Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]N)=[CH:11][CH:10]=1.O>C(O)CCC>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccccn1
Reactant: NCCc1ccc(Br)cc1
Solvent: O
Solvent: CCCCO
Product: Nc1ncccc1CCc1ccc(Br)cc1
Temperature: 230 °C
Yield: 24.8 %

Procedure:
In a sealed tube, a mixture of 1.9 g (20.4 mmol) of 2-aminopyridine and 6.1 g (30.6 mmol) of 4-bromophenethylamine dissolved in butanol (10 ml) is heated at 230° C. for 1 hour by microwave. The mixture, cooled to room temperature, is poured into water (50 ml) and extracted with ethyl acetate (3×100 ml), and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate, from 0% to 50% ethyl acetate). 1.4 g of product are obtained in the form of a white powder. Yield: 24%. Melting point: 71° C. MH+: 278.1 (tr: 3.71 min., condition 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C([O:22][C:23]([C:25]1[N:30]2[C:31]([C:34](=[O:39])C(Cl)(Cl)Cl)=[CH:32][N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)=O)C>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:23](=[O:22])[C:25]3[N:30]4[C:31](=[CH:32][N:33]=[C:29]4[CH:28]=[CH:27][CH:26]=3)[C:34]2=[O:39])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Reactant: NCCc1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CCn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 1.63 g (12.0 mmol) of 2-[4-(amino)phenyl]ethylamine and 1.68 g (13 mmol) of N,N-diisopropylethylamine in 40 ml of acetonitrile was added a solution of 3.50 g (10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was stirred for one hour at room temperature. The resulting crystalline precipitates were collected by filtration, washed with acetonitrile and dried to afford 1.03 g of the desired compound (33.6%, a yellow crystals). The filtrate was concentrated. The residne was crystallized from acetonitrile-methylene chloride. Crystalline precipitatse were collected by filtration, washed with acetonitrile to afford 1.60 g of the desired compound (52.1%, a yellow crystals).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][CH:40]([OH:52])[CH2:41][N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1>C(Cl)Cl.O>[CH2:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:50][CH2:51][N:42]1[CH2:41][CH:40]([OH:52])[CH2:39][NH:38][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(C(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
A solution of 4-sulfamoylbenzoic acid (88.4 mg, 0.44 mmol), HATU (182.4 mg, 0.48 mmol) and TEA (48.48 mg, 0.48 mmol) in DCM (10 mL) was stirred at 22° C. for 10 min. 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (100 mg, 0.48 mmol) was then added and the solution was stirred at 22° C. for another 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (49.5 mg, Yield 29%). 1H NMR (CD3OD, 400 MHz): δ 7.92 (s, 4H), 7.16-7.09 (m, 3H), 7.05-7.02 (m, 1H), 4.14-4.12 (m, 1H), 3.77 (s, 2H), 3.58-3.39 (m, 2H), 2.94-2.91 (m, 2H), 2.90-2.86 (m, 2H), 2.75-2.66 (m, 2H). LCMS (m/z): 390.1 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
A solution of triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (114 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 72, 200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-aminopyridine (110 mg, 1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (175 mg, 73%) as a white foam: mp 99-101° C.; FAB-HRMS m/e calcd for C20H23BrN2O3S (M+H)+451.0692, found 451.0689.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>>[ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(O)CNc1cccs1
Reactant: CO
Agent: Cl
Product: COC(=O)CNc1cccs1
Temperature: 50 °C

Procedure:
Gaseous HCl is passed into a solution of 6.8 g of 2-thienylaminoacetic acid in 70 ml of methanol, and the mixture is heated at 50° C. for 6 h. The excess methanol and hydrochloric acid are stripped off in vacuo, and the solid residue is washed with methanol and dried in vacuo.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23]([NH:25][CH:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:18]([O:22][C:23](=[O:24])[NH:25][CH:26]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:35][CH:36]=1)[C:27](=[O:28])[N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: c1ccc(-c2cnc(C3CCCCN3)o2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N1CCCCC1c1ncc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.20 g (0.88 mmol) of 2-(5-phenyl-oxazol-2-yl)-piperidine, 0.36 g (1.05 mmol) of 2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.49 g (1.05 mmol) of PyBrop and 0.287 mL of diisopropylethylamine was added 1 ml of dimethylformamide. The resulting mixture was allowed to stir under argon at room temperature overnight. The following morning, LC analysis indicated that about 20% of starting material remained. An additional 0.09 g (0.26 mmol) of 2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.12 g (0.26 mmol) of PyBrop and 0.072 ml (0.45 mmol) of diisopropylethylamine was added. After stirring for 3 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The product was taken to the next step as is without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](F)([F:12])[C:7](F)([F:14])[CH:6]=[CH:5]2>O1CCCC1.[OH-].[NH4+].ClCCl.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([F:14])[CH:6]=[CH:5]2
Reactant: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C

