Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@@H:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.O1CCCC1>[C:25]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=[CH:27][C:28]([C:29]([N:6]2[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]2[CH2:8][C:9]([OH:11])=[O:10])=[O:30])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)C[C@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)C[C@@H]1C[C@@H](O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of commercial [(2R,4R)-4-hydroxypyrrolidin-2-yl]acetic acid hydrochloride (5.03 g, 27.69 mmol), triethylamine (11.32 g, 110.77 mmol) in water (16.5 ml) and tetrahydrofuran (25 ml) at 0° C. under argon was added drop wise a solution of the 4-phenyl-benzoyl chloride in dry tetrahydrofuran (25 ml). The reaction was allowed to warm to RT and stirred overnight The reaction mixture was concentrated and the crude product was acidified under stirring at 5° C. adding 100 ml of HCl 1N. The white suspension was stirred at 5° C. for 10 minutes, filtered off under vacuum, rinsed with HCl 1N and water. After drying under vacuum the still wet white solid was taken up in 14 ml of tetrahydrofuran and brought to reflux until dissolution, and hexane was added to precipitate the solid. The whole was allowed to cool down to RT under stirring for 5 minutes and was filtered off and rinsed with hexane to give [(2S,4R)-1-(biphenyl-4-ylcarbonyl)-4-hydroxypyrrolidin-2-yl] acetic acid as a white powder (4.344 g). Yield: 72%. HPLC purity: 84%
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:15]C)=[N:9][C:10]([O:13]C)=[N:11][CH:12]=2)=[CH:5][S:4][N:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:8](=[O:15])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:5][S:4][N:3]=1
Reactant: COc1ncc(-c2csnc2C)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nscc1-c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-(3-methyl-4-isothiazolyl)-2,4-bis(methyloxy)pyrimidine (Prep 46, two batches combined, 30 mg, 0.148 mmol) was suspended in a 4M solution of HYDROCHLORIC ACID (1580 μl, 6.32 mmol) in dioxane the mixture was stirred at 90° for 2.5 hours. The mixture was allowed to cool to rt and dried (rotary) to afford a yellowish solid (0.126 mmol, yield considered quantitative assuming complete conversion to target compound).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:18](=[O:20])[CH3:19])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(CO)cc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(CO)ccc1C

Procedure:
The solution of 11.3 g of (3-amino-4-methylphenyl)methanol in 500 ml of chloroform is cooled to 0° C. with stirring and admixed with 13.4 ml of triethylamine. 6.03 ml of acetyl chloride are slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 2 hours. The reaction mixture is poured onto water (1 l) and extracted with dichloromethane (2×350 ml). The organic phases are washed with brine (350 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly brownish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:2 dichloromethane-diethyl ether); Rt=2.14.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[NH2:23].[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:2]2[N:11]=[C:10]([NH:23][C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:26]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccc2ccccc2c1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc4ccccc4c3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 2-naphthylamine and 3,5-dimethylpyrazole. Mp. 213.3-215.6° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[O:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]([C:4]2[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7]([CH3:8])=[C:2]([C:36]3[CH:37]=[CH:38][O:34][CH:35]=3)[CH:3]=2)=[O:21])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(-c2ccoc2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 0.0413 g, 0.07 mmol), furan-3-boronic acid (0.009 g, 0.08 mmol), Pd(PPh3)4 (0.004 g, 3.46 nmol), DME (2 ml) and Na2CO3 (2 ml, 2M) was vigorously stirred under nitrogen in a sealed vial at 80° C. for 2 h. Another portion of furan-3-boronic acid (0.005 g) and Pd(PPh3)4 (0.004 g) was added and the reaction was allowed to go for another hour. The mixture was allowed to cool, and was then partitioned between EtOAc and water. The organic phase was collected and the aqueous phase was extracted with another portion of EtOAc (10 ml). The combined organic phases were washed with water, brine, and dried over Na2SO4. Filtration and evaporation gave a crude oil which was purified on silica (heptane:EtOAc 2:1 to 1:1 to 1:2), which after evaporation of pure fractions gave 0.023 g (62%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[OH-:11].[K+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: [OH-]
Reactant: O=Cc1c(F)cccc1Cl
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1c(O)cccc1Cl
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 2-chloro-6-fluorobenzaldehyde (2.44 g, 15.4 mmol) in DMSO (20 mL) at 0° C. was added potassium hydroxide (2.23 g, 33.8 mmol) slowly. The reaction mixture was allowed to stir and warm to rt overnight and then diluted with water (65 mL). The mixture was acidified to pH<1 with conc. HCl. A white solid formed and was filtered, washed with water, and dried to give 2-chloro-6-hydroxybenzaldehyde (1.48 g, 61%). LCMS: (FA) ES-155.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)=[O:4].[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:27](N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:18](=[O:19])[CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][CH:9]=1)=[O:4])[CH3:27]
Reactant: COC(=O)c1csc(N)n1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(NC(=O)C(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h

