Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([CH:14]3[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.[C-:38]#[C-:39].[Si]([Li])(C)(C)C>C1COCC1>[C:21]([O:20][C:18]([N:16]1[CH2:17][CH:14]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)=[C:2]3[Cl:1])([OH:13])[C:38]#[CH:39])[CH2:15]1)=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: [C-]#[C-]
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li][Si](C)(C)C
Solvent: C1CCOC1
Product: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a flask containing tert-butyl 3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (500 mg, 0.93 mmol, Intermediate 13: step b) was added THF (10 mL) and the solution was cooled to 0° C. Then, TMS-lithiumacetylide (0.5 M in Et2O, 2.0 mL, 1 mmol) was added and the reaction was allowed to warm gradually to room temperature. After 5 hours, additional TMS-lithiumacetylide (2 mL, 1.0 mmol, 0.5 M in Et2O) was added and the reaction mixture was stirred at room temperature overnight. After 24 hours, the mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (1% acetone-DCM increasing to 5% acetone) provided a mixture of title compound and the silylated title compound. To a flask containing tert-butyl-3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxy-3-(trimethylsilyl)prop-2-yn-1-yl)azetidine-1-carboxylate (220 mg, 0.35 mmol) was added MeOH (8 mL) followed by 2 M aqueous KOH (0.4 mL) at room temperature. After stirring for 15 minutes, the reaction was concentrated and chromatographed directly on silica gel (5% acetone-DCM increasing to 25% acetone) to provide the title compound as an amorphous white solid. 1H NMR (500 MHz, CDCl3) δ 8.36 (d, J=1.1 Hz, 1H), 7.88-7.79 (m, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.35 (s, 2H), 4.19-4.12 (m, 1H), 4.07 (s, 3H), 4.01-3.94 (m, 1H), 3.91-3.79 (m, 2H), 3.14-3.03 (m, 1H), 2.81 (s, 1H), 2.68 (s, 1H), 1.43 (s, 9H); MS (ESI): mass calcd. for C29H28ClF3N2O4, 560.2, m/z found 504.9 [M-t-Butyl]+.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[S:10]1[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][C:12]2[CH2:18][CH2:19][CH2:20][CH2:21][C:11]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:9][C:4]1[N:3]=[C:2]([NH:17][C:15]([C:14]2[S:10][C:11]3[CH2:21][CH2:20][CH2:19][CH2:18][C:12]=3[CH:13]=2)=[O:16])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: NC(=O)c1cc2c(s1)CCCC2
Reactant: Fc1ccc(Br)nc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nc(Br)ccc1F)c1cc2c(s1)CCCC2
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A 1-L three-neck round-bottomed flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (56 mL), 37 (3.00 g, 11.7 mmol),4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (1.29 g, 7.12 mmol) and cesium carbonate (5.09 g, 15.6 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (350 mg, 0.605 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (326 mg, 0.365 mmol) were added and the reaction mixture was heated at reflux for 2 h. After this time the reaction was cooled to room temperature and filtered through, a pad of Celite 521. The filter cake was washed with methylene chloride (50 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography using 500 cc of silica and eluting with 5% EtOAc/hexanes to afford a 37% yield of 38 (940 mg) a white solid: Rf=0.55 (20% ethyl acetate in hexanes); 1H NMR (500 MHz, CDCl3) 7.80 (bs, 1H), 7.38 (m, 1H), 7.37 (s, 1H), 7.32 (dd, 1H, J=3.0, 8.0 Hz), 2.81 (t, 2H, J=6.5 Hz), 2.64 (t, 2H, J=6.0 Hz), 1.85 (m, 4H); MS (ESI+) m/z 355.1 (M+H) and N-(6-bromo-5-fluoropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide in 34% yield as a white solid: Rf=0.85 (20% ethyl acetate in hexanes); 1H NMR (500 MHz, CDCl3) 8.29 (dd, 1H, J=3.5, 9.0 Hz), 8.24 (bs, 1H), 7.47 (dd, 1H, m), 7.33 (s; 1H), 2.81 (t, 2H, J=6.5 Hz), 2.64 (t, 2H, J=6.0 Hz), 1.85 (m, 4H); MS (ESI+) m/z 355.1 (M+H).
Reaction SMILES: [C:1]1([CH3:10])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:3][CH:2]=1.C([OH:24])(C1C=CC=CC=1)C1C=CC=CC=1.ON1C(=O)C2=CC=CC=C2C1=O.O.O.O.FC(F)(F)C(C(F)(F)F)=O.FC(C1C=CC=CC=1)(F)F>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:1]12([CH3:10])[O:24][CH:2]1[CH2:3][CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6]2
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC1=CCC(C(C)C)CC1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C(C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)C1CCC2(C)OC2C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
A mixture of 3mmol of 1-p-menthene, 15mmol of benzhydrol, 0.3 mmol of N-hydroxyphthalimide, 0.0015 mmol of cobalt (II) acetate, 0.3 mmol of hexafluoroacetone trihydrate, and 3 ml of trifluoromethylbenzene was stirred at 60° C. under an oxygen atmosphere (1 atm) for 12 hours. Gas chromatographic analysis of products in a reaction mixture revealed that 1-p-menthene was converted, at a rate of 63%, into 1-p-menthene oxide (yield: 42%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([CH3:14])=[CH:4][C:3]=1[CH3:15].[CH3:16][O-:17].[Na+].CO>[Cu](Br)Br.O>[CH3:16][O:17][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([CH3:14])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C)c2c(c1Br)OC(C)(C)C2=O
Reactant: C[O-]
Agent: Br[Cu]Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C)cc(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 7-bromo-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (2.90 g, 10.8 mmol) synthesized in Reference Example 67, copper bromide (1.86 g, 13.0 mmol) and 28% sodium methoxide/methanol solution (60 mL) was stirred under heated reflux for 15 hours. After cooled to room temperature, the reaction solution was poured into water and extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 99:1 to 94:6) to give 1.18 g of the title compound (yield: 50%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5](Cl)=[C:4]([OH:10])[N:3]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CS(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([OH:10])[N:3]=1
Reactant: CS(=O)[O-]
Reactant: Cc1nc(O)c(Cl)c(O)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc(O)c(S(C)(=O)=O)c(O)n1
Yield: 90 %

