Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:15][N:2]([CH3:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18]2)=[O:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CN(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c([N+](=O)[O-])c1

Procedure:
Step 3): The mixture of 4-dimethylamino-2-nitrobenzoic acid (4.20 g, 20 mmol), 4-amino-1-diphenylmethylpiperidine (5.33 g, 20 mmol). EDCl (4.00 g, 21 mmol) and DMAP (2.45 g, 20 mmol) in CH2Cl2 (60 ml) was stirred at room temperature for 17.5 hours. The reaction mixture was diluted with CH2Cl2, washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified with chromatography on SiO2 (50% AcOEt in hexane) and recrystallized from AcOEt to obtain 4-dimethylamino-2-nitro-N-(1-diphenylmethylpiperidin-4-yl)benzamide. 5.44 g (59%): mp 183° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[C:3]([O:10][CH3:11])[CH:4]=1)=[O:7]
Reactant: COc1cc(C=O)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C=O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 51 %

Procedure:
To 400 mg (2.60 mmol) of 4-fluoro-3-methoxybenzaldehyde diluted in 10 ml of dimethylsulfoxide are respectively added 483 mg (2.60 mmol) of tert-butyl piperazine-1-carboxylate, then 394 mg (2.85 mmol) of potassium carbonate. The solution is heated to 90° C. for 40 h, then water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue obtained is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 8:2) to yield 425 mg of tert-butyl 4-(4-formyl-2-methoxyphenyl)piperazine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: [O:1]([CH2:8][C:9]#[CH:10])[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1.[Li]CCCC.C=O.[C:18](Cl)(Cl)(Cl)[Cl:19]>C1COCC1>[O:1]([CH2:8][C:9]#[C:10][CH2:18][Cl:19])[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#CCOC1CCCCO1
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCC#CCOC1CCCCO1
Yield: 85 %

Procedure:
THPO-CH2C≡CH was treated with 1.1 equivalents of n-BuLi in THF at -78° C. for 0.5 hours and then 1.4 equivalents of paraformaldehyde ((CH2O)n) Over the course of 12 hours, the reaction was allowed to rise to 25° C. and a product isolated in 84% yield. This product was then treated with 1.6 equivalents of P(oct)3 in CCl4 at 25° C. for six hours, yielding THPO-CH2C≡CCH2Cl in 85% yield. This compound was then treated with 1.0 equivalents NA2S.9H2O in EtOH:H2O (10:1) at 25° C. for 12 hours. The product, which was isolated in 47% yield, was then treated with acetic acid (AcOH):H2O:THF (7:3:10) at 25° C. for 12 hours. The resulting product, which was isolated in 64% yield, was then treated with 3.0 equivalents of mCPBA in methylene chloride for 2 hours yielding a compound having structure (2) (R3 =R5 =H, R2 =R4 =CH2OH) in 40% yield.
Reaction SMILES: [N+](C1C=CC(C(O[CH:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:14]([CH2:33][O:34][C:35](=[O:45])[C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)[CH2:13][O:12]2)=O)=CC=1)([O-])=O.[F:48][C:49]([F:64])([F:63])[C:50]1[CH:51]=[C:52]([C@H:60]([OH:62])[CH3:61])[CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([C:35]([O:34][CH2:33][C@@H:14]2[C@@H:15]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@@H:11]([O:62][C@@H:60]([C:52]3[CH:51]=[C:50]([C:49]([F:63])([F:64])[F:48])[CH:55]=[C:54]([C:56]([F:57])([F:58])[F:59])[CH:53]=3)[CH3:61])[O:12][CH2:13]2)=[O:45])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OCC1COC(OC(=O)c2ccc([N+](=O)[O-])cc2)C(c2ccc(F)cc2)C1COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](O[C@H]1OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](COCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -25 °C

