Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=O.C(=O)([O-])N.[NH2:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:35])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]4)[CH2:20][CH2:19]2)[CH:13]=[CH:14][CH:15]=1.[C:36]([C:39]1C=C(N2CCC2=O)C=C[CH:44]=1)(=[O:38])C.CC1C=CC2C(=CC=CC=2N2CCN(CCC3C=C(C=CC=3)N)CC2)N=1>>[OH:35][CH:16]([C:12]1[CH:11]=[C:10]([N:9]2[CH2:44][CH2:39][C:36]2=[O:38])[CH:15]=[CH:14][CH:13]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[CH2:20][CH2:19]1
Reactant: CC(=O)c1cccc(N2CCC2=O)c1
Reactant: Cc1ccc2c(N3CCN(CC(O)c4cccc(N)c4)CC3)cccc2n1
Agent: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: NC(=O)[O-]
Agent: NC(N)=O
Product: Cc1ccc2c(N3CCN(CC(O)c4cccc(N5CCC5=O)c4)CC3)cccc2n1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield according to the general procedure for the synthesis of cyclic amide, urea and carbamate derivatives of 1-(3-aminophenyl)2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol (Method H) starting from 1-(3-acetylphenyl)-2-azetidinone (D10) and 2-methyl-5(1l-piperazinyl)quinoline (D3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C.C(O)(C)(C)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Cl)nc3ccnn23)c1
Temperature: 100 °C

Procedure:
To the reaction flask, 5,7-dichloropyrazolo[1,5-a]pyrimidine (1.6 g, 8.2 mmol) was added along with tert-butyl 3-aminobenzoate (1.7 g, 8.7 mmol), triethylamine (1.2 mL, 8.6 mmol), and t-butyl alcohol (22 mL). The reaction was heated at 100° C. for 6 hours then diluted with water, filtered and washed with water. The product, tert-butyl 3-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was collected as a solid in quantitative yield after drying under vacuum overnight. LCMS (M+1=345)
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]1([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1.[CH:15](O)=O.C=O.[OH-].[Na+]>O>[ClH:1].[CH3:2][N:3]([CH3:15])[C:4]1([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1
Reactant: CNC1(COc2cccnc2)CC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(C)C1(COc2cccnc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.07 g of the compound of Example 18 diluted with 1.2 ml of water are added to a solution, cooled to 0° C., of 1.38 g of formic acid, 1.12 ml of 37% formaldehyde in water and 0.15 ml of distilled water. The reaction mixture is heated at reflux for 16 hours and is then cooled to 0° C. and 10 ml of 4N sodium hydroxide solution are added. The mixture is extracted with ether. The organic phase is treated in customary manner and evaporated. The residue is taken up in ethanol, concentrated again and then diluted with 20 ml of ether and 4 ml of 4N hydrochloric acid solution in dioxane. The mixture is stirred for 20 minutes, filtered, rinsed with ether and dried, allowing the expected product to be isolated.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>CCCCCC.[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>[CH:1]1([N:4]([CH3:5])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: CN(Cc1cccc(I)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CN(Cc1cccc(C#C[Si](C)(C)C)c1)C1CC1
Yield: 79.4 %

Procedure:
Following General Procedure D and using cyclopropyl-(3-iodo-benzyl)-methyl-amine (Intermediate 89, 0.97 g, 3.4 mmol), triethyl amine (10 mL), copper(I)iodide (0.051 g, 0.27 mmol), trimethylsilyl acetylene (2 mL, 14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.27 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane-5% ethyl acetate in hexane as the eluent, the title compound (0.695 g, 80%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH2:49][CH2:50][O:51]C)(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.B(Br)(Br)Br.N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH2:49][CH2:50][OH:51])(=[O:47])=[O:48])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: COCCS(=O)(=O)Nc1cc(F)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(F)cc(NS(=O)(=O)CCO)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 83 %

Procedure:
(S)—N-(3-Fluoro-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-methoxyethanesulfonamide (29 mg, 0.03 mmol, 78% purity) was treated with boron tribromide (1M in dichloromethane, 303 μl, 0.30 mmol) with dichloromethane (580 μl) as a solvent according to the method described in Example 23. and then with a solution of ammonia (7N in methanol, 600 μl, 4.20 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 15 mg (82% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27]C(=O)C)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 37.4 %

