Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:25])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>CN(C=O)C>[CH2:1]([C:8]1([OH:26])[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:17]=2[CH3:25])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1CBr
Reactant: Cc1[nH]c2ccccc2c1C(=O)N1CCC(O)(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a stirred solution of 40 mg (0.11 mmol) of (4-benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-yl)-methanone in 5 ml DMF were added 5 mg (0.11 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 28 mg (0.13 mmol) of 1-bromomethyl-2-chloro-benzene were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Preparative HPLC (30% CH3CN/H2O) afforded 33 mg (61%) of (4-benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1H-indol-3-yl]-methanone as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1oc2cccc(O)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(/C=C/C(=O)O)oc2cccc(O)c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 96.7 %

Procedure:
A mixture of ethyl-E-3-(4-hydroxy-3-methylbenzofuran-2-yl)propenoate (225 mg, 0.9 mmoles) (From Example 159), 2N sodium hydroxide (4 ml) and methanol (15 ml) was stirred at room temperature for 36 hours. The mixture was concentrated, acidified with 20% citric acid solution and extracted with ether. The ether solution was dried with Na2SO4, filtered and concentrated to obtain 190 mg of the title compound, m.p. 246°-248° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13](=O)[C:2]=12.O.NN>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][C:2]=12
Reactant: O=C1c2ccccc2-c2cccnc21
Agent: NN
Solvent: O
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)Cc1ncccc1-2
Temperature: 180 °C

Procedure:
Indeno[2,1-b]pyridin-9-one (525 mg, 2.90 mmol), 92 (J. Org. Chem. 51, 2021 (1986)) and 4.5 mL of hydrazine hydrate were combined in a sealed tube and warmed to 180° C. for 16 hours. The resulting mixture was diluted with chloroform and the layers seperated. The organics were dried over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by chromatography on silica gel eluted with 95:5, 93:7, and 90:10 of methylene chloride:ethyl ether. The product fractions were evaporated to dryness to yield the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:32]=[CH:31][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][NH:27][C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1.[CH3:33]I>CN(C=O)C>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH3:33])[C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:31][CH:32]=2)=[N:6][N:5]=1
Reactant: CI
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCNC2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCN(C)C2=O)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride suspension (0.16 g, 50%) was added to a stirring solution of (R)-(+)-Methyl 3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin-3-yl)oxy)benzoate (1.5 g) (Intermediate 20) in dry DMF taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube, at room temperature. The reaction mixture was stirred at the same temperature for 15 min. Methyl iodide (0.20 mL) was added and stirred till the reaction completed. The reaction mixture was quenched with ice-water, extracted with DCM. All organic layers were combined, washed with water, brine, dried over sodium sulphate, filtered and concentrated in vacuum to get the thick liquid product. The liquid was triturated with EtOAc:hexane to get the white solid product (1.2 g).
Reaction SMILES: C(O[C:4](=[O:27])/[C:5](/[F:26])=[C:6](\[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)/[CH3:7])C.[CH3:28]C(C[AlH]CC(C)C)C>C1COCC1>[F:26]/[C:5](=[C:6](/[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)\[CH2:7][CH3:28])/[CH2:4][OH:27]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of(E)-2-fluoro-3-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enoic acid ethyl ester (Intermediate 6, 2.2 g, 5.85 mmol) in THF (50 mL) at −78° C. was added DIBAL-H (23.4 mL, 1.0 M in CH2Cl2, 23.4 mmol) over 10 min. After stirring at −78° C. for 3 h, the reaction was quenched with aqueous NH4Cl followed by 1M HCl and was extracted with Et2O (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexane) to give the title compound (1.02 g, 45% over 2 steps).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[CH:10][N:9]=[C:8]([NH2:13])[N:7]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:18][C:14](=[O:17])/[CH:15]=[CH:16]/[C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:13])=[N:9][CH:10]=1
Reactant: Nc1ncc(I)c(-c2ccco2)n1
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cnc(N)nc1-c1ccco1

