Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+:3].[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:32]5[O:31][C:30]([C:33]([O:35]CC)=[O:34])=[CH:29][C:28]=5[CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5]>O1CCCC1.O>[C:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[C:32]5[O:31][C:30]([C:33]([O-:35])=[O:34])=[CH:29][C:28]=5[CH:27]=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].[Li+:3]
Reactant: CCOC(=O)c1cc2cccc(N3CCN(CCc4ccc5c(c4)CCN5C(C)=O)CC3)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(CCN3CCN(c4cccc5cc(C(=O)[O-])oc45)CC3)ccc21
Temperature: 100 °C
Yield: 99.3 %

Procedure:
Lithium hydroxide monohydrate (0.087 g, 2.08 mmol) was added to a solution of ethyl 7-(4-(2-(1-acetylindolin-5-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (0.481 g, 1.04 mmol) in tetrahydrofuran (9 mL) and water (1 mL) and the reaction was heated at 100° C. for 35 min in a microwave oven. The solvents were evaporated and the material was dried in vacuum over P2O5 to give 0.454 g of the crude product. The crude material was used in the next step assuming quantitative yield without further purification. MS (ES+) m/z 434.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17].C(N(CC)CC)C>C(OCC)C>[OH:17][C:11]1[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=1[NH:9][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(Br)ccc1O
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A solution of tert-butylacetyl chloride (2.7 g, 0.020 mol) in diethyl ether (20 ml) was added dropwise to a solution of 2-amino-4bromophenol (3.8 g, 0.020 mol) and triethylamine (2.1 g, 0.020 mol) in diethyl ether (160 ml) and the mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was evaporated in vacuo. Purification by flash column chromatography on silica gel, eluting initially with ethyl acetate:dichloromethane 1.5:98.5 and then with ethyl acetate:dichloromethane 2.5:97.5, gave N-(2-hydroxy-5-bromophenyl)-3,3-dimethylbutyramide (1.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:16][CH2:17][OH:18])=[C:10]([Cl:19])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:16][CH2:17][O:18][C:21](=[O:23])[CH3:22])=[C:10]([Cl:19])[CH:9]=1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(OCCO)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOc1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester (0.85 g) in pyridine (14 mL) is treated with acetic anhydride (1.24 mL) and the mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure and the residue dissolved in ethyl acetate. This solution is then washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, and then with saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure to provide the desired product as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[NH2:16][NH2:17]>O1CCOCC1>[Cl:15][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:2]([NH:16][NH2:17])[N:3]=[N:4][CH:5]=1
Reactant: NN
Reactant: Clc1ccc(-c2c(Cl)cnnc2Cl)cc1
Solvent: C1COCCO1
Product: NNc1nncc(Cl)c1-c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 22 %

Procedure:
To a solution of 3,5-dichloro-4-(4-chlorophenyl)pyridazine (2.56 g, 10 mmol) in dioxane (36 mL) at RT was added hydrazine (3.2 mL, 100 mL). After addition, the reaction was heated to 70° C. for 2 h. After cooling to RT, the reaction was concentrated under reduced pressure. To the obtained residue was added 2-propanol (80 mL) and the resulting white solid was removed by filtration. The collected liquid was concentrated under reduced pressure to give the title compound 1-(5-chloro-4-(4-chlorophenyl)pyridazin-3-yl)hydrazine as an off-white solid (560 mg, 22%) which contained 15% of by-product (1-(3-chloro-4-(4-chlorophenyl)pyridazin-5-yl)hydrazine). The mixture was used directly in the next step, 273E. LC/MS (method A): RT=1.89 min, (M+H)+=255.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C.O>[Br:19][C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(F)cc12
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)sc2ccc(F)cc12
Temperature: 40 °C
Reaction time: 0.58 h