Procedure:
16 g (0.1 mole) of 2-methyl-5-chloro-4,6-dihydroxypyrimidine and 11.2 g (0.11 mole) of sodium methylsulfinate are stirred in 50 ml of dimethyl sulfoxide for 4 hours at 125°-130° C. The suspension is filtered clear at 90° C. and chloroform is added to the filtrate. The flocculent precipitate is isolated by filtration and well dried, affording 9.4 g of approx. 90% product which is used for the further reaction without being purified.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N(CC)CC)C.[CH2:22]([OH:25])[CH2:23][CH3:24]>>[OH:13][C:12]1[C:3]([CH2:2][O:25][CH2:22][CH2:23][CH3:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: CCCO
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Solvent: CCN(CC)CC
Product: CCCOCc1c(O)ccc2c1CCCC2=O

Procedure:
According to step 1 in the method of example 19a, 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0 mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) in propan-1-ol (3.0 ml, Aldrich Chemical) to produce 123 mg of desired product as yellow crystals. Low resolution mass spectrum (APCI) m/z 235 [M+H]+.
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]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][N:34]=[C:33]([C:36](Cl)=[O:37])[CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[CH:32]=[C:31]([CH3:30])[O:35][N:34]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)on2)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 20 mg, 50 μmol) and 5-methylisoxazole-3-carbonyl chloride (22 mg, 150 μmol). Yield 19 mg (74%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.S(O)(O)(=O)=O.[NH2:39][C:40]1[NH:41][CH:42]=[CH:43][N:44]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH:41]1[CH:42]=[CH:43][N:44]=[C:40]1[NH:39][C:31](=[O:32])[CH2:30][N:27]1[CH2:26][CH2:25][CH:24]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[N:9]2)[CH2:29][CH2:28]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CC(=O)O)CC1
Reactant: Nc1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CC(=O)Nc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.7 %

