Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[N:16]=3)[CH:11]=[CH:10][C:9]2=[O:20])C(=O)C2=CC=CC=C12.NN.[ClH:29].C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>C(O)C.O>[ClH:29].[NH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[N:16]=2)[CH:11]=[CH:10][C:9]1=[O:20]
Reactant: Cc1cc(C)c2ccc(=O)n(CCN3C(=O)c4ccccc4C3=O)c2n1
Agent: Cl
Agent: NN
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2ccc(=O)n(CCN)c2n1

Procedure:
A mixture of 1-(2-phthalimidoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (5.2 gm., 0.015 mole) and 95% hydrazine (1.8 ml., 0.053 mole) in absolute ethanol (50 ml.) is refluxed for one hour. The reaction is cooled, water (37.8 ml.) and concentrated hydrochloric acid (37.5 ml.) are added. After refluxing for one half hour, the mixture is cooled in an ice bath and phthalhydrazide (2.85 gm., 0.0125 mole) is filtered off. The filtrate is concentrated and the residue is dissolved in water, made basic with saturated sodium carbonate and extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The residue containing the free base of the title compound is dissolved in a minimum amount of methanol and treated with ethereal hydrogen chloride. Recrystallization of the product from isopropanol gives 1-(2-aminoethyl)-5,7-dimethyl-1,8-naphthyridine-2(1H)-one hydrochloride melting at 253.5°-254.5° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[C:36]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1cnc(N2CCOCC2)n1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(N5CCOCC5)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 29 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 4-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-morpholine in the same manner as Example 15. ESI MS m/z 623 [C30H38N8O5S+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:15]([O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][Br:1])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)CBr
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(CBr)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-2,2-dimethyl-1-propanol (26.9 mL), 4-(dimethylamino)pyridine (2.67 g), and triethylamine (33.5 mL) were dissolved in toluene (250 mL) and cooled to 0° C. Pivaloyl chloride was added dropwise over 30 min (temperature rose to 15° C.) and upon completion the reaction was allowed to warm to 23° C. and stirred for 1 h. The reaction was filtered and the filtrate washed with 2N aqueous HCl (250 mL), aqueous sodium hydrogencarbonate solution (250 mL) and aqueous brine (250 mL). The organic layer was separated and the solvent evaporated to give the subtitle compound (53.0 g).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH2:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:32]([NH:34][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)=[CH:26][CH:25]=1)[CH3:33]
Reactant: CCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.046 mmol) in DMSO and acetic acid was added ethylamine (32 μL, 0.547 mmol). After 2 h, sodium triacetoxyborohydride (120 mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 11.5 mg of the title compound (55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:28]([OH:30])=O)[CH2:12]1)(=[O:10])=[O:9].[CH2:31]([NH:35][C:36](=[O:43])[C:37](=[O:42])[C@@H:38]([NH2:41])[CH2:39][CH3:40])[CH:32]([CH3:34])[CH3:33]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]3[C:28]([NH:41][C@@H:38]([CH2:39][CH3:40])[C:37](=[O:42])[C:36]([NH:35][CH2:31][CH:32]([CH3:33])[CH3:34])=[O:43])=[O:30])=[O:17])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: CC[C@H](N)C(=O)C(=O)NCC(C)C
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NCC(C)C

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-pentanoic acid isobutyl-amide in step 1. MS (m/e)=636.17 [M+H+].
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1Br
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ncccc2C=O)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as yellow solid. 2-(4-Methoxyphenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at rt. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the imine (2.72 g, 97%) which was used in next step without further purification. To a solution of this imine (2.7 g, 9.23 mmol) in 50 mL anhydrous DMF was added (0.190 g, 0.1 mmol) copper (I) iodide. The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with sat. aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark colored solid. Purification by column chromatography (Silica Gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl) [1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl) [1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The crude compound was adsorbed onto silica gel and purified by column chromatography (Silica Gel 230-400 mesh; 20-70% ethyl acetate in hexanes as fluent) to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. MS (ES) m/z: 223.95 (M+1), 222.95 (M); Mp. 219-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:12]1[C:20]([OH:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)[C:5](=[O:11])[NH:6]2.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:12]1[C:20]([OH:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cccc(Cl)c2C1c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a solution of 4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (6.00 g, 18.8 mmol) in anhydrous dichloromethane (70.0 mL) was added trifluoroacetic acid (30.7 g, 269 mmol) and triethylsilane (18.0 mL, 13.1 g, 113 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water (100.0 mL) and the solid was filtered. The solid was triturated with diethyl ether to afford 4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (4.71 g, 83%) as a colourless solid: mp 210-225° C. (dec.); MS (ES+) m/z 304.1 (M+1), 302.1 (M+1).
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].[CH3:8][N:9]([C:13](Cl)=[O:14])[C:10](Cl)=[O:11].[OH-].[Na+]>C1C=CC=CC=1.O>[CH3:8][N:9]1[C:13](=[O:14])[NH:7][CH:4]([S:5][CH3:6])[N:3]([CH3:2])[C:10]1=[O:11]
Reactant: CNC(=N)SC
Reactant: CN(C(=O)Cl)C(=O)Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CSC1NC(=O)N(C)C(=O)N1C
Yield: 75 %