Procedure:
60.1 g of the crude 3β-acetoxy-5-cholenic acid methyl ester was refluxed with a solution of 56.0 g of potassium hydroxide in 1.35 liters of methanol for two hours. The solution was cooled to room temperature and poured into 500 ml of 10% hydrochloric acid. The precipitate was isolated by filtration, washed with water and dried. The crude 3β-hydroxy-5-cholenic acid weighed 50.1 g. Of this, 20.3 g was refluxed for 22 hours with 2 liters of methanol containing 1 g of p-toluenesulfonic acid. The solvent was removed by distillation, the residue dissolved in ether, washed with dilute alkali and water, and the solvent evaporated. 20.3 g of 3β-hydroxy-5-cholenic acid methyl ester was obtained. On recrystallization from heptane the mp was 144°-145° C. Anal. Calcd for C25H40O3 : C, 77.27; H, 10.38. Found: C, 77.04; H, 10.01.
Reaction SMILES: [H-].[Li+].CN(P(N(C)C)(N(C)C)=O)C.CC(S)(C)C.C[O:20][C:21](=[O:50])[C:22]([CH3:49])([CH3:48])[CH2:23][C:24]1[N:25]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:26]2[C:31]([C:32]=1[S:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:29]([O:38]C)=[CH:28][CH:27]=2>CN(C=O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:25]2[C:26]3[C:31](=[CH:30][C:29]([OH:38])=[CH:28][CH:27]=3)[C:32]([S:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:24]2[CH2:23][C:22]([CH3:49])([CH3:48])[C:21]([OH:50])=[O:20])=[CH:46][CH:45]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)(C)S
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of LiH (12.6 g) and HMPA (105 mL) in DMF (1050 mL) at 0° C. was added 2-methyl-2-propanethiol (178 mL). The mixture was stirred at room temperature for 30 min, then 3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid methyl ester (150 g) (EP 419,049, Example 1, Step A) in DMF (450 mL) was added slowly. The mixture was slowly heated to 150° C. and kept at that temperature for 18 hours. After cooling to room temperature, the supernatant layer was decanted and the residue dissolved in H2O and acidifed with 1N HCl, extracted twice with Et2O, washed twice with brine, dried over MgSO4, filtered and evaporated to dryness to provide the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([Si:10]([CH3:22])([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([Si:10]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:1])=[CH2:19])=[CH:14][CH:13]=1)([CH3:22])[CH3:21])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Methyl(triphenylphosphonium) bromide (17.1 g, 48.0 mmol) was suspended in THF (96 mL) and cooled to 0° C. n-Butyllithium (2.5 M in hexane, 19.2 mL, 48.0 mmol) was added dropwise to the mixture. The red solution was stirred at rt for 0.5 h. 1-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethanone (10.0 g, 40.0 mmol) was added. The solution turned bright yellow and a white precipitate formed. The mixture was stirred for 1 h at rt and then the solution was quenched with saturated NaHCO3. The aqueous phase was extracted with diethyl ether and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, filtered and concentrated. The resultant mixture was eluted through a plug of silica gel (hexanes) and the filtrate was concentrated to provide tert-butyl-(4-isopropenyl-phenoxy)-dimethyl-silane (8.36 g, 84%) as a colorless oil. ESI MS (m/z 249, M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]([CH2:7][CH:8](C=C)[CH3:9])=[O:6])[CH3:3].[C:12](=[O:15])(O)[O-:13].[Na+].I([O-])(=O)(=O)=O.[Na+].[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(O)[O-].[Na+]>CC(C)=O.O.C1COCC1.O>[CH3:9][CH:8]([CH2:7][C:5](=[O:6])[CH2:4][CH:2]([CH3:3])[CH3:1])[C:12]([OH:13])=[O:15]
Reactant: C=CC(C)CC(=O)CC(C)C
Reactant: O=C([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)CC(=O)CC(C)C(=O)O
Temperature: 4 °C
Yield: 81 %

