Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.BrC[CH2:62][F:63]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH2:62][F:63])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: FCCBr
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2 S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a solid: MS (ESI+) for C25H26Cl2FN3O m/z 475 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41](C)[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].C([O-])(=O)C.[Na+].II.[OH-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-].[NH4+].[OH-]>CO.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([NH:41][CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: CC(=O)[O-]
Agent: II
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](NC)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50° C. followed by addition of iodine (I2) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes. Stirring was continuedfor 2 hours. TLC (CH2Cl2/MeOH/NH4OH 10:1:0.05) after 2 hours showed a single major product (Rf=0.66). The reaction was cooled to room temperature, poured into H2O (75 mL) containing NH4OH (1.5 mL) and extracted with CHCl3 (3×30 mL). The combined organic layers were washed with H2O (30 mL) containing NH4OH (1.5 mL), dried over Na2SO4 and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with CH2Cl2/MeOH/NH4OH 18:1:0.05 to 10:1:0.05 to provide compound 2 (0.41 g, 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH3:5])[CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: Cc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C=CC(=O)C=Cc2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
3-Methylbenzaldehyde (1ab, 3.00 ml, 25.4 mmol) and acetone (19, 0.94 ml, 12.7 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.50 g, 37.5 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 2.39 g (72%) of a yellow solid: mp 68-72° C. [expected mp 68-72° C.]; 1H NMR: δ 2.38 (s, 6H), 7.06 (d, 2H, J=15.9 Hz), 7.26 (m, 4H), 7.40 (m, 4H), 7.70 (d, 2H, J=15.9 Hz); 13C NMR: δ 21.3, 125.1, 125.4, 128.6, 128.8, 131.1, 134.6, 138.4, 143.1, 188.6.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH:8]([O:15]COCCOC)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:22][CH:23]=1
Reactant: COCCOCOC(CCCCC=O)COc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=CCCCCC(O)COc1ccc(F)cc1
Reaction time: 24 h
Yield: 81.9 %

Procedure:
(±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan-1-al 45 (2 g, 6.1 mmol) and 2 ml of trifluoroacetic acid are added to 10 ml of chloroform. The reaction mixture is stirred for 24 hours and then is neutralized with 1% aqueous NaOH. The organic layer is washed with water, brine, dried (Na2SO4), concentrated. The crude trifluoroacetyl-aldehyde 46 is then dissolved in MeOH:H2O (1:1) and solid K2CO3 is added to maintain pH 8. The reaction is complete is approximately 15 minutes, as monitored by TLC (ethyl acetate:hexane 3:7). Methanol is removed in vacuo and remaining solution is extracted with ethyl acetate to give (±)-7-(4-fluorophenoxy)-6-(hydroxy)-heptan-al 47 (1.2 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:15]1[C:27]2NC3C(=CC=CC=3)C=2C=C[CH:16]=1.BrBr.BrC1C=CC2[N-]C3C(C=2C=1)=CC=CC=3.[Na+].BrCC#C>>[CH2:27]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:15]#[CH:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: BrBr
Agent: Brc1ccc2[n-]c3ccccc3c2c1
Agent: C#CCBr
Product: C#CCn1c2ccccc2c2cc(Br)ccc21

Procedure:
Synthesis of 1,6-bis(N-3-bromocarbazolyl)-2,4-hexadiyne monomer was carried out by first preparing 3-bromocarbazole from carbazole and bromine. The product was converted to sodium 3-bromocarbazolide, which was then reacted with 3-bromo-1-propyne to give N-(2-propynyl)-3-bromocarbazole. Oxidative coupling of the propyne over cuprous chloride gave the desired monomer. Details of the reaction are given below.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]4[C:18](=[O:21])[CH2:19][CH2:20][C@@H:14]4[CH2:13]3)[CH2:9]2)C=CC=CC=1>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18](=[O:21])[CH2:19][CH2:20][C@@H:14]3[CH2:13]2)[CH2:11]1
Reactant: O=C1CC[C@@H]2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1CC[C@@H]2CN(C3CNC3)CCN12
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
(8aR)-2-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (0.23 g, 0.64 mmol) was dissolved in acetic acid (20 mL) and to the resultant solution was added palladium hydroxide on carbon (0.33 g). The mixture was stirred under hydrogen (5 bar) at RT for 48 h and then the catalyst was filtered off by means of Celite®. The solvent was removed by evaporation and the residue was dissolved in ethanol. The solution was filtered through a cation exchange column (Isolute SCX-2, 10 g). The column was washed with ethanol and then the product was eluted with ammonia-saturated methanol. The solvent was removed by evaporation and there was obtained 0.10 g (84%) of the title compound. 1H NMR (500 MHz, CDCl3): 1.5-1.6 (m, 2H), 1.8 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 2H), 2.7 (d, 1H), 2.8-2.9 (m, 2H), 3.2 (qn, 1H), 3.5-3.7 (m, 4H), 4.0 (dd, 1H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[C:8]=1[C:22]#[N:23]>C(O)C>[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[C:8]=1[C:22]([NH2:23])=[O:2]
Reactant: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C#N)c1N
Reactant: O=S(=O)(O)O
Solvent: CCO
Product: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C(N)=O)c1N