Procedure:
The intermediate from example 1 step G (10.95 g, 17.0 mmol) was combined with (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (4.39 g, 17.0 mmol) and dissolved in 170 mL DCM. The vessel was cooled to −25° C. followed by the addition boron trifluoride etherate (0.48 g, 3.4 mmol). The reaction vessel was maintained at −25° C. for 1 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3 and the mixture was allowed to warm to ambient temperature. The aqueous mixture was extracted several times with EtOAc and washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted toluene. The first component collected off the column was the unwanted diastereomer. The second component collected was the desired diastereomer and was determined to be 85% pure as determined by 1HNMR. The product was recrystallized from cold methanol to provide the pure title compound. 1H-NMR (CDCl3): δ 1.41 (d, 3H, J=6.5 Hz), 1.76-1.84 (m, 1H), 2.50-2.62 (m, 1H), 3.02 (dd, 1H, J=9.0, 12.0 Hz), 3.07 (dd, 1H, J=3.0, 9.5 Hz), 3.41 (dd, 1H, J=2.5, 10.0 Hz), 3.54 (dd, 1H, J=11.5, 11.5 Hz), 4.26-4.36 (m, 5H), 4.56 (dd, 1H, J=3.5, 11.0 Hz), 4.99 (q, 1H, J=6.5 Hz), 6.92-7.06 (m, 4H), 7.20-7.36 (m, 7H), 7.71 (s, 1H), 8.19 (d, 2H, J=9.0 Hz), 8.31 (d, 2H, J=9.0 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C23CCN(CC2)CC3)cc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of 4-(methyloxy)phenylmagnesiumbromide (0.5 M in THF, 6.5 mL, 3.25 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1587 g, 0.866 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.273 g, 89.0%). EI-MS m/z 354 (M+H) Rt (1.74 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[F:19][C:20]([F:27])([F:26])[C:21]1[N:22]=[CH:23][NH:24][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:24]2[CH:25]=[C:21]([C:20]([F:27])([F:26])[F:19])[N:22]=[CH:23]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cnc(C(F)(F)F)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
In a similar way a solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 5.62 mmol), 4-trifluoromethyl-imidazole (0.945, 6.74 mmol) and ethyl-diisopropyl-amine (3.94 ml, 22.5 mmol) in 10 ml of dioxane is heated to reflux for 48 hours. After a similar workup procedure 1.4 g (3.65 mmol, 65%) of amorphous 5-(4-trifluoromethyl-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester are obtained, ES-MS: m/z 384 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[CH:15][CH:16]=1)[C:12](O)=[O:13])([O-:7])=[O:6]>C(Cl)(Cl)Cl>[OH:17][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:16]=[CH:15][C:11]=1[C:12]([Cl:3])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1O
Yield: 74.5 %

