Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16](Cl)=[O:17])[CH3:14].[Cl-].[NH4+]>ClCCl>[SH:2][CH2:3][CH2:4][NH:5][C:16](=[O:17])[CH:15]([CH2:13][CH3:14])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: NCCS
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(CC)C(=O)NCCS
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
22.7 g of 2-mercaptoethylamine hydrochloride (0.2 mol) and 32.4 g of triethylamine (0.32 mol) were introduced in suspension in 130 ml of dichloromethane at 0° C.-5° C. Over the course of 25 minutes, 16.8 g of 2-ethylhexanoyl chloride (0.1 mol) were added dropwise. The batch was stirred at 0° C. to 5° C. for 1 hour, at 40° C. for 1.5 hours, and then at room temperature for 12 hours. 70 ml of saturated ammonium chloride solution were added and a phase separation was carried out. This was repeated twice and the organic phases were combined, dried over sodium sulfate, and freed of their solvent under reduced pressure. The residue obtained was purified by column chromatography (97 toluene:3 methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:3]=1.[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:5]=1
Reactant: NC1CCCCCC1
Reactant: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)c1

Procedure:
To 158a (1.0008 g, 3.5 mmol) dissolved in acetone (20 mL) was added a solution of N-cycloheptylamine (0.45 mL, 3.5 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.4 mL, 3.5 mmol) and water (3.5 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 2 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. After filtering, the sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a yellow solid (158b, 991 mg, 78%), mp 82° C.; HPLC: Inertsil ODS-3V C18, 40:10:50 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 54.5 min, 99.8% purity; MS (TOF MS ES+): m/z 440 (100), 365 (20.0), 363 (M+H, 53.2).
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][CH2:19][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].C(NC(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]=1[N+:38]([O-:40])=[O:39]>ClCCl>[CH2:1]([N:3]1[CH2:20][CH2:19][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[C:30]([N+:38]([O-:40])=[O:39])[CH:31]=4)=[CH:16][CH:17]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCC2(CCN(CCc3ccc(N)cc3)C2)C1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(F)c([N+](=O)[O-])c4)cc3)C2)C1
Reaction time: 1 h

Procedure:
4-[2-(7-Ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenylamine from above was dissolved in dichloromethane to which was added diisopropylamine (1 ml) and the reaction was cooled in an ice bath. A solution of 4-Fluoro-3-nitro-benzoyl chloride (0.5 N, 8 ml) was added and the reaction stirred for 1 h then evaporated under reduced pressure to a yellow foam which was used as is in the next step.
Reaction SMILES: F[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(#N)C.C(N(C(C)C)CC)(C)C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[NH:31])[NH2:30]>>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:4]([OH:5])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:31]=1
Reactant: O=C(Cl)c1cccnc1F
Reactant: N=C(N)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Oc1nc(-c2ccccn2)nc2ncccc12
Temperature: 90 °C
Reaction time: 27 h

Procedure:
To a stirred solution of 2-fluoro-3-pyridinecarboxylic acid (6.3 g, 44.6 mmol) in DCM (112 mL) was added thionyl chloride (15.0 mL, 205 mmol). The reaction was heated to 40° C. and stirring continued for 3.5 h. After which, the reaction mixture was concentrated in vacuo to provide 2-fluoronicotinoyl chloride as a yellow solid. The product was taken on crude to the next step. To a stirred solution of 2-fluoronicotinoyl chloride (6.3 g, 39.5 mmol) in acetonitrile (197 mL, 39.5 mmol) was added diisopropylethylamine (27.5 mL, 158 mmol) followed by picolinimidamide (5.26 g, 43.4 mmol). The reaction was heated to 90° C. and stirring continued for 27 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was placed in Et2O (100 mL) and the mixture was filtered and was further washed with Et2O. The product was dried under vacuum and used crude in the next reaction. Mass Spectrum (ESI) m/e=225.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](=[N:27]/[OH:28])/[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(Cc1ccncc1)=N/O)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from (R)-4-(4-bromo-phenyl)-1-pyridin-4-yl-4-o-tolyl-butan-2-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=409.1 ([M+H]+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:43][C:44]([CH3:46])=[CH2:45]>C1COCC1>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:5]1[CH:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[CH:10]=1)[CH2:45][C:44]([CH3:46])=[CH2:43]
Reactant: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of [2,6-bis-(4-trifluoromethylphenyl)-pyridin-4-yl]-acetic acid methyl ester (1.18 g, 2.69 mmol) in THF (30 mL) at −78° C. under argon was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 5.38 mL, 2.69 mmol). After stirring for 30 minutes, 3-bromo-2-methylpropene (273 μL, 2.69 mmol) was added and stirred for an additional 30 minutes. The reaction mixture was allowed to warm up slowly and stirred for another 30 minutes at 0° C. The mixture was then concentrated and purified by column chromatography on silica gel (0-8% ethyl acetate in heptane) to give the product as a white solid (940 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=8.29 Hz, 4H), 7.76 (d, J=8.29 Hz, 4H), 7.74 (s, 2H), 4.79 (d, J=19.59 Hz, 2H), 3.97 (dd, J=6.78, 9.04 Hz, 1H), 3.72 (s, 3H), 2.95 (dd, J=8.85, 14.51 Hz, 1H), 2.56 (dd, J=6.59, 14.51 Hz, 1H), 1.78 (s, 3H). MS m/e 494.2 (M+H)
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:23]=[CH:24][CH:25]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH:23]=[CH:24][CH:25]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 65.1 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 930 mg of 2-methylpropan-2-yl [2-(3-aminophenyl)ethyl]carbamate in place of the 2,4-difluoroaniline. 285 mg of 2-methylpropan-2-yl {2-[3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)phenyl]ethyl}carbamate are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[O:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[O:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:14]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(Cl)c1
Reactant: CC(C)CN
Solvent: Cc1ccccc1
Product: CC(C)CNC(=O)c1cccnc1Oc1cccc(Cl)c1