Procedure:
A mixture of dihydrotagetone (4) (3.53 g, 22.92 mmole), sodium bicarbonate (1.8 g, 21.43 mmole), sodium metaperiodate (22.84 g, 106.78 mmole), potassium permanganate (0.65 g, 4.11 mmole), alumina (0.8-1.2 g) and THF-water or acetone-water (20 mL, 1:3) was taken in a 250 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well for a while and then placed inside a microwave oven (Kenstar) operating at medium power (600 W) and irradiated for 2-20 minutes in parts. After completion of the reaction (monitored by TLC), the contents of the flask were poured into saturated solution of sodium bisulphite to destroy excess permanganate and resulting mixture was passed through a bed of Celite and further washed with aqueous acetone (40 mL×3, 3:1). The filtrate and washings were combined and the solution concentrated under reduced pressure to remove acetone. The mixture was cooled to 0 to 8° C. and acidified with dilute acid and then extracted with ethylacetate (3×25 mL). The ethylacetate layers were then combined, washed with saturated sodium bisulphite and sodium chloride (3×15 mL), dried over anhydrous sodium sulphate and then filtered. The solvent was removed to afford a crude product which was purified on silica column as above which afforded 2,6-dimethyl-4-oxo-heptanoic acid (3) in 81% yield as a viscous liquid. The physical and spectral data was found similar as above (Example II-i).
Reaction SMILES: C(OC([CH:11]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]2[NH:24][CH:13]([CH2:14][C:15](=[O:25])[CH2:16]2)C1)=O)C1C=CC=CC=1>CO.[Pd]>[NH:24]1[CH:13]2[CH2:11][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]1[CH2:16][C:15](=[O:25])[CH2:14]2
Reactant: O=C1CC2CC(C(=O)OCc3ccccc3)c3ccccc3C(C1)N2
Agent: [Pd]
Solvent: CO
Product: O=C1CC2Cc3ccccc3C(C1)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of carbamate (28) (1.13 g) in 100 mL of MeOH in a Parr bottle was added 500 mg of 10% Pd/C. This slurry was shaken under 50 psi of H2 (g) at room temperature overnight. The mixture was filtered through a pad of Celite and rinsed with CH2Cl2 (2×100 mL). The solution was concentrated to a crude yellow oil (29) (130 mg) and used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[N:6]=1.F[C:13]1[C:18]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:21]2[N:22]=[C:23]([CH3:25])[N:24]=[C:19]([C:18]3[C:13]([NH:11][C:8]4[CH:9]=[CH:10][C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH:7]=4)=[N:14][CH:15]=[CH:16][CH:17]=3)[N:20]=2)=[CH:42][CH:41]=1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4oc(C)nc4c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 2-methylbenzo[d]oxazol-5-amine (Bionet Research Intermediates) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown oil (100%). 1H NMR (400 MHz, CDCl3) δ 11.94 (s, 1H); 8.31 (br. s., 1H); 8.04 (br. s., 1H); 7.31-7.42 (m, 1H); 7.27-7.30 (m, 2H); 7.14-7.24 (m, 3H); 6.79-6.96 (m, 5H); 4.84 (br. s., 4H); 3.80 (d, J=9.6 Hz, 6H); 2.62 (br. s., 3H); 2.59 (br. s., 4H). m/z (ESI, +ve ion) 574.0 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5OC)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[Cl:32]C1C=CC=CC=1C[Zn+].O1C2C=CC(C3(C(NC4C=NC(Br)=CC=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:32])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Reactant: Clc1ccccc1C[Zn+]
Agent: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1ccc(Cc2ccccc2Cl)nc1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-chlorobenzyl)pyridin-3-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxybenzyl)pyridin-3-yl)cyclopropanecarboxamide from (2-chlorobenzyl)zinc(II) chloride and 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(CC)=N[NH:19][C:18]3=[O:24])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:25]([CH2:32][CH2:33]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:2][CH2:3][C:4]1[N:19]([CH2:33][CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18](=[O:24])[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)[N:8]=1
Reactant: ClCCOc1ccccc1
Reactant: CCc1n[nH]c(=O)n1CCCN1CCN(c2cccc(Cl)c2)CC1
Product: CCc1nn(CCCN2CCN(c3cccc(Cl)c3)CC2)c(=O)n1CCOc1ccccc1

Procedure:
Nefazodone and two processes for its preparation have) been described in Canadian Patent 1,198,436 and in PCT/EP93/03119 published May 26, 1994. The '436 patent relates to the preparation of 2-phenoxyalkyl-1,2,4 triazol-3-one derivatives Scheme 1 below depicts the two different methods described in the '436 patent. ##STR1## 5-Ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3-one, compound 1.3 is alkylated with 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine, compound 1.5 in the presence of base to give nefazodone. Alternatively, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl-5-ethyl-4H-1,2,4-triazol-3-one, compound 1.4, is alkylated with 2-phenoxyethyl chloride in the presence of base to give nefazodone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[S:25]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)Nc1cnccc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2cnccc2s1

Procedure:
A solution of ethyl 2-(4-chloropyridin-3-ylamino)-2-oxoacetate (R-2) (8 g, 35 mmol) and Lawesson's reagent (8.5 g, 21 mmol) in toluene (100 mL) was refluxed for 2 h, and then concentrated in vacuo. The residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 209 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C1(N2CCNCC2)C=CC=CC=1.[C:20]1([CH:26]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:27]([O:29][CH3:30])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])([O-])=O.[Cs+].[Cs+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CS(C)=O.C1C=CC=CC=1>[C:20]1([CH:26]([CH:31]2[CH2:36][CH2:35][N:34]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:33][CH2:32]2)[C:27]([O:29][CH3:30])=[O:28])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ncccn1
Reactant: COC(=O)C(c1ccccc1)C1CCNCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)C(c1ccccc1)C1CCN(c2ncccn2)CC1
Yield: 78 %