Procedure:
Thionyl chloride (1.6 mL, 22 mmol) was added slowly to a solution of 4-nitrosalicylic acid (1.0 g, 5.46 mmol) in chloroform (20 mL) at 0° C. The mixture was brought to reflux and maintained for 5 h. Excess thionyl chloride was evaporated to give 2-hydroxy-4-nitro-benzoyl chloride (0.82 g, 75%).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)=[C:2]=[O:3].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:25]=[C:24]2[C:19]([CH:20]([NH2:26])[CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1>>[CH:9]1[C:10]2[C:5](=[C:4]([NH:1][C:2]([NH:26][CH:20]3[C:19]4[C:24](=[CH:25][C:16]([C:15]([F:28])([F:14])[F:27])=[CH:17][CH:18]=4)[O:23][CH2:22][CH2:21]3)=[O:3])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: NC1CCOc2cc(C(F)(F)F)ccc21
Product: O=C(Nc1cccc2cnccc12)NC1CCOc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
3 ml of the 5-isocyanato-isoquinoline solution was added to the product of Example 4D (49 mg, 0.3 mmol) and stirred at ambient temperature overnight, and the precipitate formed was collected by filtration and washed with diethyl ether to give 23 mg of the title compound (23% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.63 (s, 1H), 8.55 (d, J=6.0 Hz, 1H), 8.32 (m, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.60 (m, 2H), 7.30-7.12 (m, 3H), 5.02 (m, 1H), 4.42-4.20 (m, 2H), 2.30-2.00 (m, 2H). MS (ESI) m/e 388 (M+H)+. Calcd. For C20H16N3O2F3.0.2; H2O: C, 62.01; H, 4.16; N, 10.85. Found: C, 61.29; H, 3.94; N, 10.64.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>>[CH3:20][C:19]1[C:10]([C:8]([C:4]2[CH:3]=[C:2]([CH:27]=[CH:26][C:25]([O:29][CH3:30])=[O:28])[CH:7]=[CH:6][CH:5]=2)=[O:9])=[CH:11][C:12]2[C:13]([CH3:23])([CH3:24])[CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]=2[CH:18]=1
Reactant: Cc1cc2c(cc1C(=O)c1cccc(I)c1)C(C)(C)CCC2(C)C
Reactant: C=CC(=O)OC
Product: COC(=O)C=Cc1cccc(C(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
In a manner similar to that of Example 1(c) by reaction of 6.54 g (15 mmol) of 3-iodophenyl-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-methanone with 1.8 ml (19.7 mmol) of methyl acrylate, 6.5 g (100%) of the expected methyl ester are obtained in the form of an orange-coloured oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([N:48]=[C:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>ClCCl>[Cl:41][C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:10]3[C:9]([CH2:8][O:7][C:6]4[CH:32]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[CH3:33])=[C:18]4[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]4[CH3:19])=[CH:12][CH:11]=3)=[C:24]([O:30][CH3:31])[CH:25]=2)=[O:50])[CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC(=O)Nc2cccc(Cl)c2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 20.3 mg, 0.0451 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), then triethylamine (13.6 μL, 0.0977 mmol) and 3-chlorophenyl isocyanate (6 μL, 0.05 mmol) were added to the mixture successively. After the reaction mixture was stirred for 1 hour at room temperature, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.4 mg) as a colorless solid. (Yield 82%)
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.Cl.CCO.[OH-].[Na+:37]>O>[Na+:37].[Na+:37].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Temperature: 70 °C

Procedure:
N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid from example 7 is dissolved in water (3.8 mL) and sodium hydroxide 1N (2.2 mL). The pH of the mixture is adjusted to 7.5-8.5, by the addition of hydrochloride acid 1N. The solution is heated at 70° C. and ethanol absolute (40 mL) is added to the mixture. The solution is allowed to cool down slowly to room temperature. The slurry is filtered and washed with a mixture of ethanol absolute and water (4:1). The resulting white solid is dried in the oven at 50° C. under vacuum over 18 h.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[OH-].[K+].[C:13](=S)=[S:14].C>O.C(O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[N:10]=[C:13]([SH:14])[NH:1][C:2]=2[CH:7]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
The procedure of Van Allan, J. A. V. and Deacon, B. D., Organic Synthesis. IV:569 was adapted. A mixture of 1,2-diamino-4,5-dichlorobenzene (510 mg, 2.88 mMol, Aldrich), potassium hydroxide (190 mg, 3.40 mMol), carbon disulfide (260 mg, 3.40 mMol), 95% ethanol (3 mL) and water (0.45 ml) was heated under reflux for 3 h. Activated charcoal (120 mg) was then added cautiously, and after the mixture has been heated at the refluxing temperature for 10 min the activated charcoal was removed by filtration. The filtrate was heated to 60°-70° C., warm water (3 mL) was added, and then acetic acid (0.25 mL) in water (0.5 mL) was added with good stirring overnight. The mixture was placed in a refrigerator for 3 h to get two crystals (brown and white). The brown crystals were removed by washing with chloroform (5 mL). Recrystallization from hot EtOH/H2O gave pure 5,6-dichloro-2-mercaptobenzimidazole (545 mg, 86%) as white long needles. Mp was measured: the color of 5,6-dichloro-2-mercaptobenzimidazole changed to yellow at 303° C.; the decomposition of 5,6-dichloro-2-mercaptobenzimidazole is obvious at 305° C. and it melted to a black liquid at 308°-10° C. IR (KBr, cm-1): 3447; 3107; 3043; 1607; 1496; 1461. NMR (1H, DMSO-d6): δ7.305 (s, 2H); 12.781 (s, 2H). HRMS: calcd for C7H4Cl2N2S (M+) m/z: 217.9425, Found: 217.9482.
Reaction SMILES: [OH:1][C@@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[N:24]([CH2:12][C@H:2]([OH:1])[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CP(C)(=O)OCC(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COP(C)(=O)C[C@@H](O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 3.32 g of isobutyl P-[2(S)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate and 1.19 g of sodium azide in 25 ml of dry dimethylformamide is heated to a temperature of 120° for a period of 3 hours, under an inert gas atmosphere. The reaction mixture is allowed to cool to room temperature, poured onto 50 ml of water and extracted twice with 100 ml of ethyl acetate. The organic extract is dried over magnesium sulphate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate to 1 part of ethanol as eluent. There is obtained isobutyl P-[3-azido-2(S)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+54.8 and +53.7 ppm (CDCl3), [α]D25 =+18.6 (0.56% in ethanol).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:7]([C:5]1[N:6]=[C:2]([C:21]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[CH3:11])[S:3][CH:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(C)c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc(C(C)(C)C)cs2)c(C)c1
Yield: 92.4 %