Procedure:
In the same manner as in Example 1(c) 1.4 grams (0.02 mole) isobutylamine and 2.7 grams (0.01 mole) of the acyl chloride produced in step (b) were combined in 50 milliliters toluene to yield 2.8 grams (92.1% of theoretical yield) of the desired product, m.p. 86°-87° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]=[O:27])=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCC=O)cc2)c(C)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCCO)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
To a solution of N-(2-chloro-4-hydroxy-benzyl)-2,4,6-trimethyl-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.036 g, 0.08 mmol) in 0.2 mL methanol and 0.2 mL methylene chloride was added sodium borohydride (0.014 g, 0.38 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (40% ethyl acetate/hexanes) afforded 0.018 g of N-(2-chloro-4-hydroxy-benzyl)-N-[4-(3-hydroxy-propyl)-phenyl]-2,4,6-trimethyl-benzenesulfonamide. MS 474.0 (M+1)+
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[C:18]3[O:17][CH2:16][C:15](=[O:19])[C:14]=3[CH:13]=[CH:12][C:11]=2[OH:20])[CH2:3]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[N:22]1.N1CCCCC1>CO>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[CH:30]=[C:16]2\[O:17][C:18]3[C:10]([CH2:9][N:4]4[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]4)=[C:11]([OH:20])[CH:12]=[CH:13][C:14]=3[C:15]\2=[O:19])=[N:22]1
Reactant: C[C@@H]1CN(Cc2c(O)ccc3c2OCC3=O)C[C@H](C)N1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: C[C@@H]1CN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)C[C@H](C)N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.166 g, 0.601 mmol) in methanol (2.4 mL) was added with 1H-indazole-3-carbaldehyde (0.0878 g, 0.601 mmol), and piperidine (0.00512 g, 0.0601 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (8 mL), suspended in methanol, and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.197 g, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39].C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:34]5[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=5)[CH:3]=4)[NH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3c2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (65 mg, 0.14 mmol) in CH3CN (1 mL) in a Personal Chemistry microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue purified via preparatory HPLC to give the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 11.78 (s, 1H), 11.03 (s, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.45 (s, 2H), 7.32 (m, 1H), 6.92 (s, 2H), 6.45 (m, 1H), 3.85 (s, 6H), 3.70 (s, 3H); HPLC retention time: 2.04 minutes; MS ESI (m/z): 400.4 (M+1)+, calc. 399.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49]1[O:53][N:52]=[CH:51][C:50]=1[C:54](O)=[O:55]>CN(C=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][N:1]([C:54]([C:50]3[CH:51]=[N:52][O:53][C:49]=3[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=3)=[O:55])[CH2:2]2)[CH:7]=1
Reactant: O=C(O)c1cnoc1-c1ccccn1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1-c1ccccn1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (15 mg, 0.1 mmol), TBTU (48 mg, 0.15 mmol, 1.5 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.1 mmol) in DMF (0.6 mL) was added to 5-pyridin-2-ylisoxazole-4-carboxylic acid (19 mg, 0.1 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound as (12 mg). MS (ESI, pos. ion) m/z calcd for C18H16N4O2: 320.1273, found 320.1273.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[O:24][C:25]([CH3:31])=[C:26]([CH2:28][CH2:29]O)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].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>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])[O:24][C:25]=2[CH3:31])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(C(C)(C)C)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(C(C)(C)C)oc2C)cc1C)OCC

