Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[C:4]([O:6]C)=O.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:2]2[C:3]=1[C:4]([OH:6])=[C:14]([C:20]([O:22][CH3:23])=[O:21])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:1]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cc(Cl)cc(Cl)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of methyl 2-amino-4,6-dichlorobenzoate (1.30 g, 5.91 mM) and dimethyl acetylenedicarboxylate (0.96 g, 6.78 mM) in t-butanol (14 mL) was refluxed for 18 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and potassium t-butoxide (0.76 g, 6.8 mM) was added to the stirred mixture whereupon a precipitate formed. After refluxing for 1.5 hr, the reaction mixture was cooled to room temperature and filtered to separate the precipitated solids. The solids were washed with t-butanol and then dissolved in water. The resulting solution was acidified with 1N H2SO4 and the resulting precipitate was collected, washed thoroughly with water and dried to give the title compound as a light green solid (1.15 g, 59%). An analytical sample was obtained by recrystallization of a portion from toluene to provide the title compound as a light tan solid, mp 109.5°-111° C. (d); MS(CI): 330 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:14][CH2:15][C:16](=[O:23])[CH2:17][C:18](OCC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[K].[C:25]([C:29]1[CH:34]=[CH:33][C:32](CI)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:27])[CH3:26]>C(OCC)C.O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([CH2:18][CH2:17][C:16](=[O:23])[CH2:15][CH2:14][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CC(=O)CCC1CCCCCC1
Reactant: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCC(=O)CCC2CCCCCC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
454 mg (4.06 mmol) of potassium-t-butoxide were added to 10 ml of a tetrahydrofuran solution containing 1.00 g (4.16 mmol) of ethyl 5-cycloheptyl-3-oxovalerate (prepared as described in Preparation 5). The mixture was then stirred for 10 minutes to prepare the corresponding potassium salt. 1.11 g (3.47 mmol) of 2-t-butyl-5-iodomethyl-1-nitrobenzene (prepared as described in Preparation 51) were added to the mixture in an ice bath, and the mixture was stirred for 2 hours at the temperature of the ice bath. The reaction solution was diluted with diethyl ether and washed with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 10 ml of ethanol. 1.73 ml of a 2N aqueous solution of sodium hydroxide were added, and the mixture was heated for 4 hours under reflux. The reaction mixture was then cooled in an ice bath, sufficient concentrated aqueous hydrochloric acid was added to adjust its pH to a value of 5.0, and the mixture was heated for a further 2 hours under reflux. At the end of this time, the reaction solution was diluted with diethyl ether and washed with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 70 g of silica gel. Elution with a 2:1 by volume mixture of methylene chloride and hexane afforded 850 mg (yield 68%) of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([O:9]N2C(=O)CCC2=O)=O)[NH:5][CH:6]=1.[Cl-].[C:18]([C:20]1[CH:21]=[C:22]([C:27]#[C:28][CH2:29][NH2+:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])[CH:23]=[CH:24][C:25]=1[F:26])#[N:19].C([O-])(O)=O.[Na+]>CC#N.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N:30]([CH2:29][C:28]#[C:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([C:18]#[N:19])[CH:21]=2)[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])=[O:9])[NH:5][CH:6]=1
Reactant: COc1ccc(C[NH2+]CC#Cc2ccc(F)c(C#N)c2)c(OC)c1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Cl)c[nH]1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN(CC#Cc2ccc(F)c(C#N)c2)C(=O)c2cc(Cl)c[nH]2)c(OC)c1