Procedure:
A mechanically-stirred solution of 5-fluoro-3-methylbenzo[b]thiophene (50.32 g, 0.303 mol, 1.0 equiv) in acetonitrile (350 mL) is treated with NBS (56.32 g, 0.318 mol, 1.05 equiv). An initial endotherm reduces the reaction temperature to 17° C. A subsequent exotherm then increases the reaction temperature to 40° C. over a 10 min. period, at which time the reaction is cooled to 18-20° C. by application of an ice water bath. The reaction is stirred at RT for an additional 35 min. and the resultant slurry is slowly diluted with water (350 mL). The slurry is stirred for 10 min and the product is filtered, washed with 50:50 acetonitrile:water (100 mL) and dried to a colorless crystalline solid (65.56 g, 88%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:47]([OH:49])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:24][C:25](=[O:27])[OH:26])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:60]([OH:63])(=[O:62])[CH3:61]>O>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:47]([O:49][CH3:60])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:24][C:25](=[O:27])[OH:26])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:61][C:60]([OH:63])=[O:62]
Reactant: CC(C)[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCCN)C(C)C

Procedure:
800 mg (approx. 0.88 mmole) of Z-Lys-Arg-Glu-Val-Tyr-Ome acetate are subjected to catalytic hydrogenation in 90 percent strength acetic acid and the product is worked up analogously to Example 25 I. Yield 680 mg (93%), [α]D22 =-31.6° (c=1, in water).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([C:3]1([CH3:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (1.0 g, 5.1 mmol) in THF (20 mL) at −78° C. was slowly added LiHMDS (1.0 M in THF, 5.6 mL, 5.6 mmol). The reaction mixture was stirred at −78° C. for 30 min then iodomethane (0.48 mL, 7.64 mmol) was slowly added. The reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature and quenched with saturated aqueous NH4Cl. Diluted with H2O and extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 40% EtOAc/hexanes) to afford 0.95 g (89%) of tert-butyl 3-cyano-3-methylpyrrolidine-1-carboxylate as a pale yellow solid.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:18]=1.[ClH:19].N([O-])=O.[Na+]>C(#N)C.O>[Cl:19][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][S:17][C:7]3[N:8]=[C:9]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:14][CH2:15][CH3:16])[C:4]4[S:3][C:2]([Cl:19])=[N:18][C:5]=4[N:6]=3)=[N:6][C:5]=2[N:18]=1
Reactant: Cl
Reactant: CCC[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC[C@H](CO)Nc1nc(SSc2nc(N[C@@H](CO)CCC)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Reaction time: 48 h
Yield: 78 %

Procedure:
(2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol (4.0 g, 14 mmol) was dissolved in acetonitrile (100 ml) and concentrated hydrochloric acid (150 mL). Sodium nitrite (1.93 g, 28 mmol) was dissolved in water (10 mL) and added at 0° C. The reaction mixture was left at 0° C. for 2 days until the reaction was complete by LCMS. The reaction mixture was poured onto ice and the precipitated product was collected by filtration. The solid was dried in vacuo to give 3.3 g (78% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH3:36])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: COc1cncc(Br)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(OC)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-methoxy-pyridine.
Reaction SMILES: I[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:20]B1OB(C)OB(C)O1>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([CH3:20])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:5]([CH3:11])[N:4]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1c(I)c(-c2ccc(OC)cc2)nn1C
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(C)c(-c2ccc(OC)cc2)nn1C
Temperature: 60 °C

