Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH3:15])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.C(=O)([O-])O.[Na+].[H][H]>CO.[Pd]>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:2][C:3]([O:14][CH3:15])=[CH:4][N:5]=2)[N:10]=1
Reactant: COc1ccc2ncc(OC)c(Br)c2n1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(OC)nc2c1
Yield: 94 %

Procedure:
8-Bromo-2,7-bis(methoxy)-1,5-naphthyridine (11.21 g, 41.673 mmol) was stirred in MeOH (400 mL) with sodium hydrogen carbonate (7.00 g, 83.35 mmol) and 10% palladium on carbon (2.8 g), and the resulting suspension was hydrogenated at 1 atmosphere of hydrogen pressure for 18 h. The mixture was filtered with suction through celite and the solids were washed with ethanol (300 ml). The filtrate was concentrated under reduced pressure and the residue treated with DCM (300 ml) and water (300 ml). The aqueous phase was extracted with DCM (2×300 ml). The combined organic phases were separated, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 2,7-bis(methoxy)-1,5-naphthyridine as a cream solid (7.45 g, 94%).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[OH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=O)=[CH:14][CH:13]=1.C(OCC)C>CCCCCC.O1CCCC1>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:18])=[CH:21][CH:22]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of n-butyl lithium in hexane (1.6M, 22.87 ml) was added to a solution of diethylamine (3.74 ml) in dry tetrahydrofuran (100 ml), at ambient temperature and under an atmosphere of argon. The reaction mixture was stirred for 15 minutes. Ethyl 4-hydroxybenzoate (5 g) was then added and the reaction mixture stirred for 16 hours. Diethyl ether was added to the reaction mixture and the mixture was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel (Merck Art No. 9385) using a 1:3 (v/v) mixture of ethyl acetate/hexane as eluent to give 4-hydroxy-N,N-diethyl benzamide as a solid (1.17 g), m.p. 122.5° C.; NMR ([CD3 ]2SO): 1.1-1.15(6H,t), 3.2-3.4(4H,m), 6.75-6.85(2H,d), 7.15-7.25(2H,d), and 9.7(1H,s); m/z 194(M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]2[CH:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N)C1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(NS(C)(=O)=O)C1

Procedure:
To a tetrahydrofuran solution (2.0 mL) of tert-butyl 5-amino-4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.342 mmol) synthesized in Reference Synthesis Example 202, triethylamine (52.0 μL, 0.374 mmol), and N,N-dimethyl-4-aminopyridine (2.00 mg, 0.0170 mmol) were added, and then methanesulfonyl chloride (29.0 μL, 0.374 mmol) was added at 0° C. with stirring, followed by stirring the resultant reaction solution for 2 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [CH2:1]1[CH:3]([C:4]([NH2:6])=[NH:5])[CH2:2]1.Cl.C(N(CC)CC)C.Cl[C:16](=[CH2:19])[C:17]#[N:18]>C(O)C>[CH:3]1([C:4]2[N:6]=[C:17]([NH2:18])[CH:16]=[CH:19][N:5]=2)[CH2:2][CH2:1]1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)C1CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccnc(C2CC2)n1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
Cyclopropylcarbamidine hydrochloride (1.0 g, 8.3 mmol) was dissolved in ethanol (25 mL) and triethylamine (1.26 g, 12.5 mmol), followed by the addition of 2-chloroacrylo-nitrile (870 mg, 10 mmol). The resulting orange-yellow solution was refluxed for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase Combiflash to afford 196a (300 mg, 27%) as a light brown solid. MS-ESI: [M+H]+ 136
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=O.[CH:15]1[CH:16]=[C:17]2[C:22]3=[C:23]([C:25]([NH:27][C:28](=[O:29])[C:21]3=[CH:20][CH:19]=[CH:18]2)=[O:26])[CH:24]=1>CN(C)C=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][N:27]3[C:28](=[O:29])[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]5[C:22]=4[C:23](=[CH:24][CH:15]=[CH:16]5)[C:25]3=[O:26])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: C=O
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1CN1CCN(c2ccccc2)CC1