Procedure:
Following the same procedure as described in Example 15 (Scheme 15), step 1, but substituting compound 54 for 2-chloropyrimidine, compound 62 for compound 92, Cs2CO3/Pd(PtBu3)2 for potassium carbonate and benzene for DMSO, the title compound 93 (0.232 g, 78%) was obtained as a white solid. LRMS (ESI): (calc) 311.38 (found) 312.32 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][C:6]([CH3:12])=[CH:5][C:4]=2[C:3]=1[NH2:13].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[C:3]([NH:13][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(N)c(F)ccc2cn1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)c(F)ccc2cn1

Procedure:
Prepared from 6-fluoro-3-methylisoquinolin-5-amine (Description 79) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 378 (M+H)+.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:24]([OH:28])[CH:25]([CH3:27])[CH3:26].O>C1COCC1>[CH2:24]([O:28][CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH:25]([CH3:27])[CH3:26]
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Reactant: CC(C)CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21

Procedure:
To a solution of compound (6) (2.0 mmol) and anhydrous calcium carbonate (0.5 g) in dry THF (20 ml) was added dropwise a solution of an appropriate iso-butanol (10 ml) in dry THF (10 ml) under N2. The reaction mixture was refluxed for 3 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[CH:8]=1)[CH2:2][CH3:3].[CH:15](=O)[CH2:16][CH3:17]>>[CH2:1]([C:4]1[NH:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[C:8]=1[CH2:15][CH2:16][CH3:17])[CH2:2][CH3:3]
Reactant: CCC=O
Reactant: CCCc1cc(C)c(C(=O)OCC)[nH]1
Product: CCCc1[nH]c(C(=O)OCC)c(C)c1CCC

Procedure:
The crude product, obtained as in Example 74 but using 2-n-propyl-4-methyl-5-carbethoxypyrrole and propionaldehyde, was distilled (80° C 1 × 10-4 mm). The partially solidified distillate was dried on tile then recrystallized twice from aqueous ethanol as colorless needles (20%), m.p. 84°-87° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([CH:18]=[N:19][CH:20]=3)[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O1C=CC(C2N3C=NN=C3C(N3CCNCC3)=NC=2)=[CH:22]1>>[CH3:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]3[N:9]([CH:18]=[N:19][CH:20]=3)[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][N:12]=2)[CH2:2][CH2:3]1
Reactant: c1cc(-c2cnc(N3CCNCC3)c3nncn23)co1
Reactant: c1csc(-c2cnc(N3CCNCC3)c3cncn23)c1
Product: CN1CCN(c2ncc(-c3cccs3)n3cncc23)CC1

Procedure:
The title compound was prepared as described in Example 1 step 7, except that 8-(piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,5-a]pyrazine was substituted for 5-(furan-3-yl)-8-(piperazin-1-yl)-[1,2,4]-triazolo[4,3-a]pyrazine. 1H NMR (300 MHz, CDCl3) δ: 8.40 (s, 1H), 7.74 (s, 1H), 7.45 (dd, J=5.1, 1.2 Hz, 1H), 7.37 (dd, J=3.6, 1.2 Hz, 1H), 7.25 (s, 1H), 7.18 (dd, J=5.1, 3.6 Hz, 1H), 3.91 (t, J=5.1 Hz, 4H), 2.59 (t, J=5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 300 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:26][C:20]=4[S:19](=[O:37])(=[O:36])[N:18]=3)[C:7]2=[O:38])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O.ClCCl>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:26][C:20]=4[S:19](=[O:37])(=[O:36])[N:18]=3)[C:7]2=[O:38])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
The product of Example 384A (195 mg, 0.36 mmol) in a mixture of trifluoroacetic acid (5 mL) and dichloromethane (5 mL) was stirred for three hours at 25° C. The solvents were removed under reduced pressure. The residue was triturated with hexanes/ethyl acetate (1:1) and filtered to give title compound (114 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (d, J=7.35 Hz, 2 H) 1.02 (m, 1 H) 2.86 (d, J=6.25 Hz, 2 H) 4.88 (s, 2 H) 6.44 (s, 1 H) 7.39 (m, 3 H) 7.67 (d, J=8.82 Hz, 1 H) 7.89 (m, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (dd, J=1.47 Hz, J=6.62 Hz, 1 H) 13.16 (s, 1 H) 14.07 (s, 1 H) 15.12 (s, 1 H). MS (ESI−) m/z 483 (M−H)−.