Procedure:
A solution of methyl 4-iodo-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate (587.8 mg, 1.579 mmol), trimethylboroxine (883 μL, 6.32 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (103 mg, 0.158 mmol) in THF (2.6 mL) was degassed by bubbling N2 through the solution. 1N K2CO3 (2.6 mL) was added and N2 was bubbled through the mixture for 30 s. The mixture was heated in a sealed tube at 60° C. overnight. Another 4 eq. of trimethylboroxine was added and the reaction was subjected to microwave irradiation (120° C., 30 min). The reaction mixture was filtered through a plug of silica, eluted with EtOAc and the filtrate was washed with 1N aq. NaOH (2×30 mL), dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl 3-(4-methoxyphenyl)-1,4-dimethyl-1H-pyrazole-5-carboxylate, as a colorless solid. Rf=0.33 (20% EtOAc/hexanes). LCMS calc.=261.03. found=261.12 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 7.51 (d, J=8.5 Hz, 2H); 6.96 (d, J=8.5 Hz, 2H); 4.16 (s, 3H); 3.92 (s, 3H); 3.83 (s, 3H); 2.36 (s, 3H).
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4](O)=[N:5][CH:6]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:22])=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:4]1[C:3]2=[CH:8][CH:9]=[CH:10][N:2]2[N:1]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnn2cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ncnn2cccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of pyrrolo[2,1-f][1,2,4]triazin-4-ol (3.70 g, 27.4 mmol, see generally, PCT Appi. WO 2000/071129 the disclosure of which is herein incorporated by reference in its entirety) in 40 mL of toluene at room temperature was added 4.77 mL (27.4 mmol) of diisopropylethylamine followed by 7.70 mL (82.6 mmol) of phosphorus oxychloride. The reaction mixture was heated at 100° C. for 18 h. After cooling to room temperature, the reaction was slowly added to a solution of 5% aq NaHCO3 solution (100 mL) at 0° C. Upon completion of the addition, the biphasic mixture was allowed to stir at room temperature for 30 min. The aqueous layer was extracted with EtOAc (3×100 mL) and the pooled organic extracts were washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (4.10 g, 97%) as a yellow solid. 1H NMR (CDCl3) δ 8.14 (s, 1H), 7.80 (dd, 1H, J=2.4, 1.5 Hz), 6.91 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cn1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 mg (0.03 mmol) of the compound from example 20A are dissolved in 0.7 ml of dry DMF, and 10 mg (0.04 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 11 mg (0.14 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 8 h. The mixture is then poured into 2 ml of saturated aqueous sodium bicarbonate solution, and the aqueous phase is extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>COCCOC.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccc(F)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of ester 325 (3.80 g, 12.9 mmol) in dry DME (100 mL) at 0° C. was added triethylamine (4.5 mL, 3.3 g, 33 mmol), copper (I) iodide (0.50 g, 2.6 mmol), and bis(triphenylphosphine) palladium (II) chloride (0.38 g, 0.54 mmol). The mixture was degassed with a stream of N2 for 5 min, then trimethylsilylacetylene (4.0 mL, 2.8 g, 29 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 3 h. It was then concentrated under reduced pressure, re-dissolved in ether, filtered and concentrated. Silica gel chromatography of the residue (eluent 10% ethyl acetate/hexanes) afforded 326 (3.30 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.23 (dd, J=8.6, 5.7 Hz, 1H); 7.14 (dd, J=9.0, 2.7 Hz, 1H); 7.00 (dt, J=8.4, 2.7 Hz, 1H); 3.79 (s, 2H); 3.70 (s, 3H); 0.25 (s, 9H). LCMS: (M+H) 265.2.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[K+].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([S:35]([C:28]3[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:37])=[O:36])[C:7](=[O:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(-c3cccc(Cl)c3)c3cc(Cl)ccc32)c(OC)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 2 g of 5-chloro-3-(3-chlorophenyl)-1,3-dihydro-2H-benzimidazol-2-one in 170 ml of THF is cooled to -40° C. and 0.97 g of potassium tert- butylate is added. The mixture is stirred for 30 minutes at -10° C. and then cooled to -50° C. and a solution of 1.7 g of 2,4-dimethoxybenzenesulfonyl chloride in 70 ml of THF is added. The reaction mixture is stirred for 2 hours, the temperature being allowed to rise to RT, and then concentrated under vacuum. The residue is taken up with water, extracted with DCM and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 2.3 g of the expected product after crystallization from a cyclohexane/DCM mixture (90/10; v/v). M.p.=173° C.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[C:2]([C:27]4[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Brc1c(-c2ccco2)nn2c(NC3CCCC3)cccc12
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(-c2c(-c3ccco3)nn3c(NC4CCCC4)cccc23)ccn1
Temperature: 75 °C
Yield: 23 %