Procedure:
A mixture of 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}acetic acid (0.06 g, 0.00013 mol), 2-aminoimidazole sulfate (0.022 g, 0.000163 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.031 g, 0.000163 mol), N,N-diisopropylethylamine (0.047 g, 0.00036 mol) and 1-hydroxy-7-azabenzotriazole (0.018 g, 0.00013 mol) in anhydrous dichloromethane (8 mL) was stirred for 18 hours at room temperature. Additional 2-aminoimidazole sulfate (0.022 g, 0.000163 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.031 g, 0.000163 mol), N,N-diisopropylethylamine (0.047 g, 0.00036 mol) and 1-hydroxy-7-azabenzotriazole (0.018 g, 0.00013 mol), were added and the mixture was stirred for 18 hour at room temperature. The mixture was warmed to 50° C. for 6 hours, then stirred at room temperature for 2 days. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield N1-(1H-2-imidazolyl)-2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}acetamide (0.005 g, 0.00001 mol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@:8]([C@@H:16]2[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CC#N.Cl>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@:8]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of (R)-tert-butyl 2-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate (0.38 g, 0.88 mmol) in MeCN (50 mL), 2 N aq HCl (50 mL) was added slowly at rt. The resulting solution was stirred at rt overnight, basified to pH=10 with 10 N aq NaOH, and evaporated under reduced pressure to remove MeCN. The aqueous layer was extracted with CH2Cl2 (4×5 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo to give (R)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol (0.27 g, 93%) as a free amine. The crude product was used for next step without purification; MS m/z 332 (M+H+).
Reaction SMILES: [N:1]#[N:2].C([O:6][C@H:7]1[C@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@H:10]([CH3:21])[O:9][C@@H:8]1[S:22][CH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:58]([NH:60][C@H:61]([C:91]([OH:93])=[O:92])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67](=[O:90])[CH2:68][CH2:69][S:70][C@H:71]1[O:88][C@@H:87]([CH3:89])[C@@H:82]([O:83]C(=O)C)[C@@H:77]([O:78]C(=O)C)[C@@H:72]1[O:73]C(=O)C)=[O:59])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:57])[CH2:35][CH2:36][S:37][C@H:38]1[O:55][C@@H:54]([CH3:56])[C@@H:49]([O:50]C(=O)C)[C@@H:44]([O:45]C(=O)C)[C@@H:39]1[O:40]C(=O)C)=[O:26])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@H:8]1([S:22][CH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:58]([NH:60][C@H:61]([C:91]([OH:93])=[O:92])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67](=[O:90])[CH2:68][CH2:69][S:70][C@H:71]2[O:88][C@@H:87]([CH3:89])[C@@H:82]([OH:83])[C@@H:77]([OH:78])[C@@H:72]2[OH:73])=[O:59])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:57])[CH2:35][CH2:36][S:37][C@H:38]2[O:55][C@@H:54]([CH3:56])[C@@H:49]([OH:50])[C@@H:44]([OH:45])[C@@H:39]2[OH:40])=[O:26])[O:9][C@@H:10]([CH3:21])[C@@H:11]([OH:17])[C@@H:12]([OH:13])[C@@H:7]1[OH:6]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)CCS[C@H]2O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@H]1OC(C)=O
Agent: N#N
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H]1O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)NC(=O)CCS[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 82.6 %

Procedure:
A solution of 25 (500 mg) in methanol-water-triethylamine 5:4:1 (v/v/v, 5 ml) is kept for 3 hours at room temperature and worked-up in the same manner as for 5 to give the title compound (300 mg, 83%): [α]D27 +28.4±0.9° (c 1.0 H2O); NMR (D2O)δ: 4.48 (d, J1,2 =9.5 Hz, 1H, H-1), 4.46 (d, J1,2 =9.5 Hz, 2H, H-1), 4.17, 4.32 (q,q, α-CH), 3.22 (m, ε-CH2), 2.98 (m, SCH2), 2.69 (t, 1H), 2.61 (t, 2H) (SCH2CH2), 1.34-1.90 (m, C-CH2CH2CH2C), 1.25 (d, J=6.0 Hz, CH3 -6).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26]OS(C)(=O)=O.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(CNc3ccccc3)cc(OC)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 20 mg (0.039 mmol) of methanesulfonic acid 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-ylmethyl ester in DMF is added aniline (excess) and the reaction is stirred for 1 h at 60° C. The reaction mixture is extracted with sat. NaHCO3/water. The organic layer is evaporated and the residue is purified via reversed phase RP18-chromatographie to give 3.3 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][O:19][CH3:20]>>[CH3:20][O:19][CH2:18][CH2:17][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: COCCBr
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: COCCn1cc(C#Cc2ccnc(C)c2)nc1C