Procedure:
From 4-furan-2-yl-5-iodo-pyrimidin-2-ylamine, methyl acrylate, bis(triphenylphosphine)palladium(II) chloride and cesium carbonate in dioxane. EI-MS m/e (%): 245 (M+, 54), 228 ([M—NH3]+, 100), 186 ([M—CO2Me]+, 56), 158 (52).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2>CCO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:3][C:4]=2[CH:10]=1
Reactant: Nc1cccc2cccnc12
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Solvent: CCO
Product: FC(F)(F)c1ccc2[nH]c(Nc3cccc4cccnc34)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (66 mg, 0.3 mol, prepared according to the procedure described in WO 2004/035549 A1) and 8-aminoquinoline (29 mg, 0.6 mmol, Aldrich) in EtOH (2 mL) was subjected to microwave irradiation at 170° C. with stirring for 30 min. The reaction mixture was allowed to cool to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 3% MeOH/DCM to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 329 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl>CO>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Br:17])=[CH:19][CH:20]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(Br)cc2)CC(C(=O)OC)=C(Nc2ccc(Br)cc2)C1
Yield: 94.9 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (4.56 gm; 20 mmol) and methanol (100 ml) were heated to boiling, then 4-bromoaniline (6.88 gm; 40 mmol) was added followed by conc. hydrochloric acid (200 μl). The mixture was refluxed for 5 hours under a nitrogen atmosphere. On cooling a cream solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 10.18 gm (95%) of dimethyl 2,5-bis{(4-bromophenyl)amino}cyclohexa-1,4-diene-1,4-dicaboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31]O)=[CH:4][C:3]=1[F:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][Br:54])=[CH:4][C:3]=1[F:33]
Reactant: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCO)c3n2CC(C)C)o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCBr)c3n2CC(C)C)o1

Procedure:
To a cold (0° C.) solution of 1.0 mmol of 4-amino-7-(4-hydroxybutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole in 20 mL of CH2Cl2 was added 3.0 mmol of PPh3 and 3.0 mmol of CBr4. After 40 min. at room temperature solvent was removed and the residue was subjected to chromatography to give 4-amino-7-(4-bromobutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole. CCl4 gave the corresponding chloro compound.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].Cl>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC(C)(N)CO
Agent: Cl
Solvent: O
Product: CC(C)(CO)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 14.1 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.3 g, 1.17 mmol) in 2-amino-2-methyl-1-propanol (2 ml, 21 mmol) was stirred for 40 h at 120° C. in a sealed flask. Water (5 ml) was added to the cooled solution and pH was adjusted to <2 by the addition of 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and recrystallised from methanol/water to give 51 mg (14%) of the pure title compound; mp 224-226° C.; 1H-NMR (DMSO-d6): δ1.30 (s, 6H), 3.43 (s, 2H), 5,17 (br s, 1H), 6.63 (br s, 1H), 7.10 (s, 1H), 10.90 (s, 1H); MS: m/e 309/311 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1.BrC1C=CC2[NH:31]C(C(Cl)(Cl)Cl)=NC=2C=1>CC(N(C)C)=O>[NH2:1][C:2]1[C:6]([C:7]([NH2:31])=[O:9])=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1
Reactant: ClC(Cl)(Cl)c1nc2cc(Br)ccc2[nH]1
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)CCc1cnc(-n3cc(C(N)=O)c(N)n3)nc1-2

