Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([O:10][C:11](OC([O-])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([O:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCO
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of 3-aminopropanol (15 mL, 0.20 mol) in methylene chloride (50 mL) at rt was treated with t-butylpyrocarbonate (42.02 g, 1 equiv) in methylene chloride (25 mL), dropwise over 2 h. After stirring overnight the mixture was evaporated, flushed with heptane (3×), and dried in vacuo to give the product as a thick oil (34.31 g, 100%). 1H NMR δ 1.48 (s, 9H), 3.12 (br, 1H), 3.22 (q, J=7.5 Hz, 2H), 3.60 (q, J=7.8 Hz, 2H), 4.81 (br, 1H). MS (DCl) 176 (MH)+. Anal calcd for C8H17NO3: C-54.84, H-9.78, N-7.99. Found: C-54.80, H-9.82, N-7.97.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=O)cc(Br)c1C
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Cc1nc(OCc2ccccc2)cc(Br)c1C
Temperature: 25 °C

Procedure:
4-Bromo-5,6-dimethyl-2(1H)-pyridinone (1 eq.), prepared according to the procedure described by McElroy, W. T.; DeShong, P. Organic Letters 2003, 5, 4779-4782, was suspended in benzene (0.13 M). To this was then added silver carbonate (0.6 eq.) and benzyl bromide (1.2 eq.) before the suspension was heated at 45° C. for 3 days in the dark. The reaction suspension was cooled to RT, diluted with benzene and filtered through a bed of celite. The filtrate was washed with sat. aq. NaHCO3, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification by way of column chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]3[N:24]([CH:32]([CH3:34])[CH3:33])[C:23]2=[O:35])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[CH3:31][C:29]1[CH:30]=[C:25]2[N:24]([CH:32]([CH3:33])[CH3:34])[C:23](=[O:35])[N:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:21][CH:20]=3)[C:26]2=[N:27][CH:28]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (198 mg) and 3-(4-hydroxyphenyl)-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (177 mg) in DMF (1.5 ml) was added NaH (40.0 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (125 mg) as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18])#[N:2].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)=[O:18])=[O:40])#[N:2]
Reactant: CCOC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(C(=O)Nc2ccccc2S(=O)c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1.51 g of ethyl 4-[2-(2-cyanophenylthio)phenylcarbamoyl]phenoxyacetate (prepared in accordance with Reference Example 6, Step 2) in 5 ml of chloroform was added dropwise a solution of 0.87 g of 70% m-chloroperbenzoic acid in 20 ml of chloroform and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate and the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to give 1.3 g of the title compound as white crystals, m.p. 128°-130° C. .
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[N:25][CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A solution of 100 mg (0.46 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 19 mg (0.48 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 125 mg (0.46 mmol) 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 170 mg (82%) of the title compound as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CCN(C(C)C)C(C)C>Cl.CCCCO>[C:16]1([NH:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[CH:3]=3)=[CH:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCO
Reactant: Clc1cc(Nc2ccc(Nc3ccccc3)cc2)ncn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2ccc(Nc3ccccc3)cc2)ncn1
Temperature: 200 °C
Yield: 32 %

Procedure:
176 mg of N1-(6-chloropyrimidin-4-yl)-N4-phenylbenzene-1,4-diamine in the form of a hydrochloride, 72 mg of ethanolamine and 153 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated and the evaporation residue was subjected to MPLC eluting the product with EtOAc. 2-(6-(4-(Phenylamino)phenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a solid.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=1[C:13]([NH:15][C:16]1[C:17]([CH3:32])=[N:18][C:19]([O:22][CH:23]([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=1)=[O:14])=[O:10])([CH3:7])[CH:3]=[N:4][O:5][CH3:6].BrN1C(=O)CCC1=O.[I:45]N1C(=O)CCC1=O>>[CH3:7][C:2]([NH:8][C:9]([C:11]1[C:36]([I:45])=[CH:35][CH:34]=[CH:33][C:12]=1[C:13]([NH:15][C:16]1[C:17]([CH3:32])=[N:18][C:19]([O:22][CH:23]([C:28]([F:31])([F:29])[F:30])[C:24]([F:26])([F:27])[F:25])=[CH:20][CH:21]=1)=[O:14])=[O:10])([CH3:1])[CH:3]=[N:4][O:5][CH3:6]
Reactant: CON=CC(C)(C)NC(=O)c1ccccc1C(=O)Nc1ccc(OC(C(F)(F)F)C(F)(F)F)nc1C
Reactant: O=C1CCC(=O)N1I
Agent: O=C1CCC(=O)N1Br
Product: CON=CC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(OC(C(F)(F)F)C(F)(F)F)nc1C
Yield: 83 %

Procedure:
2-(1,1-Dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-N-(6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-2-methylpyridin-3-yl)benzamide was treated in the same manner as in Example 36, except that the N-bromosuccinimide was replaced with N-iodosuccinimide, to obtain 2-(1,1-dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-N-(6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-2-methylpyridin-3-yl)-3-iodobenzamide (yield 83%, melting point 220° C.). Regioselectivity of iodination into the 3-position was 100%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=O)=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:28][NH2:29]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH:29][CH3:28])=[O:24])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 18 h

