Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].C[O:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])=O.S(=O)(=O)(O)O>O1CCCC1.O>[CH3:19][C:18]1[NH:17][CH:16]=[N:15][C:14]=1[C:12](=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9]
Reactant: COC(=O)c1nc[nH]c1C
Reactant: Cc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1nc[nH]c1C
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
4.9 g of dry magnesium turnings are covered with 50 ml of dry tetrahydrofuran. The mixture is heated to boiling and a solution of 34 g of 2-bromotoluene in 50 ml of dry tetrahydrofuran is added dropwise at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for about 30 minutes until the magnesium turnings no longer react. The reaction mixture is then cooled to about 50° C. and 20 g of 5-methyl-4-imidazole-carboxylic acid methyl ester are added in small portions. After the addition is complete, the mixture is refluxed for another 2 hours and the solvent is then distilled off to give about half of the original volume. The mixture is cooled and poured into 300 ml of cold water containing 15 ml of concentrated sulfuric acid, with agitation. The stirring is continued for an additional 15 minutes and the mixture is then filtered. The pH of the filtrate is adjusted to 7-11 and the solution is extracted three times with 30 ml portions of chloroform. The combined chloroform extracts are washed with water and evaporated to dryness. The residue, which contains the crude product, is converted to the hydrochloride in ethanol. After recrystallization from ethanol, the hydrochloride melts at 289°-291° C. The 5-methyl-4-(2'-methylbenzoyl)-1H-imidazole is liberated from the hydrochloride in water with sodium hydroxide. It melts at 165°-166° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C=O)C>[N:19]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc(CCl)n1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CN2CCCC2)n1
Temperature: 80 °C
Yield: 67.4 %

Procedure:
K2CO3 (66 g, 0.48 mol) was added to a solution of methyl 6-(chloromethyl)picolinate 71 (45.0 g) and pyrrolidine 72 (34 g, 0.48 mol) in DMF (300 mL). The reaction mixture was heated at 80° C. for 12 h. H2O (300 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 73 (36 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([CH3:20])=[C:15]([NH:21]C(C)(C)CC(C)(C)C)[N:14]=1)(C)(C)C>>[NH2:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([CH3:20])=[C:15]([NH2:21])[N:14]=1
Reactant: Cc1cc(F)c(NC(C)(C)C)nc1NC(C)(C)CC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)c(N)nc1N
Reaction time: 0.5 h

Procedure:
To 800 mg of trifluoroacetic acid was added 340 mg of 2-t-butylamino-3-fluoro-5-methyl-6-(1,1,3,3-tetramethylbutylamino)pyridine, and the mixture was allowed to stand at room temperature for 30 minutes. The solution was concentrated under reduced pressure to obtain crude 2,6-diamino-3-fluoro-5-methylpyridine as a pale brown solid residue.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([NH:10][C:11]2[C:12]3[C:19]4[CH2:20][CH2:21][NH:22][CH2:23][C:18]=4[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][C:4]=1[OH:24].Cl.[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31]([N:22]1[CH2:21][CH2:20][C:19]2[C:12]3[C:11]([NH:10][C:6]4[C:7]([F:9])=[CH:8][C:3]([F:2])=[C:4]([OH:24])[CH:5]=4)=[N:16][CH:15]=[N:14][C:13]=3[S:17][C:18]=2[CH2:23]1)=[O:32]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)c(F)cc1F
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)c(F)cc4F)c23)C1

Procedure:
The compound was synthesized in analogy to Example 122 from 2,4-difluoro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 71A (100 mg, 0.27 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (63 mg, 0.38 mmol) to yield 40 mg (32%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:20])=[C:5]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:11])=[N:7][C:8]=1[O:9]C)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.C(#N)C>O>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:11])=[C:5]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:4]=1[CH3:20])[CH3:2]
Reactant: CCc1c(OC)nc(C)c(-c2cccc(C#N)c2)c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1c(C)c(-c2cccc(C#N)c2)c(C)[nH]c1=O
Yield: 31.2 %

Procedure:
A stirred mixture of 3-(5-ethyl-6-methoxy-2,4-dimethylpyridin-3-yl)benzonitrile (44 mg, 0.165 mmol), sodium iodide (50 mg, 0.33 mmol), chlorotrimethylsilane (58.4 μL, 0.33 mL) and acetonitrile (2 mL) is heated at reflux temperature for 3 hr. The cooled reaction mixture is diluted with water (10 mL) and extracted with dichloromethane. The extract is dried, filtered, concentrated and the residue is purified by chromatography eluting with cyclohexane-ethyl acetate then with dichloromethane-5% methanol. Product containing fractions are combined and concentrated to afford 3-(5-ethyl-2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile (13 mg, 32%) as a beige solid. LC/MS: MS m/e=253 (M+H); RT 2.92 min.; 1H NMR (CDCl3, δ ppm) 7.69 (1H, d), 7.59 (1H, t), 7.45 (1H, s), 7.41 (1H, d), 2.63 (2H, q), 2.02 (3H, s), 1.84 (3H, s), 1.11 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Na+].[Na+].Cl.C[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl>C(O)CCC>[N:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:22][CH2:21][NH:17][CH2:18][CH2:19]1
Reactant: Nc1ccccc1O
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Oc1ccccc1N1CCNCC1
Temperature: 123 °C