Procedure:
Zinc (341 mg, 5.22 mmol) was added to a stirred mixture of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene (730 mg, 2.60 mmol) in tetrahydrofuran and concentrated ammonium hydroxide (4 mL) at 0° C. The mixture was allowed to warm slowly to room temperature. After 6 hours the reaction was diluted with 35 mL of dichloromethane and extracted. The organic layer was washed with water (2×30 mL) dried and concentrated. The residue was purified by chromatography on silica gel eluting with pentane:hexane (1:1) to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+]>[Pd].C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)n2nccc2n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn2nccc2n1
Yield: 77.9 %

Procedure:
A suspension of 7-chloro-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester (15.0 g), sodium acetate (6.54 g), and 10% palladium on carbon (665 mg) in ethyl acetate-ethanol (1-1.50 mL) was stirred under a hydrogen atmosphere. After the completion of the reaction, the reactant was filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, aqueous baking soda, and brine, dried with sodium sulfate, and concentrated in vacuo. The yellow residue was recrystallized to yield a light yellow needle crystal (9.9 g, 78%). mp:114-115° C.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>C(O)C.C(O)(=O)C>[Br:1][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:3]
Reactant: BrBr
Reactant: O=C(O)c1cccc(O)c1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Bromine (0.37 mL, 7.2 mmol) was added to 3-hydroxybenzoic acid (500 mg, 3.6 mmol) in ethanol (2 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 30 min and then concentrated and purified by column chromatography to give the product (314 mg, 40%). MS (DCI) m/z 234 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([N:28]([CH2:38][CH3:39])[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1)[CH3:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:38][CH3:39])[CH2:26][CH3:27])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)CCCC1CCCCN1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)CCCC1CCCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2-(3-diethylaminopropyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.09 minutes; C29H37Cl2N5O2 (558.55); mass spectrum: (M−H)−=558/560 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][N:62]1[CH:66]=[C:65]([CH2:67][C:68](O)=[O:69])[CH:64]=[N:63]1>CN(C)C(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:68](=[O:69])[CH2:67][C:65]6[CH:64]=[N:63][N:62]([CH3:61])[CH:66]=6)=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: Cn1cc(CC(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2cnn(C)c2)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 μL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 μL, 0.046 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in N,N-dimethylacetamide, 113 μL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to yield the title compound as an impure mixture. The material was dissolved in methanol (1 mL) and manually injected into the HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) give 0.0067 g (38%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.49 (d, J=2.44 Hz, 1H), 8.45 (d, J=2.75 Hz, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.57 (m, 2H), 4.60 (m, 2H), 4.07 (s, 3H), 3.81 (s, 3H), 3.55 (s, 2H). MS (APCI+) m/z 484.1 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:11]([CH:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1)=[O:13])[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)C1COc2ccccc2O1
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])C1COc2ccccc2O1
Yield: 33.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.91 g of 1,4-benzodioxane-2-carboxylic acid and 0.85 g of nitroxyethylamine nitrate, 0.45 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.O[C@@H]([C@@H](C1C=CC(OC)=CC=1)SC1C=CC=CC=1[N+]([O-])=O)C(O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Agent: COc1ccc([C@@H](Sc2ccccc2[N+](=O)[O-])[C@H](O)C(=O)O)cc1
Product: Clc1ccc([C@H](OC2CCNCC2)c2ccccn2)cc1