Procedure:
23.2 g (0.1 mole) of N,S-dimethyl-isothiourea hydroiodide were initially introduced into 100 ml of water and 250 ml of benzene. 15.6 (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 12 g (0.3 mole) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from two dropping funnels with vigorous stirring. The reaction took place strongly exothermically. The mixture was stirred for a further hour, any product which precipitated was filtered off, and the benzene phase was separated off, dried over calcium chloride and evaporated in vacuo. The residue, together with the filter residue, was recrystallized from isopropanol. 14 g (75%) of 1,3-dimethyl-4-methylmercapto tetrahydro-1,3,5-triazine-2,6-dione were obtained as a colorless powder of melting point 137°-139° C.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC=CC=1>CCOCC>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: O=C=Nc1ccccc1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)NN1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 8 h

Procedure:
A stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole and 3.53 g of phenylisocyanate in 100 ml. of dry benzene is refluxed for 6 hours and then allowed to stand at ambient temperature overnight. Ether is added slowly to promote crystallization. The solid product is filtered, washed with ether and dried. The solid is recrystallized twice from a dimethylformamide water mixture to give crystals m.p. 168°-171° C. of 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-phenylurea.
Reaction SMILES: CC1(C)COB([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]4[C:19]([C:20]5[C:21]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][O:23][C:24]=5[CH3:25])=[N:18][N:17]=[C:14]43)=[CH:10][CH:9]=2)OC1.Cl[C:34]1[N:39]=[C:38]([C:40]([O:42]C)=[O:41])[CH:37]=[N:36][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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.O1CCOCC1>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[C:19]1[N:13]2[CH2:12][C:11]3[C:15]([C:14]2=[N:17][N:18]=1)=[CH:16][C:8]([C:34]1[N:39]=[C:38]([C:40]([OH:42])=[O:41])[CH:37]=[N:36][CH:35]=1)=[CH:9][CH:10]=3
Reactant: COC(=O)c1cncc(Cl)n1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(B3OCC(C)(C)CO3)cc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3cncc(C(=O)O)n3)cc1-2
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
A mixture of 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole (248 mg, 0.58 mmol) (as prepared in Example 26 Step (a)), methyl 6-chloropyrazine-2-carboxylate (100 mg, 0.58 mmol), dioxane (4.8 ml) and 2M aqueous Cs2CO3 solution (0.58 ml) was degassed with a stream of N2 for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.22 μmol) was added and the stirred mixture was heated at reflux for 1.5 h. The reaction was then cooled, allowed to stand for 15 min and the supernatent decanted off. The remaining salts were washed with further dioxane (5 ml) and then partitioned between water (20 ml) and CH2Cl2 (20 ml). The pH was adjusted to 6 by dropwise addition of 2N aqueous HCl and the aqueous phase was extracted with further CH2Cl2 (2×20 ml). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white amorphous solid (89.8 mg, 34%); 1H NMR (400 MHz, CDCl3) δ 9.63 (1H, s), 9.19 (1H, s), 8.81 (1H, s), 8.38 (1H, dd, J=8.2, 1.7 Hz), 7.75 (1H, d, J=8.2 Hz), 7.56–7.48 (5H, m), 4.67 (2H, s), 2.64 (3H, s); m/z (ES+) 437 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]2[C:6]([C:7](O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[N:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc2c(O)ccnc2n1
Product: CCc1ccc2c(Cl)ccnc2n1
Yield: 83 %

Procedure:
The product from Example 8e (200 mg, 1.14 mmol) was treated with POCl3 following the procedure from Example 7d giving the title compound as a brown solid (183 mg, 83%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].O>C(O)(=O)C>[Br:1][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:9]2)=[CH:5][C:4]=1[Cl:3]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1F
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 1.0 ml of bromine to 4.6 g of ethyl 5-chloro-3-(2-fluorophenyl)indole-2-carboxylate in 250 ml of glacial acetic acid. Stir for 16 hours at room temperature, add water and collect the precipitate. Ws the precipitate with warm methanol. Collect the dry ethyl 6-bromo-5-chloro-3-(2-fluorophenyl)indole-2-carboxylate, m.p. 193°-194°.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@H:10]2[C@H:15]([C:16]([OH:18])=O)[CH2:14][CH2:13][O:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:59][C:60]1[CH:72]=[CH:71][C:63]([CH2:64][C@@H:65]2[CH2:70][CH2:69][CH2:68][NH:67][CH2:66]2)=[CH:62][CH:61]=1>ClCCl>[F:59][C:60]1[CH:61]=[CH:62][C:63]([CH2:64][C@@H:65]2[CH2:70][CH2:69][CH2:68][N:67]([C:16]([C@@H:15]3[CH2:14][CH2:13][O:12][CH2:11][C@H:10]3[NH:9][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[O:18])[CH2:66]2)=[CH:71][CH:72]=1
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Reactant: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A cloudy solution of (3S,4R)-3-[(R)-1-Phenyl-ethylamino]-tetrahydro-pyran-4-carboxylic acid (containing sodium chloride; 943 mg, 2.57 mmol) in dichloromethane (25 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (1.61 g, 3.09 mmol) and triethylamine (826 μL, 5.92 mmol) and stirred for 5 minutes. A solution of the (S)-3-(4-fluorobenzyl)-piperidine prepared above in dichloromethane (5 mL) was added and the mixture was stirred at room temperature. After 18 h, the mixture was washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (75% ethyl acetate/hexanes) to provide the product as a gum (1.10 g, 100%).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1.[OH-].[Na+]>O1CCOCC1>[C:8]([O:7][C:6]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: OCCCC1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Temperature: 0 °C