Procedure:
A solution of F1 (1.5 eq), F2 (1 eq) and NaHCO3 (2.5 eq) in a mixture of CH3CN and H2O (20:1) was heated at reflux for 12 hrs and then the MeCN was removed under reduced pressure. The resulting residue was diluted with DCM, washed with 1N HCl solution (2×) and then with brine; dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by Biotage system eluting with EtOAc/petrol ether to obtain the desired compound. MS (ES) C24H19ClFN3O3 requires: 451, found: 452 (M+H)+. 1H NMR (400 MHz, DMSOd6) δ: 11.92 (1H, br. S), 7.91 (1H, dd, J=6.2, 1.9 Hz), 7.78-7.71 (1H, m), 7.54 (1H, t, J=9.0 Hz), 7.17-7.11 (1H, m), 7.07-7.04 (1H, m), 6.62-6.57 (1H, m), 6.56-6.20 (2H, m), 4.75 (2H, br. S), 4.46 (2H, br. S), 3.81-3.72 (6H, m).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[NH:15][C:14]([CH3:21])=[C:13]3[C:22]#[N:23])[CH:10]=2)[NH:5][N:4]=1)=[O:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[OH:2][CH2:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:13]([C:22]#[N:23])=[C:14]([CH3:21])[NH:15][C:16]([CH3:20])=[C:17]3[C:18]#[N:19])[CH:10]=2)[NH:5][N:4]=1
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C=O)c3c2)C(C#N)=C(C)N1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(CO)c3c2)C(C#N)=C(C)N1
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a suspension of 4-(3-formyl-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (200 mg, 0.66 mmol) in MeOH was added NaBH4 (50 mg) at rt. After 1 hr, the reaction was diluted with brine, extracted with EtOAc, washed with water, and dried. Concentration followed by purification through flash chromatography afforded 1,4-dihydro-4-[3-(hydroxymethyl)-1H-indazol-5-yl]-2,6-dimethyl-3,5-pyridinedicarbonitrile (100 mg, 50%) as a yellow solid (Cpd. No. 144, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=9.55 (s, 1H), 7.68 (s, 1H), 7.52 (d, 1H), 7.26 (d, 1H), 5.24 (t, 1H), 4.78 (d, 2H), 4.55 (s, 1H), 2.03 (s, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:53][C@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[OH:60])=[O:9]
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][C:29]1([NH:33]CC2C=CC=CC=2)[CH2:32][O:31][CH2:30]1>>[NH2:33][C:29]1([CH2:28][CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:32][O:31][CH2:30]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCC1(NCc2ccccc2)COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminoethyl)-N-benzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95-7.89 (t, 1 H), 7.89-7.87 (t, 1 H), 7.64-7.60 (m, 2 H), 7.49-7.45 (m, 1 H), 7.31 (d, J=8.4 Hz, 1 H), 7.24-7.21 (m, 1 H), 6.87 (t, J=10.4 Hz, 1 H), 6.05 (s, 1 H), 5.08 (s, 2 H), 4.39 (m, 6 H), 3.63 (t, J=9.2 Hz, 2 H), 3.41-3.36 (m, 2 H), 2.41 (s, 2 H), 2.35 (s, 3 H), 2.08 (t, J=14.4 Hz, 2 H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(N2CCN(C)CC2)c1
Yield: 81 %

Procedure:
A solution of (S)-{1-[3-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamic acid tert-butyl ester (3.4 g, 10.7 mmol) and hydrochloric acid (4N, 11 ml) in dioxane (40 ml) was stirred at 40° C. for 5 hours. The reaction mixture was concentrated under vacuum, dissolved into dichloromethane (100 mL), and based with SN NaOH. The organic layer was washed with brine (2×100 ml), dried over sodium sulfate and concentrated under vacuum to afford the title compound as an oil (1.90 g, 81% yield) which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[C:13]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:17][CH:16]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:28]([NH:30][NH2:31])=O>C(O)C>[F:1][C:2]([F:27])([F:26])[C:3]1[C:13]2[N:12]3[CH:28]=[N:30][N:31]=[C:11]3[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:17][CH:16]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NNC=O
Reactant: CCC(=O)Nc1ccc(C2=NCC(=S)Nc3c2cccc3C(F)(F)F)cc1
Solvent: CCO
Product: CCC(=O)Nc1ccc(C2=NCc3nncn3-c3c2cccc3C(F)(F)F)cc1
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 9-(trifluoromethyl)-1,3-dihydro-5-[p-(propionylamino)phenyl]-2H-1,4-benzodiazepine-2-thione is heated in ethanol with formic acid hydrazide and the resulting product heated to 250° C. to give 10-(trifluoromethyl)-6-[p-(propionylamino)pheyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[O:15]=[S:12]1(=[O:16])[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: O=S1(=O)CCC(NCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC1CCS(=O)(=O)CC1

Procedure:
N-Benzyl-1,1-dioxotetrahydro-2H-thiopyran-4-amine (2.00 g) was added to ethanol (40 mL) in a pressure bottle. Palladium hydroxide on carbon (0.587 g,) was added and the solution was stirred under 30 psi of hydrogen at room temperature for 2 hours. The mixture was filtered through a nylon membrane and the solvent was removed under vacuum.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:37]([F:40])([F:39])[F:38])[O:27][N:26]=[C:25]([C:28]3[S:32][C:31]([CH:33]([NH2:35])[CH3:34])=[C:30]([CH3:36])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:37]([F:39])([F:38])[F:40])[O:27][N:26]=[C:25]([C:28]3[S:32][C:31]([CH:33]([NH:35][C:1](=[O:4])[CH2:2][CH3:3])[CH3:34])=[C:30]([CH3:36])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NC(C)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 19 h
Yield: 30.9 %

Procedure:
Propionyl chloride (20 mg) and Hünig base (70 μl) are added to a solution of 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethylamine (60 mg) in dichloromethane (1 ml). After 19 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-(1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethyl)-propionamide (21 mg, compound 1.49 in Table 1) as a light yellow oil. MS (HPLC/MS): 479 (MH+). Retention time: 2.01 min.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(O)C>[ClH:1].[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C@H:10]3[C@H:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:4][CH:5]=4)[CH2:14][CH2:13][N:12]([CH2:5][CH2:4][CH2:3][CH2:8][CH3:7])[CH2:11]3)=[CH:18][C:19]=2[O:25]1
Reactant: CCCCCBr
Reactant: Oc1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCOc1ccc([C@@H]2CCN(CCCCC)C[C@H]2COc2ccc3c(c2)OCO3)cc1