Procedure:
To a suspension of 2-bromo-4-(1,1-dimethylethyl)thiazole (6 g, 27.3 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9.78 g, 35.4 mmol), and potassium carbonate (11.30 g, 82 mmol) in 1,4-dioxane (20 mL) and water (5 mL), was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.113 g, 1.363 mmol). It was degassed and refilled with nitrogen, and was heated to reflux for 1 hour to see complete conversion of the 2-bromothiazole, by LCMS. It was distributed between water (50 mL) and ethyl acetate (200 mL). The organic layer was collected, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified on silica gel, eluting with 30% of ethyl acetate in hexanes, to get methyl 4-(4-tert-butylthiazol-2-yl)-3-methylbenzoate as a white solid (7.3 g, 93% yield). LCMS (M+H)+: 290.1. 1H NMR (CDCl3, 500 MHz): δ 8.00 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.02 (s, 1H), 3.97 (s, 3H), 2.70 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:42]=1)[C:37](O)=[O:38])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:42]=1)[C:37]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:38])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CN1CCN(c2cc(C(=O)O)cc(C(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
35 mg (0.12 mmol) of the compound of Example 6A and 47 mg (0.12 mmol) of the compound of Example 21A were reacted and worked up analogously to the procedure of Example 16. This gave 25 mg (95% pure, 38% of theory) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]([CH:27]=O)=[C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:20]=1[CH3:21])=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]([CH:27]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:20]=1[CH3:21])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Reactant: O=C1Cc2ccccc2N1
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)c(CCC(=O)O)c1C
Yield: 65 %

Procedure:
Oxindole (0.25 g, 1.88 mmol) was condensed with 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g, 1.97 mmol) to give 0.45 g (65%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C1COCC1>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:22]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[O:23])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1-(4-Fluoro-phenyl)-piperazine (12.2 g, 67.7 mmol) and triethylamine (4.63 mL, 67.7 mmol) were dissolved in anhydrous THF (150 mL) under nitrogen and the reaction mixture was cooled to 0° C. 4-Nitrophenyl chloroformate (13.4 g, 67.7 mmol) dissolved in anhydrous THF (150 mL) at 0° C. was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue suspended between water and EtOAc. The aqueous layer was extracted with two further portions of EtOAc, the organic layers were combined, dried (MgSO4), dried in vacuo and then recrystallised from toluene (50 mL)/hexane (60 mL) to give 4-(4-fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (15.8 g, 67%) as fine yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:18][CH2:19][CH2:20][CH2:21][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: BrCCCBr
Product: Fc1ccc(-n2ccc3cc(OCCCBr)ccc32)cc1

Procedure:
In analogy to example 3.1, 1-(4-Fluoro-phenyl)-1H-indol-5-ol and 1,3-dibromopropane were converted to yield 5-(3-Bromo-propoxy)-1-(4-fluoro-phenyl)-1H-indole as colorless solid 61-62° C., MS: 347 (M, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)=[O:26])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2cn[nH]c2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-aminoindazol (Aldrich) and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 160-164° C. (diethylether).