Procedure:
2-Aminophenol (6 g; 54 mmol) is dissolved in 1-butanol (110 ml) in the presence of sodium carbonate (2.9 g; 27.5 mmol) and N-methylbis(2-chloroethyl)amine hydrochloride (11.1 g; 58 mmol). The suspension is heated at 123° C. for 3 days. The butanol is evaporated off under reduced pressure and compound 43A is purified by flash chromatography with the following mixtures of eluents: NH4 OH/acetone/CH2Cl2 (0.5/20/80) and then NH4 OH/methanol/CH2Cl2 (1/5/95).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[NH4+].[Cl-]>O1CCCC1.CCOCC>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
In 75 ml of dry tetrahydrofuran was dissolved 3.81 g of 9-benzylamino-3,4-dihydroacridin-1(2H)-one with mechanical stirring. The solution was cooled in ice under N2 and 5.9 ml (0.5 eq) of 1.1M LiAlH4 solution in ether was added dropwise. After 0.5 hour the reaction was complete based on thin layer chromatography analysis. The excess hydride was neutralized with 0.5 ml of saturated NH4Cl solution and the inorganic salts were extracted into 30% potassium hydroxide. The tetrahydrofuran solution was decanted and evaporated to a solid which was recrystallized from 1:10 dichloromethane/EtOAc to yield 2.89 g (75%) of a solid, melting point 159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH3:15])[CH:7]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].[F:22][B-:23]([F:26])([F:25])[F:24].[H+].[N:28](OCCC(C)C)=O>C(O)C.CCOCC>[F:22][B-:23]([F:26])([F:25])[F:24].[CH2:19]([O:18][C:16]([C:6]1[C:5](=[O:21])[C:4]2[C:9](=[N:10][C:11]([O:12][CH3:13])=[C:2]([N+:1]#[N:28])[CH:3]=2)[N:8]([CH2:14][CH3:15])[CH:7]=1)=[O:17])[CH3:20]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)c(N)cc2c1=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cn(CC)c2nc(OC)c([N+]#N)cc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 12.0 g of ethyl 6-amino-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate in 120 ml of ethanol and 60 ml of aqueous 42% tetrafluoroboric acid was cooled to 0° C. To the solution kept at 0°-3° C. was added 6.0 g of isoamyl nitrite. The mixture was stirred for 30 minutes at the same temperature, and then diluted with 600 ml of ether to give a precipitate which was collected and washed with ether to give 12.8 g of 3-ethoxycarbonyl-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-6-diazonium tetrafluoroborate, decomposing at 142°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:57]1[N:62]=[C:61]([NH:63][CH2:64][CH2:65][NH:66][C:67]2[CH:72]=[CH:71]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:68]=2)[CH:60]=[CH:59][C:58]=1[N+:86]([O-:88])=[O:87]>CC#N.C1COCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:71][CH:72]=[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:61]2[CH:60]=[CH:59][C:58]([N+:86]([O-:88])=[O:87])=[CH:57][N:62]=2)[N:68]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Ethyl 2-(2,4-dichlorophenyl)-6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyridine-3-carboxylate was prepared from ethyl 3-(2,4-dichlorophenyl)-3-oxopropanoate (ref. Wemple, J.; et. al. Synthesis 1993, 290-292.) as the starting material and THF/ethanol ratio of 3:1 as the solvent in the first step. The oxidation uses DDQ. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylamine)-5-nitropyridine in CH3CN and Hüing's Hüing's base at 120° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[CH:4]=[N:3]1.N[C:14]1C(C)=NN(C)C=1C(N)=O>>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[C:4]([CH3:14])=[N:3]1
Reactant: Cn1ncc2[nH]c(=O)[nH]c(=O)c21
Reactant: Cc1nn(C)c(C(N)=O)c1N
Product: Cc1nn(C)c2c(=O)[nH]c(=O)[nH]c12

Procedure:
This compound was prepared in an analogous fashion to 1-methyl-1H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione, using 4-amino-1,3-dimethyl-1H-pyrazole-5-carb oxamide as the starting material. 1H NMR ((DMSO-d6, 400 MHz) δ ppm 11.02 (s, 2H), 3.97 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:14][C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:42][CH2:41][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)=[CH:32][CH:31]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccc(-c5cccs5)cc4)oc3C)cc2)C(=O)O)cc1