Procedure:
A suspension of the product of Example 1 (100 mg) in a 33% w/v solution of methylamine in ethanol (3 ml) was stirred for 18 hours. The solid formed, after filtration and washing with a little ethyl acetate, gave the title compound, 65 mg: m.p. 169°-171° C.; NMR (d6DMSO) δ8.14 (2H, d), 8.06 (1H, bq), 8.00 (2H, d), 7.05 (2H, d), 6.80 (2H, d), 4.56 (2H, s), 3.82 (2H, s), 3.30 (4H, t), 2.66 (3H, d), 2.61 (4H t); m/e 369 (M+H)+ ; calculated for C20H24N4O3 : C, 65.2; H, 6.6; N, 15.2. found: C, 65.0; H, 6.8; N, 15.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: Cc1ccc(Cl)cc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
5-Chloro-2-methylbenzoic acid (46, 5.0 g, 29.3 mmol) was suspended in dichloromethane (30 mL) and thionyl chloride (3.2 mL, 5.2 g, 44 mmol) was added. The solution was stirred at room temperature for 1 hour. Methanol was added and the reaction was allowed to proceed for a further 16 hours. The volatile components were evaporated under reduced pressure. The resulting residue was taken up again in methanol (30 mL) and pyridine (5 mL) was added. The solution was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford methyl 5-chloro-2-methylbenzoate (5.3 g, 96% yield) that was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1
Reactant: Nc1ccncc1Cl
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Nc4ccncc4Cl)ncnc32)CC1

Procedure:
By the procedure described in Example 3, with the exception that 3-chloro-4-aminopyridine was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A was converted into Example 120. 1H NMR (500 MHz, CDCl3) δ ppm 1.24 (d, J=6.60 Hz, 6H) 1.59-1.64 (m, 2H) 1.66-1.74 (m, 2 H) 2.85-2.93 (m, 2H) 3.44-3.47 (m, 2H) 4.25-4.29 (m, 4H) 4.80-4.87 (m, 1H) 4.87-4.94 (m, 1H) 7.60 (s, 1H) 8.09 (s, 1H) 8.31 (d, J=6.05 Hz, 1H) 8.44 (s, 1H) 8.75 (d, J=5.50 Hz, 1H). LRMS (ESI): 433.3/435.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.IC.[C:21]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(-n2ccc(OC)cc2=O)cc1

Procedure:
A solution of Example 296A (2.3 g, 10 mmol) in acetone (300 mL) was treated with iodomethane (5 mL) and K2CO3 (15 g), heated to reflux for 18 hours, and filtered. The filtrate was concentrated and the concentrate purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product. MS (ESI) m/e 260 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11].[CH2:12]=O>C(O)=O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:12])[CH2:7][C:6]1=[O:11]
Reactant: C=O
Reactant: O=C1CNCCN1CCCO
Solvent: O=CO
Product: CN1CCN(CCCO)C(=O)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
1-(3-Hydroxypropyl)piperazin-2-one (700 mg, 4.43 mmol) in formic acid (10 ml) and 37/40% aqueous formaldehyde solution (5 ml) was stirred and heated at 95° for 2 hr then the resulting solution evaporated in vacuo. The residue was taken up in 5% methanol in dichloromethane (20 ml), basified with a 7N solution of ammonia in methanol and stirred 4.5 hr at room temperature. The mixture was filtered and the filtrate purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent to give 1-(3-hydroxypropyl)-4-methylpiperazin-2-one (710 mg, 93%) as a colourless oil; NMR Spectrum:(CDCl3) 1.73 (quintet, 2H), 2.34 (s, 3H), 2.66 (t, 2H), 3.13 (s, 2H), 3.33 (t, 2H), 3.53 (m, 4H), 3.80 (s(broad, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cn1nccc1C(=O)O
Product: Cn1nccc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1-methyl-1H-pyrazole-5-carboxylic acid, as starting materials, MS (LC/MS): 409.2 (M−H).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[CH2:16]([NH:17][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCCCCCN
Reactant: CCCCCCC1CO1
Solvent: CO
Product: CCCCCCC(O)CNCCCCCCNCC(O)CCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-octene oxide (42 g.) and hexamethylenediamine (19.05 g.) and recrystallization of the resulting product from methanol gave N,N'-(1,6-hexylene)-bis[2-hydroxyoctylamine] (I: R = (CH3 (CH2)5, R' = H, X = (CH2)6, Z = H) (17.2 g., m.p. 124.0°-127.4° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[OH-].[Li+].O>O1CCCC1>[Br:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.1 %