Procedure:
An equimolar mixture of N-phenylpiperazine, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[(4-phenyl-1-piperazinyl)methyl]-1H-benz[de]isoquinoline-1,3(2H)-dione.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:14][NH:15][CH3:16].Cl.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[CH3:14][N:15]([CH3:16])[CH2:12][C:10]1[O:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: CNC
Reactant: O=Cc1ccc(-c2cccnc2)o1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.7 %

Procedure:
To a solution of 23 (54 mg, 0.31 mmol) was added a solution of dimethylamine (2.9 M, 0.65 mL, 1.89 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.16 mL, 0.63 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (20 mg, 0.31 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 48 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water, washed with Et2O (3×10 mL), adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 5/95, Rf=0.2) to afford the title compound 43 (23 mg, 37% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.91 (m, 1H), 8.46 (m, 1H), 7.94 (m, 1H), 7.28 (m, 1H), 6.68 (d, J=3.3 Hz, 1H), 6.32 (d, J=3.4 Hz, 1H), 2.31 (s, 6H); LRMS (ESI) m/z calcd for C12H15N2O [M+H]+ 203. found 203; m/z calcd for C10H8NO [M−N(CH3)2]+ 158. found 158; HRMS (ESI) m/z calcd for C12H15N2O [M+H]+ 203.1184. found 203.1205; HPLC>99% (tR=6.00 min, 60 (A):40 (B): 0.07 (C); tR=5.10 min, 60 (A):40 (B): 0.1 (C)).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH3:22])=[NH:10])[CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](OB(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(O)C>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:7]=1)=[NH:10]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1cccc(OC)c1CNC(=N)Nc1cccc(-c2ccc(F)cc2)n1

Procedure:
0.254 g (0.695 mmol) N-(6-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine, 0.128 g (0.913 mmol) 4-fluorophenylboric acid, 0.239 g (2.258 mmol) sodium carbonate, and 0.055 g (0.047 mmol) tetrakis-(triphenylphosphine)palladium(0) were heated to 110° C. in 1,2-dimethoxyethane/water/ethanol (7:3:2) in a reaction block (Variomag, Telemodul 40 CT) at standard pressure. Upon cooling of the reaction mixture a yellow solid precipitated, which was suctioned off and washed with water. After the yellow solid was dissolved in methanol and dichloromethane the catalyst was separated via a Millipore filter (Ø=25 mm, 0.45 μm). The target product N-(2,6-dimethoxybenzyl)-N′-[6-(4-fluorophenyl)pyridin-2-yl]guanidine was in the pure form after the removal of solvent, and the yield was 0.214 g (0.563 mmol, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[O:33]1[CH2:38][CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34]1>>[O:33]1[CH2:38][CH2:37][CH:36]=[C:35]([C:12]2[N:11]=[C:10]([F:22])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][S:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:6]=4)[CH2:34]1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2=CCCOC2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA1 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane MS m/z=464.9 [M+H]+. Calculated for C24H18F2N4O2S: 464.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[CH3:36]I.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:36])([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(C(F)(F)F)cc2)ccc1-c1cnc(C)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(C)c2ccc(C(F)(F)F)cc2)ccc1-c1cnc(C)o1
Reaction time: 0.5 h

Procedure:
To a mixture of 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (175 mg) in DMF (1.8 mL) was added sodium hydride (600, 17.2 mg) at 0° C., and the mixture was stirred for 30 min. Methyl iodide (0.0446 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (32.2 mg).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[C:6]1([CH2:16][NH2:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:23][CH:24]1[C:30]2[CH:31]=[C:32]([O:37][CH3:38])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:23][CH:24]1[C:30]2[CH:31]=[C:32]([O:37][CH3:38])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[CH2:28][CH2:27][CH2:26][N:25]1[CH2:2][C:3]([NH:17][CH2:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NCc1cccc2ccccc12
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2CC(=O)NCc2cccc3ccccc23)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with 1-naphtalenemethylamine and 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=[O:15])[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.[CH2:23](O)[CH2:24][CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[CH2:23][CH2:24][CH2:25][O:26][CH:14]1[C:13]1[CH:12]=[C:11]([N:10]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][C:8]([C:19]([F:20])([F:22])[F:21])=[N:9]2)[CH:18]=[CH:17][CH:16]=1
Reactant: OCCCO
Reactant: O=Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(C3OCCCO3)c2)n1
Yield: 78.5 %