Procedure:
N-[3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine (0.2 g, 0.6 mmol) was dissolved in N,N-dimethylformamide (8 mL). To this solution was added 2-fluoro-4-pyridinylboronic acid (0.09 g, 0.64 mmol), dichlorobis(triphenylphosphine)-palladium (II) (0.020 g, 0.03 mmol) and saturated aqueous sodium carbonate (580 μl). The resulting solution was heated in a 75° C. oil bath overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. The product was purified by silica gel chromatography (7:1 hexane:ethyl acetate) to give 50 mg (24%) of N-cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine as a solid. 1H NMR (CDCl3) δ 8.1 (d, 1H), 7.5 (s, 1H), 7.24 (1H), 7.03(s, 1H), 6.96 (d, 1H), 6.75 (d, 1H), 6.5 (m, 1H), 6.01 (m, 2H), 4.0 (m, 1H), 2.19–2.09 (m, 2H); 1.88–1.77 (m, 4H), 1.77–1.64 (m, 2H);MS m/363 (M+1).
Reaction SMILES: [K].Cl[CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1.C(O)C>C(O)(=O)C>[C:4]([C:3]1[N:17]2[C:16]([CH3:18])=[CH:15][CH:14]=[CH:13][C:12]2=[N:11][CH:9]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Cc1cccc(N)n1
Agent: [K]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc2cccc(C)n12
Yield: 57.1 %

Procedure:
In 10 ml of ether was suspended 560 mg (5.0 mM) of potassium tert-butoxide and while the suspension was vigorously stirred, a solution of ethyl formate:370 mg (5.00 mM) and ethyl chloroformate: 613 mg (5.00 mM) in 10 ml of ether was added dropwise over 3 minutes at room temperature. This mixture was stirred at room temperature for 30 minutes and the precipitate that formed was recovered by filtration and rinsed with a small amount of ether. This precipitate was dried in vacuo to give 700 mg (yield 73.8%) of ethyl 2-chloro-2-formylacetate potassium salt as light-yellow solid. Then, 700 mg (3.69 mM) of ethyl 2-chloro-2-formylacetate potassium salt and 399 mg (3.69 mM) of 6-amino-2-methylpyridine were mixed with 20 ml of ethanol and after addition of 0.53 ml (9.23 mM) of acetic acid, the whole mixture was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was diluted with 20 ml of ethyl acetate and 20 ml of purified water. Then, saturated aqueous NaHCO3 solution was added until the water layer became pH 8. This mixture was extracted with 40 ml of ethyl acetate and the organic layer was washed with 30 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 430 mg (yield 57.1%) of the title compound as light-yellow liquid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[O:12]=[C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH:14]=[CH:15]/[C:16](O)=[O:17].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([O:8][C:16](=[O:17])/[CH:15]=[CH:14]/[C:13](=[O:12])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(OC(=O)/C=C/C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.43 g (0.028 mole) of (+)-menthol and 0.34 g (0.003 mole) of 4-dimethylaminopyridine are added to a solution of 5.0 g (0.028 mole) of (E)-4-oxo-4-phenyl-2-butenoic acid in 60 ml of anhydrous dichloromethane. After cooling the solution to 0° C., a solution of 5.86 g (0.028 mole) of N,N-dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane is added. The mixture is stirred at 0° C. for 30 minutes, then at room temperature for one hour. The reaction mixture is worked up as described in Example 1 to give the crude product as a dark-brown oil in a yield of 8.1 g (91%) which is purified by using column chromatography as described in Example 1. The named compound is obtained in a yield of 6.7 g, Rf =0.78 (dichloromethane); [α]D25 =+65° (c=2.0, chloroform).