Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15]C)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Reaction time: 1.5 h
Yield: 112.6 %

Procedure:
A suspension of 2-(3-chlorophenyl)-4-(methoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (6.26 g, 16 mmol) in 5% NaOH (54 mL) dioxane (39.4 mL) was heated at reflux and stirred for 1.5 hours. As the reaction proceeds, the solution becomes orange and homogeneous. The mixture was cooled and poured into 1N HCl, with constant stirring. The resulting white solid was filtered and rinsed with H2O and left to dry overnight. The mostly dry product was taken up in CH2Cl2 and azeotroped with toluene to remove any remaining H2O, to provide the desired product as a white solid (yield: 6.79 g, >100%). 1H NMR (300 MHz, DMSO d6) δ 2.27 (s, 3H), 7.51–7.62 (m, 2H), 7.68 (m, 1H), 7.79 (m, 1H), 8.03 (m, 4H), 8.24 (s, 1H). MS (DCI/NH3) m/z 377 (M+H)+, 396 (M+NH4)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[C:24]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][NH:23][C:11](=[O:12])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:14])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CC#N
Product: O=C(NCC(c1ccccc1)c1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
N-(2,2-Diphenylethyl)-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following the scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and 2,2-diphenyl-ethylamine. Yield (48%). HPLC ret. time 3.55 min, 10-99% CH3CN, 5 min run; NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.70 (t, J=5.9 Hz, 1H), 8.50 (s, 1H), 8.17 (m, 1H), 7.52 (m, 1H), 7.36-7.18 (m, 12H), 4.43 (t, J=8.0 Hz, 1H), 3.90 (dd, J=8.0, 6.0 Hz, 2H); ESI-MS 369.3 m/z (MH+).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCC(C)C.C(N([CH2:26][CH3:27])CC)C>>[CH2:1]([O:20][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:26][CH3:27])[CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)O
Reactant: CCN(CC)CC
Product: CCCCCCCCCCCCOC(C)CCCCCC
Temperature: 130 °C
Yield: 5000 %

Procedure:
To 32 g (0.1 mole) of isostearic acid there is added 0.3 ml (0.002 mole) of triethylamine. The resulting mixture is heated to 130° C. under a nitrogen atmosphere and there are slowly added thereto 40 g (0.1 mole) of 2-octyl dodecyl ether of glycidyl obtained according to the above method. After heating for 3 hours and 15 minutes at 130° C., the amount of the reaction determined by acid index is 93%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][N:16]1[CH:20]=[C:19](I)[CH:18]=[N:17]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu](I)I>[CH3:15][N:16]1[CH:20]=[C:19]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:18]=[N:17]1
Reactant: Cn1cc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cn1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.164 g, 0.819 mmol) in 3 mL of isopropanol under an atmosphere of nitrogen was added 1-methyl-4-iodo-1H-pyrazole (0.204 g, 0.983 mmol), ethylene glycol (0.051 g, 0.82 mmol), copper iodide (0.031 g, 0.16 mmol), and potassium phosphate (0.695 g, 3.28 mmol). The reaction was heated to 100° C. for 8 h, cooled to rt, and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 10-100% ethyl acetate in hexanes to provide tert-butyl 4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate that gave a mass ion (ES+) of 281.1 for [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[N:22]#[C:23]Cl.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:23]#[N:22])=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]
Reactant: N#CCl
Reactant: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(OC#N)c(Cl)c1
Yield: 99.7 %

Procedure:
36.6 g (0.1 mol) of 2,2-bis-(3,5-dichloro-4-hydroxyphenyl)-propane are suspended in 500 ml of water and 400 ml of methylene chloride. After cooling to about 0° to 3° C, 20 ml (0.4 mol) of cyanogen chloride are added. A solution of 10.6 g of Na2CO3 in 50 ml of water is added dropwise over the course of 90 minutes, with vigorous stirring, in such a way that the pH value of the reaction mixture is constantly kept in the range between 7.5 and 8.5. Thereafter, 1 N NaOH is added in such a way that a pH value of the reaction mixture of about 8.0 is maintained, and persists as the final value. Thereafter, the organic phase is separated off, washed with 100 ml of water and concentrated at room temperature. 39 g (99% of theory) of 2-(3,5-dichloro-4-hydroxyphenyl)-2-(3,5-dichloro-4-cyanatophenyl)-propane are obtained as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.CN(CCN(C)C)C>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:9]2[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1c[nH]c(-c2ccccc2Cl)n1
Reactant: OB(O)c1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Product: FC(F)(F)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.1 %

