Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si](C(C)(C)C)(C)C)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[O:27]1
Reactant: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1)C(=O)OC(C)(C)C)O2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A stirred solution of methyl 2-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 82, 61 mg, 0.096 mmol) in MeOH (0.50 mL) was treated with HCl in dioxane (1 mL of a 4N solution in dioxane, Aldrich Chemical Co.) at room temperature and stirring continued for 60 minutes. The mixture was concentrated in vacuo and purified on silica gel using a gradient of 5-10% MeOH/EtOAc to provide 31 mg of product as colorless oil (77%); 1H NMR (DMSO-d6, δ): 1.65-2.04 (m, 2 H), 2.50-3.10 (m, 6 H), 3.65 (s, 3 H), 4.10 (dd, 1 H), 4.80 (d, 1 H), 6.80 (d, 1 H), 7.00 (bs, 2 H), 7.25-7.40 (m, 3 H), 7.42-7.52 (m, 1 H), 7.78-7.80 (m, 2 H), 8.52 (s, 1 H), 8.60 (s, 1 H); MS: m/z=419.3 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([C:23]([O:27][N:28]1N=NC2C=CC(=C[C:29]1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:23][O:27][N:28]([CH3:29])[C:17](=[O:19])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Reactant: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of Boc-β-(4-pyridyl)-L-alanine (75, 300 mg, 1.08 mmol) and NH(Me) OMe.HCl (1.2 eq., 1.30 mmol, 129 mg) in DCM (10 mL) was added HCTU (1.2 eq., 1.30 mmol, 536 mg) and DiPEA (3.5 eq., 3.78 mmol, 625 μL) and the mixture was stirred for 1 hour after which TLC analysis indicated complete conversion of starting material. The solvent was evaporated under reduced pressure en the residue was taken up in EtOAc, extracted with sat. aq. NaHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo. The title compound was obtained after purification by column chromatography (EtOAc->2% MeOH/EtOAc) as a pale yellow solid (yield: 334 mg, 1.08 mmol, quant.). 1H NMR (400 MHz, CD3OD): δ=8.40 (d, J=4.59 Hz, 2H), 7.29 (d, J=4.88 Hz, 2H), 6.97 (d, J=7.26 Hz, 1H), 4.77-4.68 (m, 1H), 3.76 (s, 3H), 3.15 (s, 3H), 3.02 (dd, J=13.59, 4.85 Hz, 1H), 2.83-2.77 (m, 1H), 1.32 (s, 9H) ppm. 13C NMR (100 MHz, CD3OD): δ=173.49, 157.58, 149.88, 149.50, 126.48, 80.55, 62.25, 52.71, 38.03, 32.49, 28.66 ppm. [α]D23=−2.9 (c=1, MeOH). HRMS: calcd. for C15H43N3O4 [M+H]+310.17613. found 310.17615.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[N+:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([O-:34])=[O:33]>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:38]3[CH:39]=[CH:40][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=3)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)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: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc([N+](=O)[O-])cc4)nc32)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.9 mmol), 4-nitrophenylboronic acid (0.73 g, 4.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.34 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (3 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with 1 M aqueous sodium hydroxide solution, once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was further purified by automated flash chromatography (methanol/dichloromethane) to provide tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate. MS (ES+): 536.3 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19](O)([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[C:13]([CH3:27])[N:12]=1)[CH3:2].O=S(Cl)Cl>N1C=CC=CC=1>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])=[C:13]([CH3:27])[N:12]=1)[CH3:10]
Reactant: CCCC(O)(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC=C(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]heptan-4-ol (0.6 g, 1.7 mmol) in anhydrous pyridine (10 mL) is added 1.5 mL of SOCl2 dropwise under nitrogen. The reaction mixture is stirred at room temperature for 3 h, quenched with a saturated aqueous NaHCO3 solution and extracted with DCM. The organic layer is washed with water, brine, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography eluting with 10% EtOAc-hexanes to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 7.24-7.29 (m, 1H), 7.13 (d, J=9 Hz, 2H), 5.39 (t, J=7.5. Hz, 1H), 3.91 (s, 3H), 2.46 (s, 3H), 2.24-2.43 (m, 6H), 1.28-1.33 (m, 4H), 1.10 (q, J=7.8, 4.8 Hz, 6H), 0.91 (t, J=7.2 Hz, 6H); LC-MS found 352 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#N)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.C(O)(=[O:28])C>CN(C=O)C.O.[Ni]>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:28])=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 60 °C