Procedure:
2-Amino-thiazole-4-carboxylic acid methyl ester (32 mg, 0.20 mmol) and diphenyl-acetic acid (42 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (19 mg, 0.052 mmol, 26%). ESI-MS m/z calc. 366.1. found 367.1 (M+1)+ Retention time 3.34 minutes.
Reaction SMILES: CS(OC[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16](=[O:36])[NH:17][C:18]3[CH:23]=[C:22]([C:24]4[N:28]=[C:27]([CH:29]5[CH2:32][C:31]([F:34])([F:33])[CH2:30]5)[O:26][N:25]=4)[CH:21]=[CH:20][C:19]=3[CH3:35])=[CH:14][N:15]=2)[CH:12]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:43]([OH:46])[CH2:44][OH:45]>>[F:34][C:31]1([F:33])[CH2:30][CH:29]([C:27]2[O:26][N:25]=[C:24]([C:22]3[CH:21]=[CH:20][C:19]([CH3:35])=[C:18]([NH:17][C:16]([C:13]4[N:11]5[CH:12]=[C:7]([O:45][CH2:44][CH2:43][OH:46])[CH:8]=[CH:9][C:10]5=[N:15][CH:14]=4)=[O:36])[CH:23]=3)[N:28]=2)[CH2:32]1
Reactant: OCCO
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(COS(C)(=O)=O)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(OCCO)cn12
Temperature: 80 °C

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (F37) (0125 mg, 0.285 mmol) was dissolved in DCM (1 mL) and DIEA (0.854 mmol). MsCl (0.57 mmol) was added dropwise. After 15 minutes at room temperature the solvent was removed. MeOH (5 mL) and water (10 mL) were added to the residue. After sonication, most of the MeOH was removed from the mixture. Solid product was filtered and dried under vacuum to give the crude mesylate, which was used in the next step without purification. MS m/z 518.0 (M+1)+. A mixture of (3-((5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate (10.4 mg, 0.02 mmol) and K2CO3(8.3 mg, 0.06 mmol) in ethane-1,2-diol (0.5 mL) was heated at 80° C. for 20 minutes. The reaction mixture was purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (F38). 1H NMR (400 MHz, CDCl3) δ 9.56 (m, 1H), 8.60 (d, J=1.5 Hz, 1H), 8.21 (s, 1H), 7.89 (dd, J=1.7, 7.9 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.60 (s, 1H), 7.50 (dd, J=1.7, 9.2 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 4.65 (s, 2H), 3.82 (s, 2H), 3.73-3.61 (m, 3H), 3.15 (m, 4H), 2.46 (s, 3H), 2.04 (s, 1H). MS m/z 484.2 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH:34]=O>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:34][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: O=Cc1ccc2sc3ccccc3c2c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2sc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with synthesized dibenzo[b,d]thiophene-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 431.87 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][C:3]=1[OH:39].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:49][CH2:48][O:47]1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:9]=2)=[CH:4][C:3]=1[O:39][CH2:49][CH2:48][OH:47]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(O)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(OCCO)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-fluoro-3-hydroxyphenyl)-5-nitro-1-trityl-1H-indazole 7AU (1.25 g, 2.42 mmol), K2CO3 (402 mg, 2.91 mmol) and ethylene carbonate (2.6 mL, 24.00 mmol) in DMF (10 mL) was stirred in a sealed tube at 160° C. for 4 h and cooled to rt. H2O was added to quench the reaction. The resulting mixture was extracted with EtOAc, which was washed with H2O, brine, dried (MgSO4) and concentrated to give a yellow oil. Chromatograph on silica gel (4:1, hexanes/EtOAc) gave 3-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 14AX (1.4 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=[O:4].[CH2:9]([Mg]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]([OH:4])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCC(C)(C)C=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Product: C=CCC(C)(C)C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethylpent-4-enal (11.2 g) in 200 mL of Et2O cooled to 0° C. was added dropwise a solution of benzylmagnesium chloride (70 mL, 2M in THF). After stirring for 1 h at 0° C., the reaction was quenched with 200 mL of saturated solution of NH4Cl and the product was extracted with 200 mL of 1:1 EtOAc/hexane. The extract was dried over Na2SO4 and concentrated. The residue was distilled under reduced pressure to give 16 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:27])[C:18]=1[N:19]1[CH2:23][C:22](=[O:24])[NH:21][S:20]1(=[O:26])=[O:25])[CH:15]=[C:14]([C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:31]=[CH:32][CH:33]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].OS(O)(=O)=O>C(OCC)(=O)C>[CH2:39]([O:37][C:36](=[O:38])[CH2:35][CH2:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[C:17]([F:27])[C:18]([N:19]4[CH2:23][C:22](=[O:24])[NH:21][S:20]4(=[O:26])=[O:25])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:15]=2)[CH:29]=1)[CH3:40]
Reactant: O=C(O)CCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)c(F)c3c2)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)c(F)c3c2)c1