Procedure:
2-(2-Chloro-phenyl)-4-trifluoromethyl-1H-imidazole (370 mg, 1.5 mmol), 4-bromo-phenylboronic acid (600 mg, 3 mmol), and [Cu(OH).TMEDA]2Cl2 (140 mg, 03 mmol) were mixed with 6 mL dry dichloromethane, and stirred at room temperature under atmosphere of dioxygen for 2 days. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated under vacuum, and the residue was purified by chromatography on silica gel (Hexane/EtOAc 8/2) to give a solid (151 mg, 25% yield). 1H-NMR (400 MHz, CDCl3): δ 7.02 (d, 2H), 734 (m, 3H), 7.47 (ol, 2H), 7.53 (dd, 1H), 7.56 (dd, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:37](=[O:39])[C:36]1[CH:35]=[CH:34][C:33]([Cl:32])=[CH:41][CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Yield: 95.7 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 88 mg (0.560 mmol) of 4-chlorobenzoic acid, 143 mg (0.561 mmol) bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (210 mg, 80%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.44, FD-MS: M+ =565, 567.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([NH:44][C:45]([O:47][CH:48]([CH3:50])[CH3:49])=[O:46])[CH:36]=1>O1CCCC1>[C:45]([NH:44][C:37]1[CH:36]=[C:35]([NH:34][C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=[O:40])([O:47][CH:48]([CH3:50])[CH3:49])=[O:46]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)OC(=O)Nc1cc(N)ccc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)ccc1C(=O)O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
A solution was prepared by dissolving 249 mg of N-carbobenzoxy-L-proline and 101.0 mg of N-methylmorpholine in 5 ml of dry tetrahydrofuran and cooling to a temperature of -15° C. The solution was mixed with 136.6 mg of isobutyl chloroformate and the mixture was stirred at a temperature of -15° C. to -10° C. for 2 minutes. Then, a solution of 238 mg of 4-amino-2-carboisopropoxyaminobenzoic acid and 101.2 mg of N-methylmorpholine in 2 ml of dry tetrahydrofuran was added dropwise to the above-mentioned mixture. The resultant reaction mixture was stirred at a temperature of -15° C. to -10° C. for one hour, gradually heated to room temperature, and then stirred at room temperature for 18 hours. The resultant deposit generated in the reaction mixture was removed by filtration, the filtrate was concentrated under a reduced pressure, and an oily yellow substance was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K35) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (261 mg).
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.Cl.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[N:31]=1>CCOC(C)=O>[CH3:29][C:30]1[N:31]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([C:9]([O:11][C:12]4[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=4)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc(N2CCC(CCC3CCNCC3)CC2)n1
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCC3CCN(c4cccc(C)n4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (505 mg) was added to an acetonitrile (10 ml) solution of 2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridine dihydrochloride (520 mg) and TEA (0.50 ml), followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with EtOAc, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2 (v/v)) to obtain methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl}carbonyl]oxy}nicotinate (424 mg).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:41]([O:43][C:44](=[O:57])[C@H:45]([OH:56])[C@H:46]([NH2:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54])[CH3:42].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:41]([O:43][C:44](=[O:57])[C@H:45]([OH:56])[C@H:46]([NH:55][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:4]2[C:5](=[O:7])[CH2:6][C:2]([CH3:1])=[N:3]2)=[CH:16][CH:15]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54])[CH3:42]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)c1ccc(N2N=C(C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
4-(3-Methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid (100 mg, 0.6 mmol, 1.0 eq.) was combined with DMF (1000 μL) and HATU (250 mg, 0.7 mmol, 1.2 eq.) and stirred at room temperature for 15 minutes. (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (TFA salt, 200 mg, 0.6 mmol, 1.0 eq.) in DIPEA (200 μL, 2.0 eq.) and DMF (1000 μL) was then added and the resulting mixture was stirred overnight at room temperature. Excess solvent was removed and the product was dissolved in AcOH/H2O (50%) and purified by preparative LC (1″ column; gradient 2-50% MeCN/H2O, 0.05% TFA, over 80 minutes; 15 mL/min flow; UV 280 nm). The fractions were collected, frozen, and lyophilized to yield the title compound (100 mg, 98% purity). MS m/z [M+H]+ calc'd for C23H24ClN3O5, 458.14. found 458.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:14])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32](=[O:43])/[CH:33]=[CH:34]/[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:30].C(OCC)(=O)C>C(OCC)C>[C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:14][C@H:33]([C:32]([O:31][CH2:29][CH3:30])=[O:43])[CH2:34][C:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CC(=O)c1ccccc1)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.0 g (20 mmoles) of Nε -t-butoxycarbonyl-(S)-lysyl-(S)-proline-t-butylester are dissolved in 100 ml of diethyl ether and 4.48 g (22 mmoles) of E-ethyl-3-benzoyl-acrylate are added to the solution. The reaction mixture is stirred at room temperature for 5 hours. After evaporation of the solvent the title product is isolated on a Kieselgel column in the form of transparent oil. Rf =0.49 i(in a 7:3 eluent mixture of ethyl acetate and ether).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][CH:10]([O:23][CH2:24][CH3:25])[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][Si](C)(C)C)=[N:15][CH:16]=1)[CH3:8]>CO>[CH2:24]([O:23][CH:10]([O:9][CH2:7][CH3:8])[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[CH:18])=[N:15][CH:16]=1)[CH3:25]
Reactant: CCOC(OCC)c1ccc(C#C[Si](C)(C)C)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(OCC)OCC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
In THF (10 mL) was dissolved 2-bromo-5-(diethoxymethyl)pyridine (1.00 g, 3.84 mmol) obtained in Step 1. To the solution were added trimethylsilyl acetylene (1.09 mL, 7.69 mmol), copper iodide (I) (37.0 mg, 0.192 mmol), (bistriphenylphosphine) palladium (II) chloride (135 mg, 0.192 mmol), and triethylamine (1.07 mL, 7.69 mmol), and the mixture was stirred at 70° C. for 6 hours. The solvent in the reaction mixture was evaporated under reduced pressure, and water and ethyl acetate were added. The mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 5-(diethoxymethyl)-2-((trimethylsilyl)ethynyl)pyridine (1.07 g). In methanol (10 mL) was dissolved 5-(diethoxymethyl)-2-((trimethylsilyl)ethynyl)pyridine obtained. Potassium carbonate (1.06 g, 7.69 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure, and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 5-(diethoxymethyl)-2-ethynylpyridine (703 mg, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2c1
Yield: 65.8 %