Procedure:
A solution of benzimidazole-2-aldehyde 1 (0.5 mmol) and diamine 2 (0.5 mmol) in dimethylacetamide (4 mL) was stirred at 100° C. for 12 h. Solvent was evaporated and residue was purified by preparative HPLC to give benzimidazole derivative 3. 1H NMR (300 MHz, MeOH-d4): δ 2.52 (s, 3H), 2.85 (brs, 4H), 3.25 (brs, 4H), 7.05-7.15 (m, 2H), 7.25-7.35 (s overlapped with m, 2H), 7.60-7.75 (m, 4H); LCMS m/z 333 (M+H+), ELSD 99%.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14]3[N:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:13]=3[CH2:12][N:11]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:10]=2[CH:38]=1)C(O)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN.Cl.C(N(C(C)C)CC)(C)C.[CH3:78][N:79]([CH:81]=[O:82])C>>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14]3[N:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:13]=3[CH2:12][N:11]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:10]=2[CH:38]=1)[C:81]([NH:79][CH3:78])=[O:82]
Reactant: CN(C)C=O
Reactant: O=C(O)C(O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of hydroxy[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]acetic acid (51 mg, 0.091 mmol, Example 513), BOP (60.1 mg, 0.136 mmol), MeNH2—HCl (12.2 mg, 0.181 mmol), and diisopropylethylamine (0.08 ml, 0.453 mmol) in DMF was stirred for 2.5 h at rt. LC-MS showed the reaction complete. The solution was concentrated and the residue was purified by mass-directed HPLC eluting with H2O/MeCN/TFA (90:10:0.1-10:90:0.1) to give the title compound; Mass Spectrum: m/e=576 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[O:13])=[CH:6][CH:5]=1.[OH-].[Li+]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=2)[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[O:13])=[C:22]([CH3:28])[CH:23]=1
Reactant: COC(=O)c1ccc([C@H](CC(=O)c2ccnc(C)c2)c2ccc(Cl)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 272, step 2, from 4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-benzoic acid methyl ester in presence of 1 M aq. lithium hydroxide solution was prepared the title compound as an off-white solid, MS (ESI−): m/z=392.0 ([M−H]−).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].Br[CH2:28][CH2:29][CH2:30][O:31][CH3:32]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: COCCCBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCOC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a pre-cooled THF solution (200 ml) under an argon atmosphere was added at −5° C. LDA (2M in THF/heptane/ethylbenzene, 16.24 ml) then dropwise piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.4 g, 4.2 ml) in THF (50 ml). The mixture was stirred between −5° C. to 0° C. for 3 hour then 1-bromo-3-methoxypropane (4.97 g) was added slowly at 0° C. The mixture was then stirred overnight at RT, the solvent was evaporated off, the residue taken up in AcOEt and washed with water and brine. The layers were separated, the organic layer dried over sodium sulphate and then evaporated off to give the desired 4-(3-methoxy-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester a light brown oil (6.058 g) oil that was used in next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].O[CH2:11][C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH:21]([CH3:23])[CH3:22])[O:14][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:11][C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH:21]([CH3:23])[CH3:22])[O:14][N:13]=1
Reactant: COC(=O)c1c(CO)noc1C(C)C
Reactant: Sc1c(Cl)cccc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1c(CSc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2,6-dichlorobenzenethiol (530 mg, 2.96 mmol), methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (629 mg, 2.46 mmol) and triphenylphosphine (1.29 g, 4.93 mmol) in dichloromethane (20 mL) was added di-tert-butyl azodicarboxylate (1.14 g, 4.93 mmol). The solution was stirred at ambient temperature overnight. The solution was then adsorbed onto silica gel and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient elution) to afford methyl 3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl) -4-isoxazolecarboxylate (886 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ 7.52-7.35 (m, 3H), 4.18 (s, 3H), 3.72 (s, 2H), 3.64 (septet, J=7 Hz, 1H), 1.20 (d, J=7 Hz, 6H). LRMS (APCI) m/z 360 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH3:7])[CH2:5][CH2:4][C@H:3]1[CH2:8][O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[ClH:16]>CCOCC>[ClH:16].[ClH:16].[CH3:1][N:2]1[C@H:6]([CH3:7])[CH2:5][CH2:4][C@H:3]1[CH2:8][O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1CC[C@@H](COc2cccnc2)N1C
Agent: Cl
Solvent: CCOCC
Product: C[C@@H]1CC[C@@H](COc2cccnc2)N1C