Procedure:
The title compound, MS: m/e=256.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-bromoethyl-methylether.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>O.C(O)C>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)N(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
22.6 g (0.08 mol) of ethyl N,N-diphenylcarbamoylacetate (m.p.=75°-76° C.) are added to a solution of 5.6 g(0.1 mol) of KOH in a mixture of 50 ml of water and 25 ml of ethanol. The mixture is heated to 40° C. with agitation until dissolution is complete (that is, for about 1 hour) and agitation is continued for two hours. Acidification is then carried out with 3 N HCl, followed by drying without heat, washing with water and drying.20.2 g (yield: 98%) of N,N-diphenylcarbamoylacetic acid (m.p.=126°-127° C.) are obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([F:29])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=2)=[C:22]([F:29])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1F
Reactant: O=C(O)c1nc(Br)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1nc(-c2ccc(OCc3ccccc3)cc2F)ccc1F
Yield: 41 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 4-(benzyloxy)-2-fluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(4-(benzyloxy)-2-fluorophenyl)-3-fluoropicolinic acid in 41% yield. LC/MS=342.1 (M+H), Rt=1.06 min.
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[NH:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[NH:23][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc3nc(-c4ccccc4)c(-c4ccccc4)nc23)cc1
Solvent: C1CCOC1
Product: Nc1ccc(Nc2cccc3nc(-c4ccccc4)c(-c4ccccc4)nc23)cc1

Procedure:
5.4 g (2.9 mmol) of 2,3-diphenyl-5-(4-nitrophenyl)aminoquinoxaline was dissolved in 100 ml of tetrahydrofuran, and a reaction container was purged with nitrogen. Thereafter, 5.0 g of 5% Pd/C (hydrous) was added, followed by sufficient purging with nitrogen again. This system was purged with hydrogen, followed by reaction at room temperature for 10 hours. After completion of the reaction, the system was filtered, and the resulting filtration residue was washed with tetrahydrofuran and filtered again. The solvent was removed from the resulting filtrate, and a reaction product was recrystallized from a mixed solvent of tetrahydrofuran/heptane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:21]=[C:22]([C:26]([N:38]5[C:39]6[C:35](=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:40]=6)[CH2:36][CH2:37]5)=[O:28])[N:23]=[CH:24][N:25]=4)[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: COc1ccc2c(c1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccc(OC)cc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.20 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]pyrimidine-4-carboxylic acid and 30 mg (0.20 mmol) 6-methoxy-2,3-dihydro-1H-indole in 50 μL (0.36 mmol) TEA and 1.5 mL DMF were combined with 70 mg (0.22 mmol) TBTU and the mixture was stirred for 1 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1C.[Cl:22][C:23]([Cl:33])=[CH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[CH:24]=[C:23]([Cl:22])[Cl:33])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1C=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccccn1
Product: CC(C)C(C(=O)OCc1ccccc1C=C(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
2.8 g (0.012 mole) of 2-(4-chlorophenyl)-isovaleryl chloride in 50 ml of absolute toluene are introduced into 1.2 g (0.013 mole) of -picoline and 3.2 g (0.015 mole) of 2-(2,2-dichlorovinyl)-benzaldehyde in a conical flask at room temperature, while stirring. After 30 minutes, the mixture is filtered under suction over silica gel, and washing is carried out with toluene.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[N:6][CH:7]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1(C)C=CC=CC=1>[S:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][N:6]=2)=[CH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]1=2
Reactant: Clc1ccc(-c2cc3ccccc3s2)nc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccc(-c3cc4ccccc4s3)nc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 20.4 %

Procedure:
In a 100 ml-three-necked flask, 4.91 g (20.0 mM) of 5-chloro-2-(benzo[b]thienyl)pyridine, 3.66 g (30.0 mM) of phenylboronic acid, 9.58 g (40.0 mM) of tripotassium phosphate hydrate, 3.2 mg (0.020 mM) of palladium (II) acetate, 11.9 mg (0.040 mM) of 2-di-tert-butylphosphinobiphenyl and 60 ml of toluene were placed and refluxed under stirring for 24 hours at 100° C. under nitrogen stream. After the reaction, the reaction mixture was cooled on an ice bath to precipitate a crystal, which was then filtered out and washed with water. To the crystal, 25 ml of methanol was added and washed under stirring at room temperature, followed by recovery by filtration. The crystal was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from a chloroform-methanol mixture solvent to obtain 1.17 g (Yield: 20.4%) of 2-(benzo[b]thienyl)-5-phenylpyridine (colorless crystal).