonate (10.6 g) in water (15 ml), and then the mixture was stirred for 20 minutes. This reaction solution was iced, and stirred for 1 hour. The precipitated solid was collected by filtration, washed with cold water and ethanol, and then dried under reduced pressure to give the titled compound (16.8 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH:29]([OH:34])[CH:30]([OH:33])[CH2:31][OH:32])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.O1CCOCC1>CO.[Pd]>[OH:34][CH:29]([CH:30]([OH:33])[CH2:31][OH:32])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OCC(O)C(O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: OCC(O)C(O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.3 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(2,3,4-trihydroxybutan-1-yl)oxy]quinazoline (800 mg) in methanol (6 ml)--dioxane (6 ml) is added 10% palladium/carbon (160 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 17 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallized from acetone, and the resulting crystalline substance is recrystallized from ethanol-diethyl ether to give 4-[(2RS,3SR)-(2,3,4-trihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (316 mg) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(OCC)(O[CH2:13][CH3:14])(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH3:14]
Reactant: Oc1ccccc1Br
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1Br
Temperature: 25 °C

Procedure:
A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulphate and 170 ml of 10% NaOH solution is refluxed for 2 hours. After cooling the reaction mixture to RT, it is extracted with EtOAc and the organic phase is washed with 2N NaOH solution, dried over Na2SO4 and the solvent is evaporated off under vacuum. 19.6 g of the expected product are obtained.