Procedure:
By treating (±)-4-[(4-chlorophenyl)(2-pyridyl)-methoxy]piperidine and (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)propionic acid in the same manner as in Example 4-(1), (2) and (3) to afford (S)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31](Br)[CH3:32])[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH:31]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH3:32])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(Br)c1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(C(C)c3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 52 mg (0.19 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 9 mg (0.23 mmol) of 60% sodium hydride, 60 mg (0.23 mmol) of 2-bromo-6-(1-bromo-ethyl)-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 32 mg of a white solid: LC-MSD, m/z for C25H21BrN2O2 [M+H]+=461.0, 463.0; HPLC retention time: 2.6 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([C:17](O)=[O:18])[N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[NH2:44][C@H:45]([C:49]([OH:51])=O)[CH2:46][CH2:47][SH:48]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([C:17](=[O:18])[NH:44][CH:45]3[CH2:46][CH2:47][S:48][C:49]3=[O:51])[N:13]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H](CCS)C(=O)O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](C(=O)NC1CCSC1=O)N(C(=O)OC(C)(C)C)C2
Reaction time: 16 h
Yield: 56.8 %

Procedure:
A solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,5-(S),6-tri-carboxylic acid 3,6-di-tert-butyl ester (0.30 g, 0.75 mmol) and triethylamine (0.21 mL, 1.51 mmol) in tetrahydrofuran (10 mL) was cooled to −20° C. before isobutyl chloroformate (0.103 mL, 0.75 mmol) was added. The reaction mixture was stirred 15 min at −20° C. before homocystein hydrochloride (116 mg, 0.75 mmol) was added. The cooling bath was removed and the reaction mixture was left for 16 hours at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography (SiO2, Flash 40, heptane/ethyl acetate 2:1) to give 212 mg (56%) of 2-amino-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[NH4+:14].[OH-]>C(O)(C)C>[NH2:14][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(OC[C@H]2CO2)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#Cc1ccc(OC[C@H](O)CN)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
4-[(2R)-Oxiranylmethoxy]benzonitrile (see step (i) above; 14.65 g, 83.6 mmol) was mixed with NH4OH (conc., 64 mL) and 87 mL of isopropanol. The mixture was stirred at rt for 18 h. The reaction mixture was then filtered and evaporated to give 14.6 g (91%) of the sub-title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(C#N)cc2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Cyano-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:28])[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c1ccccc1n2C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Yield: 117.1 %

Procedure:
A mixture of 4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (511 mg), NBS (354 mg), and BzOOBz (12.7 mg) in carbon tetrachloride (20 mL) was refluxed for 25 min; then cooled, solvents were removed, the residue was purified with column to give the title compound (773 mg). ESI MS (m/z): 349 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21](Cl)=[O:22])[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>ClCCl>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:21]([C:18]1[S:19][CH:20]=[C:16]([C:14]2[CH:13]=[N:12][C:11]3[N:10]([N:9]=[CH:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=2)[CH:17]=1)=[O:22]
Reactant: O=C(Cl)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Reactant: CN(C)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Reaction time: 8 h

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carbonyl chloride (5-4, 5.0 mg, 0.015 mmol, 1 equiv), diisopropylethylamine (60 TL, 0.030 mmol, 2.0 equiv), and N,N-dimethylethane-1,2-diamine (41 TL, 0.016 mmol, 1.1 equiv) in dichloromethane (1 mL) was mixed and allowed to stand for 8 hours. The reaction mixture was washed with aqueous half-saturated sodium bicarbonate solution (0.5 mL). The organic layer was dried over sodium sulfate and concentrated to give N-[2-(dimethylamino)ethyl]-4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxamide (5-5) as a yellow solid. LRMS m/z: Calc'd for C21H22N5OS (M+H) 392.2, found 392.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[N:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:12]1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:19][O:18][C:16]([C:13]1[N:14]=[CH:15][N:11]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)=[O:17]
Reactant: COC(=O)c1nc[nH]n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ncn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 12.1 g (77.1 mmol) 3-chlorophenylboronic acid and 10.0 g (77.1 mmol) methyl 1,2,4-triazole-3-carboxylate in 200 mL DCM was added 19.0 mL (235 mmol) pyridine followed by 14.0 g (77.1 mmol) copper (II) acetate. The reaction mixture was stirred at RT for 3 days, and then filtered over celite. The filtrate was washed with 1M aqueous KHSO4 solution and saturated aqueous bicarbonate solution. The organic layer was dried over sodium sulfate, concentrated in vacuo and dried.