Procedure:
The crude (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonitrile was dissolved in DMF (10 mL). Pyridine (10 mL) and acetic acid (5 mL) were added, followed by NaH2PO2/H2O (1.76 g, 20 mmol/5 mL) and Raney-Nickel 2400 (slurry in H2O, 1 mL). The resulting mixture was heated at 60° C. for 1 h before cooling to rt. The mixture was diluted with H2O and extracted with EtOAc (50 mL×3). The combined extracts were dried (Na2SO4) and concentrated to give an orange liquid. H2O (50 mL) was added and the resulting suspension was sonicated, suction filtered, rinsed with H2O and dried to give crude (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (540 mg) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 10.15 (s, 1H), 8.57 (d, 2H, J=4.0 Hz), 8.40 (d, 1H, J=8.0 Hz), 8.20 (s, 1H), 7.89 (d, 1H, J=16.4 Hz), 7.73-7.68 (m, 3H), 7.55 (d, 1H, J=16.8 Hz); MS ESI 249.9 [M+H]+, calcd for [C23H16N4O+H]+ 250.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1>>[O:28]1[C:29]2[CH:30]=[CH:31][C:23]([CH2:22][N:32]3[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[C:8]3=[O:12])=[CH:24][C:25]=2[O:26][CH2:27]1
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 226 and using 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (400 mg) and piperonylamine.
Reaction SMILES: N#N.Br[CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCO.[Ni]>[N:10]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: N#CCCCCBr
Agent: [Ni]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCO
Product: NCCCCCN1CCCC1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 5-bromovaleronitrile (0.21 mL, 1.80 mmol), pyrrolidine (0.15 mL, 1.81 mmol), K2CO3 (498 mg, 3.60 mmol) and KI (60 mg, 0.36 mmol) in dry CH3CN (15 mL) was refluxed for 1 h. The mixture was filtered and concentrated under reduced pressure. A 0.05 mol/L solution of the crude nitrile (59 mg, 0.39 mmol) in EtOH (8 mL) was hydrogenated at rt using the H-Cube® (1 mL/min) with a Raney Nickel cartridge (30 mm) under 50 bar until completion of the reaction. The solution was then concentrated under reduced pressure to give crude 5-(pyrrolidin-1-yl)pentan-1-amine as a colorless oil. LC-MS-conditions 01: tR=0.16 min; [M+H]+=157.19.
Reaction SMILES: [CH2:1]([C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([O:14]CC)=[O:13])=[C:7]2[CH:6]=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:7]2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cnn2c(CC)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc2c(C(=O)O)cnn12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 0.40 g (1.83 mmol) of ethyl 7-ethylpyrazolo[1,5-a]pyridine-3-carboxylate, 8 ml of 2.5N aq. NaOH solution and 8 ml of ethanol were added, followed by stirring at 100° C. for 8 hours. After the reaction, post treatments were conducted in a similar manner to the syntheses bf the 5-methyl and 2,7-dimethyl derivatives so that crystals were obtained. Yield: 0.34 g (1.79 mmol) (98%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:23]=[CH:22][C:11]2[N:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13](=[O:16])[N:14]([CH3:15])[C:10]=2[CH:9]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:12]1[C:11]2[CH:22]=[CH:23][C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:10]=2[N:14]([CH3:15])[C:13]1=[O:16]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Br)cc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3ccccc3)cc21
Reaction time: 0.25 h

Procedure:
An aqueous solution of Cesium carbonate (54.8 mg, 0.17 mmol, 5.0 eq) in water (2 mL) was charged with a solution of 5-bromo-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-5, 10 mg, 0.034 mmol) and phenylboronic acid (8.21 mg, 0.067 mmol, 2.0 eq), then deoxygenated. The 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.37 mg, 1.68 μmol, 0.05 eq) was introduced and the mixture was irradiated in a microwave at 125 deg C. for 15 min. LC/MS showed complete conversion, so the reaction was partitioned between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (95 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present), affording the desired compound, 1-(2,2-dimethylpropyl)-3-methyl-5-phenyl-1,3-dihydro-2H-benzimidazol-2-one (1-6), with >95% purity. 1H NMR (300 MHz, CDCl3) δ 7.59 (d, 2H, J=7.3 Hz), 7.45 (t, 2H, J=7.3 Hz), 7.30-7.36 (m, 2H), 7.19 (s, 1H), 7.10 (d, 1H, J=8.2 Hz), 3.70 (8, 2H), 3.49 (s, 3H), 1.07 (s, 9H). LRMS m/z: Calc'd for C19H22N2O (M+H) 295.4, found 295.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1ccco1
