Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16](O)[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9].[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>ClCCl.O>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ccc(C(COc2ccc(C=O)cc2)S(C)(=O)=O)nc1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
0.89 g (0.0088 mol) triethyl amine was added to a solution of 0.2 g (0.0007 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde and 0.098 g (0.0008 mol) mesyl chloride dissolved in 5 mL dichloromethane at 0-5° C. Reaction mixture was stirred at 0-5° C. for 4 hr. Progress of the reaction was monitored by TLC and after completion of reaction, substantial work-up in excess water yielded 0.18 g (70%) of the desired product. The product obtained was characterized by Mass and 1H NMR, which are as given below.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.CC(C)([O-:34])C.[K+]>C(O)(C)(C)C.COCCOC>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C:17](=[O:21])[C:18]([OH:34])([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: C[C@H](CCC(=O)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 40 °C

Procedure:
248 mg (0.6 m mol) of 1α,3β-dihydroxy-24-oxo cholesta-5,7-dien and 101 mg (0.9 m mol) of potassium-t-butoxide was dissolved in a mixture of t-butyl alcohol and ethyleneglycol dimethyl ether (1:1 V/V) warming at 40° C., and while cooling the solution with icewater to about 0° C. and stirring violently.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[CH:32]=3)[C:27]([CH3:43])([CH3:42])[CH2:26]2)=[O:24])[CH2:10][C@H:9]1[CH3:44])=O)(C)(C)C.[ClH:45]>CCOC(C)=O.O1CCOCC1>[ClH:45].[ClH:45].[F:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][C:31]1[CH:32]=[C:33]2[N:25]([C:23](=[O:24])[CH2:22][N:11]3[CH2:10][C@@H:9]([CH3:44])[NH:8][CH2:13][C@@H:12]3[CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[CH3:21])[CH2:26][C:27]([CH3:42])([CH3:43])[C:28]2=[N:29][CH:30]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccccc3F)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccccc4F)cc32)[C@@H](CN2CCOC[C@H]2C)CN1

Procedure:
(2R,5S)-4-{2-[6-(2-Fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.43 g, 2.35 mmol) was dissolved in EtOAc (34 mL) and 4 M HCl in dioxane (59 mL) and stirred at room temperature for 18 h. The solvent was removed in vacuo, then residue was re-dissolved in methanol and concentrated. The crude product was purified by recrystallisation (isopropanol/diethyl ether) to give the title compound (0.90 g). 1H NMR (DMSO-d6): 10.64-10.27 (1H, m), 9.97-9.64 (1H, m), 9.43-9.02 (1H, m), 8.23 (1H, s), 8.08 (1H, s), 7.43-7.35 (1H, m), 7.35-7.26 (1H, m), 7.22-7.13 (2H, m), 4.07-3.84 (8H, m), 3.69-3.30 (6H, m), 3.26-2.95 (4H, m), 2.91-2.82 (1H, m), 1.32 (6H, d), 1.28-1.13 (6H, m). MS: [M+H]+=510.
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[CH2:3][NH2:4].[CH:6]([CH:8]=O)=O>O>[CH3:1][CH:2]1[NH:5][CH:8]2[NH:4][CH2:3][CH:2]([CH3:1])[NH:5][CH:6]2[NH:4][CH2:3]1
Reactant: CC(N)CN
Reactant: O=CC=O
Solvent: O
Product: CC1CNC2NC(C)CNC2N1
Temperature: 5 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To an ice-cold solution of 148 grams, 2.0 moles, of 1-methylethylenediamine in 150 ml of water was added dropwise 145 grams of 40% aqueous glyoxal (58 grams, 1.0 mole). After the addition was completed, the solution was stirred at 5° C. for one hour, then at room temperature for 5 hours. The solution was evaporated on an open tray, and the resulting semi-solid was stirred in 500 ml of acetonitrile and filtered to give 76 grams (46% of product, m.p. 228°-235° C. (dec). Recrystallization from ethanol gave white crystals, m.p. 246-249 (dec.), literature m.p. 210° C.