Procedure:
In analogy to the Mitsunobu-procedure described in example 1, step f, [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 46 b]) was reacted with 2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethanol (example 1, step e]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield [rac]-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([CH3:16])([CH2:14][OH:15])[CH2:12]O.C(C=P(CCCC)(CCCC)CCCC)#N.O.O.[Sn](Cl)Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:11]1([CH3:16])[CH2:14][O:15][CH2:12]1)[NH2:8]
Reactant: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1Br
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: Cl[Sn]Cl
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2ccc(N)cc2Br)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (0.145 g, 0.500 mmol) was dissolved in 2.5 mL of anhydrous benzene. Cyanomethylenetributylphosphorane (CMBP) (0.181 g, 0.750 mmol) was then added and the solution was allowed to stir at room temperature for 72 hours. The mixture was evaporated to dryness and then re-dissolved in 4 mL of EtOH. Tin(II) chloride dihydrate (0.564 g, 2.50 mmol) was then added and the resulting solution was heated at 70° C. for 1 hour. The mixture was cooled to room temperature and then quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were evaporated to dryness and purified by preparative LC/MS to yield 3-bromo-4-(3-methyloxetan-3-yl)aniline as a pale yellow oil (0.032 g, 32%) NMR (400 MHz, CD3CN) δ 7.13 (dd, J=0.7, 1.8 Hz, 1H), 6.94-6.88 (m, 2H), 6.75 (br s, 2H), 4.98 (d, J=5.6 Hz, 2H), 4.51 (d, J=6.1 Hz, 2H), 1.74 (s, 3H). ESI-MS m/z calc. 241.0, found; 242.1 (M+1)+ Retention time 0.53 minutes.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[Cl:13][C:14]1[C:23]([NH2:24])=[C:22]([NH:25][CH2:26][C:27]2[O:31][N:30]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:28]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[C:23]2[N:24]=[C:1]([CH2:2][CH3:3])[N:25]([CH2:26][C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[CH:28]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 110 °C
Yield: 67.9 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (0.020 g, 0.19 mmol), triethyl orthopropionate (2.5 g, 14 mmol), 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined and heated at 110° C. for 18 hours. Most of the volatiles were removed under reduced pressure to provide a suspension. The solid was isolated by filtration, washed with diethyl ether, and dried to provide 2.624 g of 4-chloro-2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CCO>[CH:7]1([C:4]2[N:3]=[C:2]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][C:20]4[CH:29]=[CH:30][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[CH2:28][CH2:27]3)[S:6][N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Clc1nc(C2CCCCC2)ns1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCN(c3nc(C4CCCCC4)ns3)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 5-chloro-3-cyclohexyl-1,2,4-thiadiazole (32.0 mg, 158 μmol), 1-(4-methoxyphenethyl)piperazine dihydrochloride (51.0 mg, 174 μmol) and DIPEA in EtOH was heated for 30 min at an oil bath temperature of 90° C. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 13.7 mg (22%) of the title compound as light brown solid. MS (m/e): 387.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[NH:8][C:4]=3[CH:3]=2)[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
To a vial with 5-amino-1H-benzo[d]imidazol-2(3H)-one (298.3 mg, 2.0 mmol) and 2,4-dichloro-5-fluoropyrimidine (434.1 mg, 2.6 mmol), MeOH (8 mL) and H2O (2 mL) were added. The turbid solution was stirred at rt for 3 days. Precipitate from reaction mixture was collected by filtration, and washing with EtOAc (3 mL×2), and was further dried in vacuo. 5-(2-Chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one was obtained as an off-white solid: 390.3 mg (70% yield); 1H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 10.63 (s, 1H), 9.87 (s, 1H), 8.27 (d, J=3.6, 1H), 7.35 (d, J=1.9, 1H), 7.18 (dd, J=1.9, 8.3, 1H), 6.93 (d, J=8.3, 1H); LCMS (M+) m/z 279.80.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:32][Si](C=[N+]=[N-])(C)C>CO>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30][CH3:32])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Yield: 99 %

Procedure:
N-(2-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-hydroxybenzamide (0.050 g, 0.113 mmol) was dissolved in methanol (5 ml) and after adding thereto 10% trimethylsilyldiazomethane (hexane solution) (3.5 ml), the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the obtained residue was recrystallized from a mixed solvent of ether and hexane (1:1) to obtain the titled compound (0.051 g, 0.112 mmol, 99%).