Procedure:
A solution of 6 g of di(tert-butyl)carbonate in 20 ml of dioxan was introduced into a solution of 3.2 g of 3-(4-piperidinyl)propanol in 50 ml of dioxan containing 25 ml of a 2N aqueous solution of sodium hydroxide, cooled at 0° C. The mixture was allowed to react for 16 hours at room temperature. The solution was then evaporated and the residue was extracted with ethylether. The organic layer was washed with a 10% solution of KHSO4 and then dried over MgSO4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-:25])=[O:24])=[C:6]([CH:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:9](C(OC)=O)[C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N+:42]([O-:44])=[O:43])=[C:31]([CH:33]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][C:35]([OH:37])=[O:36])[CH:32]=1.[Cl-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-:25])=[O:24])=[C:6]([CH:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N+:42]([O-:44])=[O:43])=[C:31]([CH:33]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][C:35]([OH:37])=[O:36])[CH:32]=1
Reactant: COC(=O)CC(c1cc(Cl)ccc1[N+](=O)[O-])C(C(=O)OC)C(=O)OC
Agent: O=C(O)CC(CC(=O)O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC(CC(=O)OC)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Variant B: Adapting literature known protocols (Krapcho, Synthesis, 1982, 805-822 & 893-914; and Stowe, et al., Org. Lett., 2010, 12(4), 756-759), a solution of trimethyl 2-(5-chloro-2-nitro-phenyl)propane-1,1,3-tricarboxylate (18b′) (3.74 g, 10.0 mol) and sodium chloride (NaCl) (292 mg, 5.0 mmol) in a mixture of dimethylsulfoxide (DMSO) (23 mL) and water (780 μL) is heated to reflux for about 12 h. The reaction is monitored by TLC and/or analytical LC/MS to completion. Aqueous work-up and purification by silica gel column chromatography using ethyl acetate (EtOAc) and hexanes mixtures afford dimethyl 3-(5-chloro-2-nitro-phenyl)pentanedioate (18b″). Adapting literature known protocols (Nejman, et al., Tetrahedron, 2005, 61, 8536-854), 3-(5-chloro-2-nitro-phenyl)pentanedioic acid (18b) is prepared heating a solution of dimethyl 3-(5-chloro-2-nitro-phenyl)pentanedioate (18b″) (3.16 g, 10.0 mmol) in a mixture of 6.0 M hydrochloric acid (HCl) and 1,4-dioxane for about 12 h to reflux (105° C. oil bath temperature) to effect complete ester hydrolysis and decarboxylation. The reaction is monitored by TLC and/or analytical LC/MS to completion. The solvents are distilled off under reduced pressure using a rotary evaporator. Aqueous work-up and purification by crystallization from ethyl acetate (EtOAc) and hexanes mixtures afford the title compound (18b).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][N:21]=[C:22]2[N:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-c2cccnc2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4cccnc4)n3)cnc2n1
Yield: 23.8 %

Procedure:
6-Bromo-2,3′-bipyridine (0.37 g, 1.6 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-5%) and trituration with isohexane gave 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,3′-bipyridine (130 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.40 (1H, d, J 7), 7.50 (1H, dd, J 8 and 8), 7.72 (1H, d, J 8), 7.85 (1H, d, J 8), 7.97 (1H, dd, J 8 and 8), 8.30 (1H, m), 8.59 (1H, s), 8.75 (1H, m), 9.29 (1H, s), 10.51 (1H, d, J 7); m/z (ES+) 341 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Br[CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].CCN(C(C)C)C(C)C.[I-].[K+]>C(#N)C>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CC(=O)c1ccccc1N
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccccc1C(C)=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
1-(2-Aminophenyl)ethanone (250 mg, 1.85 mmol), ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol), DIPEA (0.32 mL, 1.85 mmol) and a catalytic amount of potassium iodide are dissolved in acetonitrile (4 mL) and heated under MW irradiation at 100° C. for 2 hours and then at 120° C. for 1 hour. Acetonitrile is evaporated and the crude is purified by flash chromatography (petroleum ether/EtOAc=93/7) to obtain intermediate I110 as a yellow oil (367 mg, quantitative yield).