Reaction SMILES: Br.C(O[C:5]([C:7]1[C:8]([Br:23])=[N:9][C:10]2[CH:11]=[C:12]3[O:22][CH2:21][CH2:20][O:19][C:13]3=[CH:14][C:15]=2[C:16]=1[CH2:17]Br)=[O:6])C.C(N(CC)CC)C.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl.O>[Br:23][C:8]1[C:7]([CH2:5][OH:6])=[C:16]([CH2:17][N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)[C:15]2[CH:14]=[C:13]3[O:19][CH2:20][CH2:21][O:22][C:12]3=[CH:11][C:10]=2[N:9]=1
Reactant: CCOC(=O)c1c(Br)nc2cc3c(cc2c1CBr)OCCO3
Reactant: CN1CCNCC1
Agent: Br
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2c(CO)c(Br)nc3cc4c(cc23)OCCO4)CC1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a mixture of 7-bromo-9-bromomethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid ethyl ester hydrobromic acid salt, prepared as in example 17 (10 g, 19.6 mmol) in dichloromethane (100 mL) is added triethylamine (5.4 mL. 39.2 mmol) followed by N-methylpiperazine (2.79 mL, 25.5 mmol). After stirring 30 min, water (50 mL) is added and the mixture is stirred 10 min. The layers are separated and the aqueous phase is extracted with dichloromethane (50 mL). The organic phases are combined and washed with water (2×50 mL). The organic solution is then concentrated to an oil. The oil is diluted with dichloromethane (50 mL) and stirred while diisobutylaluminum hydride (1.0M in dichloromethane, 53 mL. 53 mmol) is added slowly while keeping the reaction temperature below 30° C. using an ice bath. The reaction is stirred for 10 min and then slowly poured into an aqueous solution (75 mL) saturated with potassium sodium tartrate tetrahydrate (Rochelle's salt). The temperature is kept <30° C. with an ice bath during the addition. The mixture gels and is stirred overnight at room temperature. The layers are separated and the aqueous phase is extracted with dichloromethane (2×75 mL). The organics are combined and washed with water (2×50 mL). The organic phase is then concentrated under vacuum (crystallization occurs during concentration) to about 20 mL and the rest of the product crystallized out by adding tert-butyl methyl ether. The slurry is filtered and dried on high vacuum at room temperature overnight to provide 6.87 g (86%) of [7-bromo-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol as a tan solid. MP (184°-186° C.), HRMS calc for C18H22N3O3Br: 407.0841, Found: 407.0827.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]2=O)[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]2[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][NH:23][N:22]=2)[C:10]([OH:9])=[CH:11][C:12]=1[OH:13])[CH3:2]
Reactant: NN
Reactant: CCc1cc2c(=O)c(-c3ccccc3)coc2cc1O
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2n[nH]cc2-c2ccccc2)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 6-Ethyl-7-hydroxy-3-phenyl-chromen-4-one (0.29 g, 1.1 mmol), hydrazine hydrate (4 ml), ethanol (20 ml). The crude product was columned to give 4-Ethyl-6-(4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a off white solid (0.23 g, 74.73%); Rf 0.7 Cf SM 0.9 ethyl acetate/hexane (70/30).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>CC#N>[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cc1cccc(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2ccc([N+](=O)[O-])cc2Cl)n1
Temperature: 70 °C
Yield: 61.5 %

Procedure:
To 35 mL CH3CN was added (6-Methyl-pyridin-2-yl)-methanol (3.5 g, 28.4 mmol), followed by potassium carbonate (17.9 g, 129.6 mmol), and 2-Chloro-1-fluoro-4-nitrobenzene (6.48 g, 36.9 mmol). The suspension was stirred and heated at 70° C. for 30 h, after which time the bright yellow mixture was allowed to cool to rt. The contents were cooled to rt, filtered, and washed with CH2Cl2. The filtrate was concentrated in vacuo to a a light yellow solid which was triturated with Hex/EtOAc (5:1), yielding 2-[(2-chloro-4-nitrophenoxy)methyl]-6-methylpyridine (4.87 g, 61%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=O)[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:25]P(=O)(OCC)OCC)#[N:24].[H-].[Na+].O>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[CH:25][C:23]#[N:24])[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 6-(4-phenylbutoxy)-3,4-dihydronaphthalen-1(2H)-one (300 mg) in tetrahydrofuran (10 mL), diethyl cyanomethylphosphonate (199 mg) and sodium hydride (60%, 97.8 mg) were added, followed by stirring at room temperature for 24 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, concentrated and then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to thereby give the title compound (E/Z mixture, 207 mg) having the following physical properties.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](=[S:10])[NH2:9])[CH2:4][CH2:3]1.[CH3:12][O:13][C:14](=[O:22])[CH:15](Cl)[C:16](=O)[CH2:17][O:18][CH3:19]>C(O)C>[CH3:12][O:13][C:14]([C:15]1[S:10][C:8]([CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:11])[CH2:3][CH2:4]2)=[N:9][C:16]=1[CH2:17][O:18][CH3:19])=[O:22]