Procedure:
To a stirred solution of 122 (3.25 g, 10.62 mmol) in PhMe (53 ml) was added 1,3-propanediol (1.616 g, 21.24 mmol) followed by p-toluenesulfonic acid monohydrate (0.202 g, 1.062 mmol) and the resulting solution was allowed to stir at reflux with a Dean-Stark trap for 16 h. The solution was evaporated to dryness, and saturated NaHCO3 aqueous solution was added and the mixture was extracted with EtOAc and the extracts were dried over Na2SO4 and evaporated. The residue was purified via Biotage (5% to 40% EtOAc/Hexane; 40+M column). The title product 146 (3.04 g, 8.34 mmol, 79% yield) was obtained as an off-white solid. LRMS (ESI): (calc.) 364.3; (found) 365.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:12])=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Se](=O)=[O:14]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]2[C:9]([CH:12]=[O:14])=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1cccc2occ(C)c12
Solvent: C1COCCO1
Product: COc1cccc2occ(C=O)c12

Procedure:
To a solution of 4-methoxy-3-methyl-benzofuran (J. Chem. Res. Synopses (1996),132) (4 g, 24.66 mmol) in 40 ml of dioxane is added selenium dioxide (3.39 g, 29.59 mmol) and the mixture is heated under reflux for 24 hours. It is then cooled and filtered. The solvent is evaporated and the crude red solid is used as such in the next step.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([C:9](=[O:11])[CH3:10])=[CH:7][N:8]=1.COC([O:17][CH3:18])OC.[C:19]([O-])(O)=O.[Na+]>C(O)CO>[Br:3][C:4]1[S:5][C:6]([C:9]2([CH3:10])[O:17][CH2:18][CH2:19][O:11]2)=[CH:7][N:8]=1
Reactant: CC(=O)c1cnc(Br)s1
Reactant: COC(OC)OC
Reactant: O=C([O-])O
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2cnc(Br)s2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanone (16.22 g, 78.71 mmol) in ethylene glycol (85 mL) was treated with trimethylorthoformate (18 mL, 164.19 mmol) followed by LiBF4 (1.51 g, 15.74 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. NaHCO3 was added and the mixture was extracted with Et2O (3×). The org. extracts were washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 3:1 hept-EA) gave the title compound as a yellow solid. TLC:rf (1:1 hept-EA)=0.63. LC-MS-conditions 02: tR=0.89 min; [M+H]+=250.24.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>C(Cl)Cl>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1)=[O:37]
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)Cc1cccs1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 88.7 %

Procedure:
Compound (II) (3.1 g, 7.8 mmole), 2-thiopheneacetic acid (1.14 g, 8.0 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.8 mmole) were stirred in 50 mL of methylene chloride for 12 hrs. at ambient temperature. The reaction was diluted with methylene chloride, washed with 1N hydrochloric acid, 1N NaOH, water and brine. Purification of the residue obtained on evaporation was accomplished with silica gel chromatography using 50% ethyl acetate in hexanes as the eluent to yield 3.6 g of the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]=2)[CH2:5][C@@H:4]([C:20](O)=[O:21])[NH:3]1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:46][C@H:47]([C:54]([N:56]1[CH2:63][CH2:62][CH2:61][C@H:57]1[C:58]([NH2:60])=[O:59])=[O:55])[CH2:48][C:49]1[N:53]=[CH:52][NH:51][CH:50]=1>C(N(CC)CC)C.CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:10]=2)[CH2:5][C@@H:4]([C:20]([NH:46][C@H:47]([C:54]([N:56]2[CH2:63][CH2:62][CH2:61][C@H:57]2[C:58]([NH2:60])=[O:59])=[O:55])[CH2:48][C:49]2[N:53]=[CH:52][NH:51][CH:50]=2)=[O:21])[NH:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N[C@H](C(=O)O)C2
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O)C2
Reaction time: 1.5 h
Yield: 33.3 %