Procedure:
A 25 mg sample of the compound of compound from step 89a was treated with HCl in ether according to Example 14c to afford 37 mg of the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.42-8.38 (m, 1H), 8.34-8.28 (m, 11), 7.80-7.76 (m, 1H1), 7.67-7.63 (m, 1H), 4.60-4.54 (m, 11H), 4.47-4.41 (m, 1H), 4.03-3.95 (m, 1H), 3.62-3.52 (m, 1H), 3.03 (s, 3H), 2.40-2.30 (m, 2H), 2.13-2.03 (m, 1H1), 1.93-1.80 (m, 1H), 1.47 (d, J=6.7 Hz, 3H). [α]25D =+15.420 (c=0.50, methanol). Anal. Calc. for C12H18N2O·0.40 HCl: C, 49.06; H, 7.00; N, 9.54; Found: C, 49.22; H, 6.47; N, 9.69.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]([O-])=O.[Na+]>C(O)(=O)C.[OH-].[NH4+]>[CH3:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1)[NH:9][N:13]=[CH:8]2
Reactant: O=N[O-]
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c2[nH]ncc2c1
Reaction time: 12 h
Yield: 8.8 %

Procedure:
4,6-Dimethyl-2-nitro-phenylamine (10.6 g, 64.08 mmol) prepared in Step A was dissolved in acetic acid (150 mL). Sodium nitrite (5.3 g, 76.90 mmol) was added in drops thereto, and the mixture was stirred for 12 h. After completion of the reaction, the reaction mixture was diluted with ammonium hydroxide, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.0 g, Yield 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([OH:18])=[N:5]2>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([OH:18])=[N:5]2
Reactant: CCOC(=O)c1c(O)nc2cc(Cl)ccc2[n+]1[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccc(Cl)cc2nc1O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Phosphrous tribromide (0.36 mL) was added dropwise to a solution of 6-chloro-2-(ethoxycarbonyl)-3-hydroxyquinoxaline-1-oxide (0.50 g, 1.86 mmol) in anhydrous DMF (16 mL) at room temperature under nitrogen, after which the mixture was stirred for 12 h (at which point 1H NMR analysis of an aliquot indicated that the reaction was complete). The mixture was poured into ice-water mixture (100 mL) and extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with water (45 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure to provide 6-chloro-2-(ethoxycarbonyl)-3-hydroxyquinoxaline as a light yellow solid that was suitable for use without further purification: 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.48 (d, 1H), 7.37 (dd, 1H), 4.54 (q, 2H), 1.48 (t, 3H) ppm; ESI MS m/z 251 [M−H]−.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Br:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:8])[CH3:7].[N+:21]([O-])([OH:23])=[O:22]>O>[C:6]([NH:9][C:10]1[C:19]([N+:21]([O-:23])=[O:22])=[C:14]([C:13]([Br:20])=[CH:12][CH:11]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:8])[CH3:7]
Reactant: COC(=O)c1cc(NC(C)=O)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 62 %

Procedure:
To conc. sulfuric acid (150 mL), methyl 5-acetylamino-2-bromobenzoate (Reference Compound No. 1-(2), 18.5 g, 68.1 mmol) was added portionwise at 0° C., and conc. nitric acid (150 mL) was added dropwise thereto over 1 hour. The reaction mixture was stirred for 30 minutes, poured into iced water (1 L), and then the whole was extracted with ethyl acetate (500 mL, twice). The organic layer was washed with water (1 L, twice), saturated aqueous sodium hydrogen carbonate solution (1 L), and saturated brine (1 L) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (13.4 g) as a yellow solid. (Yield 62%)
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16])([O-:7])=[O:6]>C1COCC1>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][O:16][C:1]([Cl:4])=[O:2])([O-:7])=[O:6]
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1CCO
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1ccccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 94 %

Procedure:
Phosgene was introduced into a solution of 2-(2-nitrophenyl)ethanol (5.2 g, 31 mmol) in THF (20 ml, dist. over CaH2) at room temperature under stirring. After 1.5 h, the excess phosgene and the solvent were removed by distillation in a high vacuum. 2-(2-nitrophenyl)ethoxycarbonyl chloride (6.69 g, 94%) was obtained as a yellow oil.