Reactant: NC(=S)C1CCC(F)(F)CC1
Reactant: COCC(=O)C(Cl)C(=O)OC
Solvent: CCO
Product: COCc1nc(C2CCC(F)(F)CC2)sc1C(=O)OC
Yield: 33.5 %

Procedure:
7.0 g 4,4-Difluoro-cyclohexanecarbothioic acid amide and 8.46 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester were dissolved in 70 ml ethanol and heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by silica chromatography with the eluent n-heptane:ethyl acetate=4:1=>2:1 to obtain 4.0 g 2-(4,4-Difluoro-cyclohexyl)-4-methoxymethyl-thiazole-5-carboxylic acid methyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH3:16])[C:7]2=[O:15].Cl.CCOC(C)=O.C(Cl)Cl>C(O)C.[Fe]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([Br:1])=[C:3]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[CH:5]=[CH:4]2
Reactant: Cn1ccc2c(Br)ccc([N+](=O)[O-])c2c1=O
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1ccc2c(Br)ccc(N)c2c1=O
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a solution of 5-bromo-8-nitro-2-methylisoquinolin-1(2H)-one (Compound 123B, 0.350 g, 1.2 mmol) in ethanol (15 mL) was added iron powder (0.5 g) and 2 N HCl (3 mL). The resulting mixture was heated at reflux for 2 h. TLC (EtOAc/CH2Cl2: 1:9) showed the reaction was complete. After cooled to room temperature, the reaction mixture was filtered, solids washed with ethanol/CH2Cl2 mixture. The combined filtrate was evaporated to dryness, neutralized with aq. Na2CO3 (20 mL), and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (20 mL), dried and evaporated to give a residue, which was purified by column chromatography on silica gel (EtOAc/CH2Cl2: 1:9)) to afford the desired product as a solid (0.120 g, 39%). 1H NMR (CDCl3, 300 MHz): δ=3.51 (s, 3H), 6.44 (d, J=7.8 Hz, 1H), 6.53 (br, 2H), 6.71 (d, J=7.8 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 78 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (5 g, 21.2 mmol) was added to a solution of 4-hydroxyacetophenone (2.87 g, 21.1 mmol), and K2CO3 (7.28 g, 0.052 mol) in DMF (50 mL). The mixture was heated at 80° C. for 15 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by flash chromatography eluting with (hexanes/ethyl acetate 70:30) to give the title compound (4.8 g, 77.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9](SC)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([N:21](CC)C(C)C)(C)C.N.O>CN1CCCC1=O.ClC1C=CC=C(C(OO)=O)C=1>[NH2:21][C:9]1[N:8]=[C:7]([NH:14][CH2:15][CH2:16][CH3:17])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=1
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Reactant: CCN(C(C)C)C(C)C
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCNc1nc(N)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(methylthio)-4-(propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1, 11.7 g) in N-methylpyrrolidone (90 mL), meta-chloroperbenzoic acid (70 to 75% wt, 20.8 g) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, N,N-diisopropylethylamine (23.9 mL) and 10% aqueous ammonia (60.0 mL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water (400 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain ethyl 2-amino-4-(propylamino)pyrimidine-5-carboxylate (C3, 8.0 g).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[NH:23][C:22]2=[O:37])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:42](=[O:46])[C:43]([O-:45])=[O:44])(C)(C)C.O>C1C=CC=CC=1>[OH:46][CH:42]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:37])[C:43]([O:45][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:44]
Reactant: O=C1NC(SCC#CCOC2CCCCO2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1

Procedure:
3-(Triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidin-2-one (934 mg) and t-butylglyoxylate (2.5 g) were refluxed in benzene (20 ml) with provision for the removal of water. After 1 hour the cooled solution was washed with water (6 × 5 ml), dried and evaporated. Chromatography on silica gave 1-(1-hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidine-2-one which still contained some t-butylglyoxylate. Re-chromatography on silica affored the pure material as an amorphous solid (519 mg) νmax (CHCl3) 3500, 3350, 1770, 1738 cm-1.