Procedure:
Another grouping present in these novel compounds, namely the 4-carbonitrile group, can also be utilized to prepare derivatives. This carbonitrile group can be readily hydrolyzed to the 4-carboxamido grouping by allowing the carbonitrile to react with concentrated sulfuric acid in absolute ethanol. Illustratively, when 5-amino-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile is allowed to react with concentrated sulfuric acid in absolute ethanol at steam bath temperature for about one hour, there is obtained 5-amino-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)-pyrazole-4-carboxamide.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24])=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:6]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:37]([O:36][C:34](=[O:35])[CH2:33][O:24][CH2:23][CH:22]([CH3:25])[CH2:21][O:20][C:18]1[C:19]2[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=3)=[C:12]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:13][C:14]=2[N:15]=[CH:16][N:17]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)CO)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)COCC(=O)OC(C)(C)C)c23)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Add 1.14 ml of 12.5 N sodium hydroxide solution to a solution of 500 mg (1.28 mmol) 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-2-methylpropan-1-ol in 10 ml toluene at 70° C. After adding 44 mg (0.13 mmol) tetra-n-butylammonium hydrogensulphate and 500 mg (2.56 mmol) tert.-butyl bromoacetate, stir the reaction mixture for 20 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid and extract three times with 50 ml dichloromethane each time. Wash the combined organic extracts with satd. aqueous sodium chloride solution, dry over sodium sulphate, filter, and concentrate by vacuum evaporation. Purify the raw product by preparative RP-HPLC (gradient: water/acetonitrile). 298 mg (46% of theor.) of the desired product is obtained as racemate.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[CH:12]=[C:11]2[S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:42])[C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)(=[O:22])=[O:21])(=O)=O)C=CC=CC=1.[OH-].[K+].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl.CO>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[C:11]([S:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:42])[C:30]4[CH:31]=[CH:32][C:33]([C:36]5[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=5)=[CH:34][CH:35]=4)[CH2:25][CH2:24]3)(=[O:22])=[O:21])[NH:10]2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3n2S(=O)(=O)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3[nH]2)CC1
Reaction time: 2 h

Procedure:
In tetrahydrofuran (4.0 ml), 1-[(1-phenylsulfonyl-6-chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine (380 mg) was dissolved, followed by the addition of methanol (4.0 ml) and potassium hydroxide (34.3 mg) at room temperature. The resulting mixture was stirred for 2 hours. To the reaction mixture, a saturated aqueous solution (30 ml) of ammonium chloride was added to make it weakly acidic. Then, a saturated aqueous solution (40 ml) of sodium bicarbonate was added to make the resulting mixture to weakly alkaline. The resulting mixture was added with dichloromethane (30 ml). The organic layer thus separated was extracted further with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue thus obtained was purified by preparative thin-layer chromatography on a silica gel (dichloromethane:acetone:methanol=20:2:1), followed by recrystallization from a mixed solvent of hexane and dichloromethane, whereby the title compound (157 mg, 53%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CCCCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)on1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2CC2CCCCC2)on1
Temperature: 60 °C

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (0.2 g; 0.731 mmol) in N,N-dimethylformamide (4 mL) is added bromomethyl-cyclohexane (0.153 mL; 1.097 mmol), potassium iodide (0.032 mg, 0.197 mmoL), and potassium carbonate (0.505 g; 3.655 mmol). The mixture heated at 60° C. for 7 days. After this time, the mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organics are washed with water, 1N hydrochloric acid and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material is purified by preparative reverse phase HPLC to afford title compound. ESI m/z 334 [M+H]+
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C([N:27](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:14]1[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=[C:9]([CH:13]=1)[C:10]([NH2:27])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 148.5 %

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid 38 (120 mg, 0.38 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and HBTU (151 mg, 0.40 mmol) was stirred at room temperature for 0.5 h. To the above solution was added a solution of the orange oil from step 7 (207 mg, 0.57 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield an oily residue. Purification by flash column chromatography (silica, 90:10 methylene chloride/methanol) gave N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[({2-(dimethylamino) methyl]pyridin-4-yl}methyl)amino]-2-hydroxypropyl}-5-(1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamide (178 mg): mp 63–66° C.; ESI MS m/z 663 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[NH2:15]O.Cl>O.CCO>[C:6]1([C:2]2[O:1][N:5]=[C:4]([NH2:15])[CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a stirred solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) and NaOH (452 mg, 11.3 mmol) in water (10 mL)/EtOH (10 mL) was added hydroxylamine hydrochloride (785 mg, 11.3 mmol). The mixture was stirred at 80° C. for overnight. At this point, conc. HCl (1.3 mL, 15.5 mmol) was added and the resulting mixture was heated at 80° C. for 2 h. It was then basified to pH 10 and extracted with ethyl acetate. The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with ethyl acetate/petroleum ether (1:50 to 1:10) to afford 299a as a yellow solid (1.1 g, 68%). MS-ESI: [M+H]+ 161.3.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2>CC(C)=O>[CH3:26][O:25][C:24]1[C:15]([NH:14][C:2]([NH2:3])=[S:1])=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2
Reactant: COc1ccc2ncccc2c1N
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc2ncccc2c1NC(N)=S