Procedure:
To a solution of 6.38 g (0.016 mol) 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid methyl ester in 120 ml tetrahydrofuran was added at room temperature 17 ml of a 1M lithium hydroxide solution in water (0.017 mol) and the mixture was stirred at room temperature for 45 minutes. The resulting clear reaction mixture was partitioned between 10% aqueous citric acid solution and ethyl acetate. The phases were separated and the organic layer washed with water and brine, dried over magnesium sulfate and evaporated to yield 6.05 g (99% yield) of the title compound as white crystalline solid. MS (ISP) (M+H+)=363.0 and 364.9
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CO.O>[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18](=[O:2])[CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CCCC2N(CCC3(O)CCCCC3)C(=O)CS2=O)cc1

Procedure:
Sodium metaperiodate (0.75 g., 3.5 mmoles) is added to a cold (0°-5° C.) solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (1.33 g., 3.4 mmoles) in methanol (20 ml.) and water (5 ml.). The resulting mixture is stirred without further cooling for 16 hours. The precipitated solid is then removed by filtration. The filtrate is diluted with water and extracted with chloroform. The organic extract is washed with brine, dried over sodium sulfate, and evaporated in vacuo to leave an oily residue which is chromatographed on silica gel (25 g.). Elution with 4% acetic acid in chloroform affords the title compound as a viscous, yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([I:31])[C:28]=1[O:29][CH3:30])[CH:24]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:24]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)[CH:26]=[C:27]([I:31])[C:28]=1[O:29][CH3:30]
Reactant: COc1cc(C=O)cc(I)c1OC
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(I)c1OC

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (1.404 g,5.40 mmole), 3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (1.30 g, 4.45 mmole) and 0.542 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 12 hours. The benzene was removed in vacuo, and the remaining oil redissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3 and H2O. The organic layer was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.0 cis/trans ratio (2.38 g, 100%). The trans isomer can be isolated by recrystallization from methanol.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(F)CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(F)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An amount of thionyl chloride of 8.99 g (0.08 mol) was introduced at 20-25° C. into a dry 50 ml round-bottomed flask under a nitrogen atmosphere. Ethyl 3-hydroxy-2-fluoropropionate (10.0 g, 0.07 mol) were subsequently metered in in 1 h and the mixture was subsequently stirred at ambient temperature for a further 2 h. An amount of toluene of 3.98 g (0.04 mol), together with 0.286 g of pyridine (5 mol %), were introduced into a second round-bottomed flask with an Anschutz head and the mixture was heated to 80° C., The mixture from the 1st round-bottomed flask was added dropwise to the preheated solution in 1 h at 75-85° C. Solvents were distilled off under reduced pressure and the residue was subsequently finely distilled at 120° C. and 10 mbar. 4.1 g of distillate were obtained as a colorless liquid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][C:8]3=[CH:9][C:4]=2[NH:3][C:2]1=[O:16].[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:13]([C:11]2[O:10][C:8]3[C:7](=[CH:6][C:5]4[O:1][C:2](=[O:16])[NH:3][C:4]=4[CH:9]=3)[CH:12]=2)=[O:15])[CH2:27][CH2:26]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3oc(=O)[nH]c3cc2o1
Solvent: CCOCC
Product: O=C(c1cc2cc3oc(=O)[nH]c3cc2o1)N1CCC(OCc2ccccc2)CC1

Procedure:
The title compound is prepared from 3H-furo[2,3-f]benzoxazole-2-one-6-carboxylic acid and 4-benzyloxypiperidine according to the method described in Example 1/c. Mp.: 217-219° C. (diethyl ether).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[C:13](=O)([O-])[OH:14].[K+]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:14][CH3:13])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: O=C([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1C
Reaction time: 10 h
Yield: 94.4 %

Procedure:
2,3-Dimethyl-4-nitropyridine-1-oxide (5 g) was dissolved in methanol (30 ml). To the solution were added tetrabutylammonium bromide (0.5 g) and potassium hydrogen carbonate (5.6 g), and the mixture was heated (temperature 80°-85° C.) under reflux with stirring for 10 hours. The solid matter was removed from the reaction mixture by filtration, and the filtrate was concentrated and applied to a silica gel (100 g) column. Elution with methanol-dichloromethane (1:9) and recrystallization from ethyl acetate-hexane gave 4.3 g of white 2,3-dimethyl-4-methoxypyridine-1-oxide. Melting point 85°-86° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:14])[CH:7]=1>S(=O)(=O)(O)O>[Br:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:14])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])c(Br)cc1F
Reaction time: 2 h

Procedure:
Nitric acid (25 mL) is added dropwise to a solution of 4-bromo-2-fluorobenzaldehyde (5.12 g, 25.2 mmol) in sulfuric acid (25 mL). The mixture is stirred for 2 hours and then is poured over ice. Product is extracted into MTBE (100 mL). The organic layer is washed with saturated aqueous NaHCO3 (100 mL), dried (Na2SO4), and evaporated yielding 5.98 g of yellow solid. 1H NMR (DMSO-d6) δ 6 10.13, 8.49, 8.22.