Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=2)=[CH:26]\[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.[Cu]I.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>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:50])[F:51])[CH:43]=3)=[CH:26]\[CH2:27][O:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=3)=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: C#CCN1CCC(O)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (191 mg, 1.374 mmol) and diisopropylamine (0.45 mL, 3.23 mmol) were added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (400 mg, 0.687 mmol; prepared as described in example 34) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10.4 mg, 0.055 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24.1 mg, 0.034 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 96:4) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)c1cccs1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4cccs4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.080 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[C:8]([CH3:12])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[N:5]=1.S(Cl)([Cl:26])=O>>[Cl:26][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:7][C:8]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)nc(C)c1CO
Product: COCc1nc(-c2ccc(OC(F)(F)F)cc2)nc(C)c1CCl

Procedure:
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.C(Cl)(=O)CCCC>O>[CH2:11]([C:10]1[NH:1][C:2]2[C:3]([CH:8]=1)=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13][CH3:14]
Reactant: c1ccncc1
Reactant: Cc1ccccc1N
Agent: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 84 %

Procedure:
o-Toluidine (55 g) was mixed with 100 ml dry pyridine and 200 ml dry tetrahydrofuran in a 1-L 3-necked round bottom flask fitted with a Trubore stirrer, thermometer and a dropping funnel, under nitrogen. Then, with cooling in a refrigerated bath, valeryl chloride (60.3 g) was added dropwise over 1 hour. The mixture was stirred for another hour at room temperature and then poured onto 500 g ice and water. The precipitate was washed repeatedly with water on a Buchner funnel. The precipitate (88.9 g, 93%) was cyclized according to Verley and Bedure, 1925, Bull. Soc. Chim. Fr. (37): 190 to afford 2-n-butyl indole (67.4 g, 84%) as a very slightly yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C2CCC(O)CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2CCC(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution of 4-methoxybenzyl 4-hydroxycyclohexanoate (7.5 g, 28 mmole), 4-dimethylaminopyridine (0.73 g, 6 mmole) and N-benzyloxycarbonyl-L-valine (7.54 g, 30 mmole) in dichloromethane (90 ml) was added dicylohexyl-carbodiimide (6.8 g, 33 mmole) and the mixture was stirred for 2 days at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated and 250 ml ethyl acetate was added. The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 13 g=93%
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2)=[O:5].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:23][S:24]([O:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2)=[O:5])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc2cnccc2c1)C(CO)c1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To 3-hydroxy-N-(isoquinolin-6-yl)-2-phenylpropanamide (E402) in pyridine at 0° C. was added MsCl, and this solution was stirred at 0° C. for 2.5 h. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated to give 3-(isoquinolin-6-ylamino)-3-oxo-2-phenylpropyl methanesulfonate (E403).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][S:7][C:8](=[N:14][NH:15]C(OC)=O)[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].[S:21](Cl)(Cl)=O>ClCCl>[CH3:11][C:10]([C:9]1[S:21][N:15]=[N:14][C:8]=1[S:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])([CH3:13])[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CCSC(CC(C)(C)C)=NNC(=O)OC
Solvent: ClCCl
Product: CCOC(=O)CCSc1nnsc1C(C)(C)C

Procedure:
A mixture of [1-[(3-ethoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylic acid, methyl ester, thionyl chloride and dichloromethane was heated at reflux for 40 hours and then quenched with ice water. The orange product was extracted twice into ether. The extracts were combined, washed with 0.1N sodium hydroxide twice, water twice, saturated sodium chloride twice, dried and concentrated in vacuo. The resulting orange liquid was evaporated onto 70 g of silica gel. The gel was dried and poured onto a column of silica gel packed in petroleum ether. The column was eluted with a gradient of 1-10% ethyl acetate in petroleum ether. The desired fractions were purified on silica gel preparative TLC plates eluting with 3% ethyl acetate in petroleum ether, giving 2.9 g of the desired compound as a light yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 1.23 (t, 3H, J=7.0 Hz, CH3); 1.49 (s, 9H, t-butyl); 2.84 (t, 2H, J=7.0 Hz, CH2CO); 3.59 (t, 2H, SCH2); 4.14 (q, 2H, OCH2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.C(OCC)(=O)C.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>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:23]3[CH:24]=[C:19]([NH2:18])[CH:20]=[CH:21][CH:22]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 99 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 3-aminophenylboronic acid (134 mg), and bis(triphenylphosphine)palladium(II) dichloride (55 mg) in 0.6 mL of 1M Na2CO3 aqueous solution and 0.6 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate (80 mL), washed with H2O (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to yield 270 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH:24]=[CH2:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (500 mg, 1.67 mmol) in methyl ethyl ketone (6 mL) was treated with allyl bromide (232 mg, 1.92 mmol, 0.17 mL) and potassium carbonate (311 mg, 2.25 mmol) and then heated to reflux. After 18 h, the mixture was cooled to ambient temperature and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 10% EtOAc/hexanes) to provide the desired product (478 mg, 84%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J=8.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.97 (dt, J=7.6, 1.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 2H), 6.84 (t, J=8.4 Hz, 2H), 6.05 (ddd, J=17.2, 10.6, 5.2 Hz, 1H), 5.41 (dd, J=17.2, 1.6 Hz, 1H), 5.28 (dd, J=10.8, 1.4 Hz, 1H), 4.22 (d, J=5.2 Hz, 2H), 4.19 (q, J=6.8 Hz, 2H), 3.27 (A of AB, J=14 Hz, 1H), 3.11 (B of AB, J=14 Hz, 1H), 1.40 (s, 3H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[CH3:15][O:16][C:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=2)[N:18]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([N:19]2[N:18]=[C:17]([O:16][CH3:15])[O:21][C:20]2=[O:22])=[CH:24][C:25]=1[O:30][CH3:31])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Reactant: COc1nn(-c2ccc(N)c(OC)c2)c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nn(-c2ccc(NC(=O)NC(=O)c3ccc(F)cc3Cl)c(OC)c2)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 0.39 g of 5-methoxy-3-(4-amino-3-methoxyphenyl)-3H-[1,3,4]oxadiazol-2-one hydrochloride and 0.2 ml of triethylamine in 5 ml of acetonitrile and the mixture is stirred at room temperature overnight. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[CH:10][CH:11]=1.[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH2:28])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:28][CH:26]3[CH2:27][C:22]([CH3:31])([CH3:21])[NH:23][C:24]([CH3:30])([CH3:29])[CH2:25]3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCCc1ccc(-c2nc(Cl)ncc2C)s1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: COC(=O)CCCc1ccc(-c2nc(NC3CC(C)(C)NC(C)(C)C3)ncc2C)s1
Yield: 60 %