Procedure:
A mixture 2-(p-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 3, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-2-p-tolyloxy-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 2H, J=8.4 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.42 (dd, 1H, J=3.8, 1.0 Hz), 7.36 (dd, 1H, J=5.0, 1.0 Hz), 7.26–7.25 (m, 1H), 7.18 (d, 2H, J=8.4 Hz), 7.12 (dd, 1H, J=5.0, 3.8 Hz), 7.05 (d, 2H, J=8.4 Hz), 6.81 and 6.81 (d of Abq, 4H, J=8.8 Hz), 4.23 (t, 2H, J=6.2 Hz), 3.23 and 3.12 (d of Abq, 2H, J=14.0 Hz), 3.07 (t, 2H, J=6.2 Hz), 2.43 (s, 3H), 2.28 (s, 3H), 1.39 (s, 3H). IR (KBr) 3450, 1718, 1681, 1509, 1216 cm−1. HRMS (ES+) m/z exact mass calcd for C33H32NO5S 554.2001, found 554.2015.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]2[CH2:16][O:17][C@H:11]([O:12]2)[C@@H:10]1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:27](Br)[CH2:28][CH3:29]>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:27][CH2:28][CH3:29])[C@H:13]2[CH2:16][O:17][C@H:11]([O:12]2)[C@@H:10]1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@@H](OC2CCCCO2)[C@@H]2OC[C@H]1O2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCO[C@@H]1[C@@H](OCc2ccccc2)[C@@H](OC2CCCCO2)[C@@H]2OC[C@H]1O2
Temperature: 50 °C

Procedure:
A solution of 10 g of 1,6-anhydro-3-O-benzyl-2-O-tetrahydropyranyl-β-D-gulopyranose in 20 ml of absolute dimethylsulphoxide is treated with 3 g of potassium hydroxide powder, while stirring and with the exclusion of moisture, in a nitrogen atmosphere, and the mixture is warmed to 50° C. A solution of 3 ml of propyl bromide in 10 ml of dimethylsulphoxide is added dropwise at this temperature in the course of 2 hours and the reaction mixture is stirred for a further 3 hours. A further 3 g of potassium hydroxide powder are added, a solution of 3 ml of propyl bromide in 10 ml of dimethylsulphoxide is added dropwise and the mixture is stirred for 2 hours. The reaction mixture is now cooled and poured into ice-water. The resulting mixture is extracted with ether and the ether phase is washed with water until neutral and dried over magnesium sulphate. After evaporating off the solvent, 1,6-anhydro-3-O-benzyl-4-O-propyl-2-O-tetrahydropyranyl-β-D-gulopyranose is obtained in the form of yellow oil with a Rf value of 0.42 on silica gel thin layer plates in the system methylene chloride/ethyl acetate, 85:15.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[N:22][N:21]=2)=[C:16]([N+:29]([O-:31])=[O:30])[CH:15]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:25]([C:23]1[S:24][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[N+:29]([O-:31])=[O:30])=[N:21][N:22]=1)(=[O:27])=[O:26])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1nnc(S(=O)(=O)Cl)s1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.40 (d, 1H), 8.05 (dd, 1H), 8.02 (d, 1H) 4.07 (q, 2H), 3.30 (s, 2H), 3.19 (t, 2H), 2.67 (t, 2H), 1.18 (t, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@@H:19]1[CH2:41][C@@H:40]2[C@:35]([CH3:49])([CH2:36][CH2:37][C@H:38]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH2:39]2)[C@@H:34]2[C@@H:20]1[C@H:21]1[C@:31]([CH3:50])([CH2:32][CH2:33]2)[C@@H:24]([C@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:11]([O:18][C@@H:19]1[CH2:41][C@@H:40]2[C@:35]([CH3:49])([CH2:36][CH2:37][C@H:38]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH2:39]2)[C@@H:34]2[C@@H:20]1[C@H:21]1[C@:31]([CH3:50])([CH2:32][CH2:33]2)[C@@H:24]([C@H:25]([CH3:30])[CH2:26][CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
DMSO (0.01 ml, 0.14 mmol) in CH2Cl2 (0.1 ml) was added dropwise to a stirred solution of oxalyl chloride (0.008 ml, 0.0917 mmol) in anhydrous CH2Cl2 (2 ml) at -78° C. under anhydrous conditions (drying tube). This solution was stirred at -78° C. for 15 minutes. Steroid 2008 (0.0234 g, 0.0423 mmol) in dry CH2Cl2 (0.5 ml) was then added dropwise and the solution stirred for 40 minutes at -78° C. Diisopropylethylamine (DIPEA) (0.08 ml, 0.458 mmol) was added and the solution allowed to warm to 0° C. with stirring over a 30-minute period. Aqueous saturated NaHCO3 solution (5 ml) was added and the solution extracted 3× with 5 ml CH2Cl2. The combined organic extracts were washed 2× with 5 ml of aqueous saturated NaCl solution, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. Flash chromatography (SiO2, 10:1 hexanes:EtOAc) gave compound 2009 (0.0226 g, 97%) as a white solid foam. 1H NMR (500 MHz, CDCl3) δ: 9.76 (s, 1 H, C-24 H), 7.35-7.34 (m, 5 H, benzyl Ar-H), 4.71-4.69 (m, 1 H, THP ether methine H), 4.59 (d, J=11.8 Hz, 1/2 H, benzyl-CH2), 4.585 (d, J=11.8 Hz, 1/2 H, benzyl-CH2), 4.30 (d, J=12.0 Hz, 1/2 H, benzyl-CH2) 4.29 (d, J=12.0 Hz, 1/2 H, benzyl-CH2), 3.95-3.89 (m, 1 H, THP OCH2), 3.63-3.58 (m, 3 H, C-24 H & THP OCH2), 3.50-3.47 (m, 1H, C-3 H), 3.45 (s, 1 H, 7-H), 2.49-2.42 (m, 1 H, C-23 H), 2.37-2.31 (m, 1 H, C-23 H), 0.958 (d, J=6.5 Hz, 3 H, C-21 H), 0.81 (s, 3H, C-19 H), 0.63 (s, 3 H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 2900, 1700 cm ; MS (CI/isobutane) m/z 552 (M+1, 0.4%), 465 (M+1-THP, 3%), 449 (M+1-THPO, 14%), 375 (M+1-THP-Bn, 7%), 359 (M+1-THP-HOBn, 68%), 341 (M+1-THP-HOBn-H2O, 100%); m.p. 50°-54° C.; Anal. calcd. for C36H54O4 : C=78.50, H=9.88; Found: C=78.11, H=10.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19](S(C)(=O)=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:28]#[N:29].[Na+].O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:28]#[N:29])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(S(C)(=O)=O)n2)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(C#N)n2)CC1
Reaction time: 10 h