Procedure:
To a suspension of iron powder (5 g) in acetic acid (10 g), 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-6-nitroindazole [Compound No. 3] (3 g) and water (10 g) were added, and the resultant mixture was refluxed for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-6-aminoindazole (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)=[O:22])=[CH:15][CH:16]=1
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CCCC3=O)cc1
Yield: 92 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with p-anisoyl chloride (90 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (135 mg, 0.46 mmol, 92% yield) as a white powder after purification by flash chromatography on silica gel (eluent: EtOAc/DCM 0/10 to 2/8).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1ccc(N)cc1
Solvent: CC#N
Product: N#CCc1ccc(N)c(Br)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of 4-aminophenylacetonitrile (1.45 g, 10.9 mmol) in acetonitrile (10 mL) at 0° C. was treated with NBS (1.95 g, 10.9 mmol) in acetonitrile (10 mL) dropwise via an addition funnel. The reaction was allowed to warm to room temperature and then concentrated in vacuo. The crude product was dissolved in EtOAc (50 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and dried (Na2SO4). Removal of the solvent in vacuo afforded the title compound (2.12 g, 92%) as a reddish solid. Mass spectrum (ESI, m/z): Calcd. for C8H7BrN2, 210.9 (M+H), found 211.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[S:17][C:18]([CH:21]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([Cl:32])[CH:30]=3)[N:25]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)O)=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[S:17][C:18]([CH2:21][C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([Cl:32])[CH:30]=3)[NH:25][CH:24]=2)=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cnc(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)s2)c2cc(Cl)cnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ncc(Cc2c[nH]c3ncc(Cl)cc23)s1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of {5-[(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (627, 120 mg, 0.186 mmol) in acetonitrile (3 mL) was added trifluoroacetic acid (0.14 mL, 1.86 mmol) and triethylsilane (0.30 mL, 1.86 mmol). The resulting mixture was stirred for 2 hours at 40° C. The solvent was then removed in vacuo and the residue was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[B:14](OC)([O:17]C)[O:15]C>>[F:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1-c1ccncc1
Product: OB(O)c1cccc(-c2ccncc2)c1F

Procedure:
4-(2-Fluorophenyl)pyridine was lithiated and reacted with trimethyl borate as described in Example 11 to afford 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as a white solid: m/z (ES+) 218 (M++H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[NH:11][C:8](=[O:10])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[C:19]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1ccccn1
Yield: 23 %

Procedure:
Synthesized from (2-pyridyl)-acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2 Yield 23%.