Procedure:
1.7 g or ammonium thiocyanate are dissolved in 50 ml of acetone, 2.5 ml of benzoyl chloride are then added and the reaction mixture is heated at reflux for 15 minutes. 2.9 g of amine (Compound 14), dissolved in 20 ml of acetone, are added and the reaction mixture is then heated to reflux for 30 minutes. Evaporation is carried out to dryness and the residue is taken up in water and then extracted with ethyl acetate. The residue is deprotected by treatment with 5 ml of 33% ammonia in 10 ml of ethanol at reflux for 2 hours. The precipitate formed is separated off by filtration, the filtrate is evaporated and the residue is triturated with a 75/25 (v/v) ethyl acetate/hexane mixture, to obtain 3.5 g of white powder. 1H NMR (CDCl3): 3.93 (s, 3H, --OCH3), 7.50-7.53 (m, 1H, H3), 7.70 (d, 1H, J=9.5, 1H, H7), 8.00 (d, J=9.5, 1H, H4), 8.08 (d, 1H, H8), 8.75 (d, J=2.5, 1H, H2).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.CS([Cl:34])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:34][C@@H:6]1[CH2:7][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:14][CH:15]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCCN1CCc1ccc(N2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl[C@@H]1CCCN(CCc2ccc(N3CCCC3)cc2)C1
Reaction time: 2 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-pyrrolidinophenethyl)pyrrolidine (4.96 g, 19.1 mmol) was dissolved in 70 ml of dichloromethane. 3.21 g (24.8 mmol) of diisopropylethylamine and 2.84 g (24.8 mmol) of methanesulfonyl chloride were added to the obtained solution under stirring under cooling with ice. They were stirred under cooling with ice for 1 hour and then at room temperature for 2 hours. The reaction mixture was distributed into dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-pyrrolidinophenethyl)piperidine in the form of a light yellow solid (3.23 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[C:22]([O:28][CH2:29][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C@@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc([C@@H](C)c2nccn2COC(=O)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of the compound of Example 1 (120 mg, 0.6 mmol) and potassium carbonate (246 mg, 1.8 mmol) in dimethylformamide (4 ml) was added chloromethyl pivalate (215 μl, 1.5 mmol) and the reaction mixture stirred at room temperature overnight. Water (10 ml) was added and the mixture then extracted with ethyl acetate (2×10 ml). The organic layers were combined, washed with water (10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×21.2 mm LUNA C18(2) 5 μm column) using an acetonitrile:water gradient [50:50 to 95:5]. The appropriate fractions were concentrated in vacuo to give the title compound (136 mg).
Reaction SMILES: O[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:20]1([CH:2]2[O:19][C:5]([C:6]3[C:7]([O:12][C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4][CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(NCC(O)c1ccccc1)c1cccnc1Oc1cccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc(C2CN=C(c3cccnc3Oc3cccnc3)O2)cc1
Temperature: 25 °C
Yield: 10.2 %

Procedure:
A solution of N-(2-Hydroxy-2-phenyl-ethyl)-2-(pyridin-3-yloxy)-nicotinamide (0.450 grams, 1.3 mmole) and phosphorus oxychloride (1.25 ml, 13 mmole) in toluene (5 ml) was stirred over night. The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate (0.500 g) was added. The mixture was stirred at room temperature over night. The mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, and concentrated to give an oil that was purified by chromatography on silica gel eluting with ethyl acetate to give a colorless oil (0.042 g). HRMS 318.1269; 1H NMR (400 mHz, CDCl3) d 4.09 (dd, J=15.1 Hz, 8.1 Hz, 6H), 4.57 (dd, J=15.1 Hz, 10.3 Hz, 1H), 5.67 (dd, J=10.2 Hz, 7.9 Hz, 1H), 7.09-7.13 (m, 1H), 7.32-7.39 (m, 6H), 7.54-7.57 (m, 1H), 8.20-8.22 (m, 1H), 8.29-8.31 (m, 1H), 8.46 (dd, J=4.6 Hz, 1.0 Hz, 1H), 8.61-8.64 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].CCN(CC)CC.CN(C1C=CC=CN=1)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl.O>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8])=[O:31]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1sccc1N
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1ccsc1C(N)=O
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A solution of 3-aminothiophene-2-carboxamide (0.90 g, 6.3 mmol), Et3N (0.97 mL, 7.0 mmol), and dimethylaminopyridine (0.15 g, 1.3 mmol) in CH2Cl2 (21 mL) was cooled in an ice bath, and 2-methoxybenzoyl chloride (1.1 g, 6.3 mmol) was added dropwise. The reaction was stirred for 1 h, and water (20 mL) was added. The solids were filtered, washed with water, and dried under vacuum to give 3-(2-methoxybenzamido)thiophene-2-carboxamide (1.4 g, 79% yield). LC/MS: m/z 277.3 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).