Procedure:
To a solution of the crude 4-[2-(6-chloro-2-methanesulfonylpyrimidin-4-yl oxy)ethyl]-piperidine-1-carboxylic acid tert-butyl ester (4.9 g) and NaCN (14 mmol) in CH2Cl2:H2O (50 mL, 4:1) is added TBAB (tetrabutylammonium bromide) (0.06 mmol) at room temperature. After stirring at the same temperature for 10 h, TBAB (0.19 mml) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 2 h and H2O is added. The organic layer is separated, dried over MgSO4 and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-[2-(6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester; 1H-NMR (CDCl3), δ: 1.14-1.28 (2H, m), 1.45 (9H, s), 1.56-1.78 (7H, m), 2.69 (2H, t), 4.11 (2H, m), 4.49 (2H, t), 6.93 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]3)=[CH:4][C:3]=1[C:29]([CH3:32])([CH3:31])[CH3:30].[OH:33]O>>[OH:1][C:2]1[C:3]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][C:5]([S:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]3)=[O:33])=[CH:6][C:7]=1[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: OO
Reactant: CC(C)(C)c1cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(S(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)cc(C(C)(C)C)c1O

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-hydroxy-3,5-di-tert. butylphenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][S:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=O)(C)(C)C.[ClH:24]>CO>[ClH:24].[NH2:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][S:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CSC1CCCCC1
Agent: Cl
Solvent: CO
Product: CC(C)CC(N)C(O)CSC1CCCCC1
Reaction time: 10 h

Procedure:
To a stirred solution of approximately 0.25 mmol of the resultant compound of Example 3 in methanol was added methanolic HCl (10 ml of approximately 0.75M). After 8-12 hours, the solvent was evaporated, and the desired compound was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
g (2.78 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 10 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>[OH-].[Na+]>[C@H:3]12[CH2:4][C@H:5]([CH2:1][CH2:2]1)[CH2:6][C@H:7]2[NH:8][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cccnc1Cl
Reactant: NC1CC2CCC1C2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccnc1N[C@@H]1C[C@H]2CC[C@@H]1C2
Temperature: 160 °C
Reaction time: 24 h

Procedure:
A mixture of exo-2-aminonorbornane and 2-chloronicotinic acid was stirred at 160° C. for 1 day and then spontaneously cooled. The reaction liquid was diluted with 1 M sodium hydroxide aqueous solution and then washed with diethyl ether. The water layer was neutralized with 1 M hydrochloric acid and then the precipitated crystals were collected by filtration to obtain rel-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]nicotinic acid.