Product: COC(=O)C=Cc1ccc(C(=O)OC)o1
Yield: 28 %

Procedure:
The reaction was carried out in the same manner as described in Example 21 except that 25 ml of 2-(methoxycarbonyl)furan and 0.939 g of methyl acrylate were used. Unreacted 2-(methoxycarbonyl)furan was removed from the obtained reaction solution by distillation under reduced pressure. Recrystallization of the solid residue gave 0.65 g of methyl β-(5-methoxycarbonyl-2-furyl)acrylate (4) (the yield was 28%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.C(N)(=O)C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:12][C:4]1[CH:3]=[C:2]([F:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([NH:42][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:8]
Reactant: NCCc1ccc(F)cc1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: NC(=O)c1ccccc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4,5-difluoro anthranilic acid (2.0 g, 11.6 mmol) in anhydrous THF (30 mL) was added hydroxybenzotriazole hydrate (HOBt) (1.56 g, 11.6 mmol), diisopropylethyl amine (2.01 mL, 11.6 mmol), and 4-fluorophenylethyl amine (1.52 mL, 11.6 mmol). After all of the HOBt had completely dissolved, EDCI (2.21 g, 11.6 mmol) was added and the resulting orange solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue was chromatographed on silica eluting with 15% EtOAc in hexanes giving the desired benzamide (2) as white crystals (3.07 g, 10.4 mmol, 90%).
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([CH3:17])[CH2:8][CH2:9][O:10][CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:15]1[CH:11]([O:10][CH2:9][CH2:8][CH:7]([CH3:17])[CH3:6])[CH2:12][CH2:13][C:14]1=[O:16])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CCOC1CCC(=O)N1C(=O)c1ccccc1

Procedure:
12.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.3 g of 5-(3-methylbutoxy) pyrrolidin-2-one in 140 cm3 of tetrahydrofuran. The mixture is maintained for 20 minutes at this temperature, then a solution of 2.7 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The solution is returned to ambient temperature, concentrated to dryness under reduced pressure and chromatographed on silica (eluent: hexane-ethyl acetate 7-3) 3.5 g of expected product is obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[Li]CCCC.CON(C)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:25].O>C1COCC1>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][C:11]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CON(C)C(=O)c1ccccn1
Reactant: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(C(=O)c3ccccn3)s2)c(C)[nH]c1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-ethyl-6-methyl-5-thiophen-2-yl-1H-pyridin-2-one prepared in accordance with the procedures of Example 24, Step 3 (100 mg, 0.456 mmol) in anhydrous THF (3 ml) is cooled to −78° C., and n-BuLi (2.5 M in hexane, 0.4 ml, 1 mmol) is added. The resulting dark green mixture is stirred for 20 min, and then N-methoxy-N-methylpyridine-2-carboxamide (83 mg, 0.5 mmol) in THF (1 ml) is added. The reaction mixture is then added to water (5 ml) and extracted with ethyl acetate. The organic phases are washed and dried, and the residue is purified on silica gel. The product is dissolved in a minimal amount of methanol and treated with HCl in diethyl ether. The resulting brown precipitate is filtered off with suction and dried (12 mg, as hydrochloride). MS: m/e=325 (M+H). 1H-NMR (D6-DMSO, δ ppm) 11.85 (s, 1H); 8.81 (d, 1H); 8.30 (d, 1H); 8.12 (m, 2H); 7.71 (m, 1H); 7.44 (s, 1H); 7.29 (d, 1H) 3.37 (m, 2H); 2.50 (s, 3H); 1.14 (t, 3H, J=7.4 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.Cl>>[OH:9][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[N:15]2[N:14]=[CH:13][CH:12]=[C:11]2[N:10]=1
Reactant: O=C(Nc1ccn[nH]1)c1cccnc1Cl
Agent: Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1nc2ccnn2c2ncccc12
Temperature: 25 °C

Procedure:
103 g. of 2-chloro-N-(1H-pyrazol-5-yl)-3-pyridinecarboxamide are suspended in 600 ml. of diphenyl ether and heated with stirring at 180° until the evolution of HCl gas ceases. After cooling to room temperature, 5-hydroxypyrazolo[1,5-a]pyrido[3,2-e]pyrimidine is filtered off, yield: 75 g. (88%); m.p. ≥ 300° (DMF).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16](O)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.[NH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]([CH3:50])[C:45]([O:47][CH2:48][CH3:49])=[O:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]([CH3:50])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C)CCCCN
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)CCCCNC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At RT, 72 μl (0.415 mmol) of DIEA were added to a solution of 148 mg (0.377 mmol) of (+)-cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid and 98 mg (about 0.66 mmol, crude material) of ethyl 6-amino-2-methylhexanoate in 1.0 ml of DMF. The resulting mixture was cooled to 0° C., and four portions of altogether 186.4 mg (0.49 mmol) of HATU were then added. The reaction mixture was slowly warmed to RT, stirred at RT for 16 h and then added to water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by preparative RP-HPLC (acetonitrile/water gradient) gave 134.0 mg (64.9% of theory) of the target compound as a diastereomer mixture.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:28][NH2:29])=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:29][CH2:28][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cnc(CN)c(C)c1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(CNc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(3,5-dimethyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:57]([C:59]1[CH:60]=[C:61]([N:65]2[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[C:66]2=[O:73])[CH:62]=[CH:63][CH:64]=1)[CH3:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:70]([CH:67]1[CH2:68][CH2:69][N:65]([C:61]2[CH:62]=[CH:63][CH:64]=[C:59]([CH2:57][CH3:58])[CH:60]=2)[C:66]1=[O:73])=[O:71]
Reactant: CCc1cccc(N2CCC(C(=O)O)C2=O)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)c1
Yield: 33.6 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.099 g; 0.428 mmol), PyBOP (0.335 g; 0.643 mmol), N,N-diisopropylethylamine (0.222 mL; 1.29 mmol) and 1-(3-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.428 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.059 g (33%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:23]([N:25]3[C:33]5C(=C[C:30]([C:34]6[C:35](C7C=CC(F)=C(C)C=7)=[N:36]C=CC=6)=[CH:31][CH:32]=5)C=N3)=[O:24])[N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:48].Cl>>[NH2:36][C@H:35]1[CH2:34][CH2:30][CH2:31][CH2:32][C@@H:33]1[NH:25][C:23]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([C:13]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:48])[CH:4]=4)=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1)=[O:24]
Reactant: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)n3ncc4cc(-c5cccnc5-c5ccc(F)c(C)c5)ccc43)c2)ccc1F
Agent: Cl
Product: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)N[C@H]3CCCC[C@@H]3N)c2)ccc1F

Procedure:
LCMS: rt 4.58 min (A), purity 94%, MS (m/e) 444 (MH+-HCl).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[NH:24][C:23](=[O:25])[C:21]3[C:22]4[C:14](=[CH:15][NH:16][C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH2:13]2)(=O)=O)=CC=1.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([N:33]2[CH2:38][CH2:37][N:36]([CH2:11][CH:12]3[NH:24][C:23](=[O:25])[C:21]4[C:22]5[C:14](=[CH:15][NH:16][C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH2:13]3)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c[nH]c4cccc(c34)C(=O)N2)cc1
Product: O=C1NC(CN2CCN(c3ccccc3)CC2)Cc2c[nH]c3cccc1c23
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2.2 g of 4-(p-toluenesulfonyloxymethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (for preparation see Example 7E) were mixed with 9 ml of 1-phenylpiperazine, and the mixture was stirred at a temperature of 80° C. for 4 hours. Subsequent cooling resulted in the crude title compound crystallising out. It was filtered out and washed with a mixture of equal parts of methanol and water. Drying resulted in 1.7 g of 4-(4-phenyl-1-piperazinylmethyl)- 3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole with a melting point of 184° to 185° C.