Reaction SMILES: Cl.[CH:2]1([C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][CH:21]([C:25]([NH:27][C:28]5[CH:29]=[C:30]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=5)[CH2:31][NH:32]C(=O)OC(C)(C)C)=[O:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:4][CH2:3]1>O1CCOCC1>[NH2:32][CH2:31][C:30]1[CH:29]=[C:28]([NH:27][C:25]([CH:21]2[CH2:20][CH2:19][C:18]3[C:23](=[CH:24][C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]([CH:2]5[CH2:4][CH2:3]5)=[O:6])[CH:13]=4)=[CH:16][CH:17]=3)[CH2:22]2)=[O:26])[CH:42]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:40]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3C2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3C2)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of 4M HCl in dioxane (30 mL) was added to tert-butyl [3-({[7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl}-amino)-5-(trifluoromethyl)benzyl]carbamate (3.80 g, 6.08 mmol). The suspension was allowed to stir for 2 h. The solvents were evaporated and the residue was purified by column chromatography to give N-[3-(aminomethyl)-5-(trifluoromethyl)phenyl]-7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-417 (2.60 g, 82%) as a white solid. The HCl salt was prepared by dissolving the solid in DCM and adding 2M HCl in Et2O. The solvents were evaporated. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 11.62-11.77 (m, 1H), 10.77 (s, 1H), 8.43 (br s, 2H), 8.22 (d, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.33 (s, 1H), 7.24 (d, 1H), 7.04-6.95 (m, 2H), 6.88-6.82 (m, 1H), 4.05-4.11 (m, 2H), 2.99-2.75 (m, 5H), 2.17-1.72 (m, 3H), and 0.91-0.80 (m, 4H). LCMS: (FA) ES+ 525.6, ES− 523.3.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH2:26]([CH2:33][C:34](=[O:36])[CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([CH2:35][C:34](=[O:36])[CH2:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCc3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
An oily suspension (50% by weight; 4.7 g) of sodium hydride is added at a temperature in the region of 0° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (15 g) in anhydrous dimethylformamide (280 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. A solution of benzylacetone (14.4 g) in anhydrous dimethylformamide (20 cc) is added and stirring is continued for 21 hours at a temperature in the region of 0° C. The reaction mixture is then poured into distilled water (1.5 litres). The pH of the aqueous phase is brought to approximately 5 by adding 4 N aqueous hydrochloric acid solution. The product i$ extracted with methylene chloride (3×500 cc). The organic phases are combined and washed with distilled water (3×80 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The oily residue obtained is purified by chromatography under pressure (50 kPa) on silica gel (0.040-0.063 mm; 200 g) contained in a column 2.8 cm in diameter. Elution is performed with methylene chloride, collecting 50-cc fractions. Fractions 9 to 21 are combined and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). After the solid obtained is recrystallized in ethanol, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(2-oxo-4-phenylbutyl)-1-isoindolinone (3.4 g), m.p. 180° C., is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:4][CH2:3][CH2:2][Br:1])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Yield: 70.4 %

Procedure:
1,3-Dibromopropane (6.78 mL, 66.8 mmol) is added to a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (4.15 g, 22.2 mmol) and diisopropylethylamine (7.73 mL, 44.4 mmol) in anhydrous 1,4-dioxane (40 mL). The resultant mixture is heated in an oil bath at 90° C. for 20 hours. At ambient temperature ethyl acetate (160 mL) and half-saturated aqueous sodium bicarbonate (NaHCO3) (120 mL) are added to the mixture. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated. The crude oil is subjected to chromatography on silica gel and eluted with 2 M NH3/MeOH in dichloromethane 0-3% to provide the title compound as a dark oil (4.80 g, 70% yield).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:12])[N:7]([CH3:11])[C:8](Cl)=[O:9])[CH3:4]>C(OCC)C.ClC(Cl)C>[CH2:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([N:7]([CH3:11])[C:8]([NH:2][CH3:1])=[O:9])=[O:12])[CH3:4]
Reactant: CCN(C(=O)N(C)C(=O)Cl)c1ccccc1
Reactant: CN
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CCN(C(=O)N(C)C(=O)NC)c1ccccc1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
In 30 ml of anhydrous ethyl ether, 6.2 g (0.2 mole) of methyl amine was dissolved and cooled below 0° C. Then a solution prepared by dissolving 24.1 g (0.1 mole) of 4-ethyl-2-methyl-4-phenylallophanoyl chloride in 80 ml of anhydrous dichloroethane was added dropwise under stirring. The reaction was continued at a room temperature for 1 hour, the reaction mixture was washed with water and dried with anhydrous sodium sulfate. The solvent was removed by distillation to obtain a residue, and the residue was recrystallized from ether-petroleum ether to obtain 17.6 g (yield 75%) of 1-ethyl-3,5-dimethyl-1-phenylbiuret having a melting point of 57°-58° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:29])[CH3:28])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:28])[CH3:29])[N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
6.2 g (15.5 mmol) of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 8.0 ml of Huinig base, dissolved in 50 ml of methylene chloride, are treated with 2.3 ml of valeryl chloride with stirring and further processed analogously to Example 29b. The title compound is thus obtained as a yellow oil which is further used in crude form (Rf 0.51, toluene-methanol 19:1)