Procedure:
The following examples are prepared using appropriate starting materials and general procedures described in Example 16 and Example 9 with the following exceptions. For 35-1, after step A of Example 9, the material is esterified by stirring 100 mg of 3-{3-[6-Benzyloxy-8-fluoro-7-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-naphthalen-2-yl]-phenyl}-propionic acid with 10 mL Ethanol and 0.2 mL H2SO4 for 3.5 hours. Ethyl acetate is added followed by evaporation of ethanol. The material is then extracted between ethyl acetate and water, and the organic layer is dried over sodium sulfate, filtered, concentrated to afford 3-{3-[6-Benzyloxy-8-fluoro-7-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-naphthalen-2-yl]-phenyl}-propionic acid ethyl ester and used in the next step, analogous to Example 9 step B, without purification. For 35-4, after step A of Example 9, the ester, 3-[6-Benzyloxy-8-fluoro-7-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-naphthalen-2-yl]-benzoic acid ethyl ester is hydrolyzed by addition of 0.84 mL of 1 M NaOH and heated in by microwave irradition for 30 min at 120° C. The aqueous layer is filtered and extracted with 1:1 ether hexanes. The aqueous layer is acidified and extracted 3 times with EtOAc, and the combined organic layers are dried over Mg2SO4, filtered and concentrated to afford 3-[6-Benzyloxy-8-fluoro-7-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-naphthalen-2-yl]-benzoic acid which is used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH:18][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccc(Cl)c(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 2-chloro-5-methoxyaniline (47 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (35 mg, 44%). 1H NMR (CDCl3): 8.82-8.80 (m, 1H), 8.47 (d, J=7.8 Hz, 1H), 7.86-7.81 (m, 1H), 7.77 (d, J=2.7 Hz, 1H), 7.41-7.36 (m, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 6.68 (s, 1H), 6.65 (dd, J=2.7, 8.7 Hz, 1H), 3.85 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([OH:57])[CH2:51][N:52]2[CH:56]=[CH:55][N:54]=[CH:53]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[N:52]1([CH2:51][C@@H:50]([OH:57])[CH2:49][O:48][C@H:10]2[C@H:11]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=3)[C@@H:12]([O:14][CH2:15][C:16]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:13][NH:8][CH2:9]2)[CH:56]=[CH:55][N:54]=[CH:53]1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3ccnc3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(CO[C@H]2CNC[C@@H](OC[C@H](O)Cn3ccnc3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (l) the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-imidazol-1-yl-propoxy)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-1-imidazol-1-yl-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propan-2-ol as colorless foam; MS: 683 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(Cl)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-chlorobenzyl chloride
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[CH:5][CH:4](CO)[CH2:3]1.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>C(N(CC)CC)C>[C:10]([O:13][CH:4]1[CH:5]=[CH:6][CH2:7][N:2]([CH3:1])[CH2:3]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CC=CC(CO)C1
Solvent: CCN(CC)CC
Product: CC(=O)OC1C=CCN(C)C1

Procedure:
A solution of (1-methyl-1,2,3,6-tetrahydro-3-pyridyl)methanol (0.7 g, 5.5 mmol), triethylamine (25 ml), and acetic anhydride (20 ml) was refluxed for 2h. The reaction mixture was extracted with methylene chloride and pH was adjusted to 10 with aqueous sodium hydroxide. The solution was extracted with methylene chloride, which was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified on a silica gel column (Eluent: methanol/methylene chloride (1/9)) to give 1-methyl-1,2,3,6-tetrahydropyridin-3-yl acetate as an oil (Yield: 0.69 9, 70%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(I)cc1
Reactant: c1cc2[nH]ccc2cn1
Product: Fc1ccc(-n2ccc3cnccc32)cc1

Procedure:
The title compound was prepared from 5-azaindole (1.00 g, 8.47 mmol) and 1-fluoro-4-iodobenzene analogously as described in example 1, step 1. Yield: 1.23 g.