Procedure:
was prepared by refluxing 4-(4-hydroxyphenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride (0.35 g) with 1-bromopentane (1.8 ml) and K2CO3 (1 g) in abs. ethanol (25 ml) for 2 h. The rinse-up procedure described in example 1 gave the title compound. M.p. 148.2° C.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:12])=[C:7]1[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1.C(Cl)Cl>O>[CH2:13]([C:11]1([CH3:12])[C:27]2[CH:26]=[CH:25][S:24][C:23]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(C)(O)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC1(C)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (1.33 mL) was added dropwise to 2-(2,2′-bithiophene-3-yl)undecan-2-ol (IIc) (0.70 g, 2.08 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ic) (0.106 g, 16.0%). 1H-NMR (CDCl3): δ=7.13 (d, J=4.8 Hz, 2H), 6.94 (d, J=4.9 Hz, 2H), 1.82-1.75 (m, 2H), 1.41 (s, 3H), 1.29-1.07 (m, 14H), 0.84 (t, J=6.6 Hz, 3H). 13C-NMR (CDCl3): δ=160.04, 136.50, 125.27, 121.95, 49.53, 39.66, 32.50, 30.63, 30.36, 30.20, 30.07, 29.91, 25.65, 24.36, 23.32, 14.77.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]1[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:13]2=[N:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Br:8][C:4]1[N:3]=[C:2]([N:17]2[CH2:16][CH2:15][N:14]3[C:10]([CH3:9])=[N:11][N:12]=[C:13]3[CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1nnc2n1CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1CCN(c1cccc(Br)n1)C2
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 2,6-dibromopyridine (434 mg, 1.832 mmol, Aldrich), 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (380 mg, 2.75 mmol, MolBridge) and potassium carbonate (253 mg, 1.832 mmol) in dioxane (1.8 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 4 h. The reaction was cooled to RT, H2O was added and the resulting precipitate was collected by filtration, washed with H2O and dried to give the crude product. MS (ESI, pos. ion) m/z: 294 (M+1).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)O)co1)NOCc1ccccc1
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
A solution of ethyl 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}4-cyclohexylbutyl)-1,3-oxazole4-carboxylate (Preparation 64) (1.31 g, 2.96 mmol) in 1,4-dioxane:water (10 ml:5 ml) was treated with lithium hydroxide monohydrate (0.19 g, 4.44 mmol) and stirred in a cold water bath for 3.5 hours. The mixture was diluted with water (100 ml) and washed with ethyl acetate. The layers were separated and the aqueous layer was acidified with solid citric acid then extracted with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (0.75 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH:28]([CH2:33][C:34]#[CH:35])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH:28]([CH2:33][C:34]#[C:35][C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]3=[N:6][CH:7]=2)[CH2:27]1)=[O:25])([CH3:20])([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Reactant: C#CCC1CN(C(=O)OC(C)(C)C)CCC1C
Product: CC1CCN(C(=O)OC(C)(C)C)CC1CC#Cc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Yield: 85.5 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (1.67 g, 5.09 mmol) and (+/−)-4-methyl-3-prop-2-ynyl-piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 5.09 mmol) were reacted under the same conditions as described in example 4 above. The crude product was adsorbed onto silica (10 g) and purified by silica gel chromatography, eluting with 5% to 30% ethyl acetate in hexanes to afford 2.11 g of (+/−)-4-methyl-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow viscous oil. MS (M+H)+=485.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:31]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.750 g, 2.2 mmol) in dry CHCl3 (100 mL), NBS (0.320 g, 1.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (700 mg) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5](OC)=[O:6].[NH3:16]>CN(C)C=O.C(OCC)(=O)C>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:6])[NH:16][CH2:2]2)([O-:15])=[O:14]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NCc2cccc([N+](=O)[O-])c21

Procedure:
1.5 g (5.473 mmol) methyl 2-bromomethyl-6-nitro-benzoate are dissolved in 20 ml N,N-dimethylformamide and combined with 15 ml of methanolic ammonia (7 mmol/ml). After 20 h at 25° C. the mixture is diluted with 100 ml of ethyl acetate and extracted 3 times with saturated sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[O:24]1[C:28]2[C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:29]2[C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=[CH:31][CH:30]=2)=[O:34])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1OCC2
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,3-Dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=479.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C=CCN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCCN1CCN(Cc2ccccc2)CC1
Yield: 60.6 %

Procedure:
A solution of methyl 4-(4-benzylpiperazin-1-yl)but-2-enoate (10.2 g, 0.04 moles) in methanol was added to 20% palladium hydroxide on carbon and placed under 40 psi hydrogen gas for 7 h. The resulting solution was filtered through celite and evaporated to afford methyl 4-(4-benzylpiperazin-1-yl)butanoate (6.70 g, 97%). MS (ESI+) for m/z 187 (M+H)+.