Procedure:
A mixture of (3S)-1-oxo-7-tert.-butyloxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (680 mg), N-hydroxysuccinimide (280 mg), DCC (500 mg) and DMF (7 ml) is stirred for 1.5 hours. L-Histidyl-L-prolinamide.2HBr (990 mg) and triethylamine (1 ml) are added to the mixture. The mixture is stirred for 2 days. Insoluble materials are filtered off, and the filtrate is distilled under reduced pressure to remove DMF. The residue is dissolved in 20% citric acid, and washed with chloroform. The washed solution is adjusted to pH 9, and the solution is passed through a column (2.6×20 cm) packed with CHP-20P resin. The column is washed with water (one liter) and 30% methanol (1.5 liter) successively, and then the product is eluted with 50% methanol. The fraction positive to Pauly reagent are collected, and the collected solution is lyophilized, whereby Nα -[(3S)-1-oxo-7-tert.-butyloxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-L-histidyl-L-prolinamide (400 mg) is obtained. Yield: 33.3%.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:42]1[CH:43]=[CH:44][C:39]([CH2:38][CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=5)=[N:6][C:7]=34)=[O:13])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])=[CH:40][CH:41]=1
Reactant: Nc1cccc(S(=O)(=O)NCCc2ccncc2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCCc2ccncc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-pyridin-4-yl-ethyl)-benzenesulfonamide (example B.7) according to general procedure II. Yellow solid. MS (ISP) 615.3 [(M−H−]; mp 238° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:41](OC1C=CC([N+]([O-])=O)=CC=1)=[O:42].Cl.Cl.[NH2:55][CH2:56][CH2:57][C:58]1[N:62]=[CH:61][NH:60][CH:59]=1>ClCCl.CN(C)C=O>[C:17]([C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][C:41]([NH:55][CH2:56][CH2:57][C:58]2[N:62]=[CH:61][NH:60][CH:59]=2)=[O:42])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:6][CH2:7]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCc1c[nH]cn1
Reactant: CCCC(=O)C1(c2ccccc2)CCN(C(=O)[C@@H](N)Cc2ccc(OC)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(=O)C1(c2ccccc2)CCN(C(=O)[C@H](Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 100 mg (0.245 mmol) of 1-{1-[(S)-2-amino-3-(4-methoxy-phenyl)propionyl]-4-phenylpiperidin-4-yl}butan-1-one in 10 mL of dichloromethane are added 64 μL of diisopropylethylamine and then 74 mg (0.368 mmol) of 4-nitrophenyl chloroformate. The medium is stirred at room temperature for 1 hour 30 minutes. A solution containing 90 mg (0.489 mmol) of histamine dihydrochloride and 0.15 mL of diisopropylethylamine in 5 mL of dichloromethane and 2 mL of dimethylformamide is added to this mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[CH2:16][N:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)=[N:12]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(Br)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cnc3c(c2)c(-c2ccn(Cc4cc(F)cc(F)c4)n2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 37.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 63) (100 mg, 0.184 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 17) (65 mg, 0.22 mmol) using sodium carbonate (58 mg, 0.552 mmol) and Pd(PPh3)4 (10 mg, 0.0092 mmol) in toluene/ethanol/water (2/2/1 ml) to afford 46 mg (37.7% yield) after purification by preparative TLC (silicagel-1000 micron) using 40% ethyl acetate in hexane as eluent. MS: m/z=664.1 (M+1).