Procedure:
4-{5-[5-Methyl-2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-thiophen-2-yl}-butyric acid methyl ester was prepared analogous to Step C of Method A, starting from 4-[5-(2-chloro-5-methyl-pyrimidin-4-yl)-thiophen-2-yl]-butyric acid methyl ester and added 2,2,6,6-tetramethyl-piperidin-4-ylamine. Yield: 60%.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:43]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:57]([O:56][P:52](/[CH:43]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:53][CH2:54][CH3:55])=[O:59])[CH3:58]
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C)c(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a mixture of methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.13 g), tetraethyl methylenediphosphonate (0.63 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-methylbenzoate as colorless crystals (0.57 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:3]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[N:41]1([C:2]2[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])=[O:7])=[C:4]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[CH:3]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCOCC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 129 °C
Yield: 57.1 %

Procedure:
The 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (203 mg, 0.35 mmol) was diluted with morpholine (4 mL, 45.9 mmol). The mixture was heated to 129° C. for 2 days. The reaction was diluted with methylene chloride (100 mL) and washed with water (2×10 mL). The aqueous layers were combined and extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 25 g silica, 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2) to give the desired product (125 mg, 0.20 mmol, 56%) as a white solid.
Reaction SMILES: [Cl:1][CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[S:10]([NH:20][NH2:21])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>C1COCC1.CCOCC>[Cl:1][CH:2]([C:7](=[N:21][NH:20][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(C)=NNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25 ml of methyl 2-chloroacetoacetate in 25 ml of THF was added dropwise over 30 minutes to a solution of 37.5 g of tosyl hydrazine in 150 ml of THF. The mixture was allowed to stand overnight, then heated at reflux for 2 hours, cooled to room temperature and stripped of solvent. The residue was then dissolved in 200 ml of ether. Crystallization occurred at room temperature. The collected solids were dried to give methyl 2-chloro-3-(tosylhydrazono)butanoate (7B), as a light yellow solid, m.p.: 97°-101° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Na].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1nccc(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a stirred solution of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in absolute ethanol (10 mL), was added sodium salt of benzenethiol (0.89 g, 6.73 mmol)in small portions. The mixture was stirred at room temperature for 2 hours, then at 40° C. for 16 hours. It was diluted with ethyl acetate (20 mL), and filtered. The filtrate was concentrated in vacuo, and the residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (1:99→25:75) as eluant to give the desired product (498 mg, 36%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[O:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C([O-])(=[O:24])C.[Na+].O>C(O)(=O)C>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[O:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:24])[NH:7][N:6]=3)[CH:21]=[CH:20][C:11]=2[N:12]=1
Reactant: Clc1ccc(-c2ccc3nc(-c4cccs4)oc3c2)nn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccc3nc(-c4cccs4)oc3c2)n[nH]1
Temperature: 120 °C
Reaction time: 96 h

Procedure:
550 mg (1.75 mmol) 6-(6-chloro-pyridazin-3-yl)-2-thiophen-2-yl-benzoxazole in 15 mL glacial acetic acid are placed under protective gas in a pressurised vessel, 173 mg (2.11 mmol) sodium acetate are added and the mixture is stirred for 4 days at 120° C. The reaction mixture is combined with H2O and extracted with DCM. The solv. of the org. phase is eliminated i.V. The residue is suspended in ACN and a solid is suction filtered. The solid is suspended in DCM, stirred for 2 h at RT and suction filtered again.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:41][CH:40]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: COc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: COc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3nccn3)C2)c1
Yield: 93 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide, gave Compound 69, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide (180 mg, 93%). 1H-NMR (400 MHz, CDCl3): σ 9.15 (s, 1H), 7.71 (s, 2H), 7.42 (d, 2H), 7.00 (t, 2H), 6.93-6.89 (m, 4H), 6.80-6.72 (m, 4H), 5.32-5.23 (m, 1H), 4.84 (d, 1H), 4.80 (d, 1H), 3.81 (s, 3H), 3.51 (dd, 1H), 3.17 (t, 1H), 2.99-2.88 (m, 2H), 2.69-2.59 (m, 2H), 1.73-1.65 (m, 1H). MS (EI) for C29H28FN5O4. found 530.2 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([N:23]6[CH:27]=[C:26]([C:28]([OH:30])=O)[CH:25]=[N:24]6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:49]([CH3:51])[CH3:50])C2C=CC=CC=2N=N1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:50][N:49]([CH3:51])[C:28]([C:26]1[CH:25]=[N:24][N:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)=[CH:15][N:16]=3)[CH:19]=2)[CH:27]=1)=[O:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylic acid (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (65 mg, 0.15 mmol), dimethylamine (2M in THF, 0.10 mL, 0.2 mmol) and N,N-diisopropylethylamine (0.10 mL). The mixture was stirred at RT for 2 h, and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=424.1.