Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17].Cl>>[O:11]=[C:6]1[N:7]([CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[CH:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C(O)CCl
Reactant: O=c1[nH]ccc2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ncccc2c1=O
Temperature: 100 °C

Procedure:
To 1,6-naphthyridin-5(6H)-one (0.625 g, 4.28 mmol) was added 5 M sodium hydroxide solution (1.7 mL) followed by chloroacetic acid (0.404 g, 4.28 mmol). The reaction mixture was heated at 100° C. for 2 h. After cooled down to ambient temperature and neutralized with 2 N hydrochloric acid (2.1 mL), the title compound was collected by filtration as a yellow solid. 1H NMR (DMSO-d6): δ 13.1 (s, 1H), 8.94 (dd, J=4.6, 1.8 Hz, 1H), 8.51 (dd, J=8.0, 1.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.52 (dd, J=8.0, 4.6 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 4.72 (s, 2H). LC/MS 205.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:3]1.[C:17]1([C:23]#[C:24][Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:1][C:2]1([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3][C:4]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]2)[O:5][CH2:6]1
Reactant: Br[Mg]C#Cc1ccccc1
Reactant: CCOC(=O)N1CCC2(CC1)CC(=O)CO2
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CC1)CC(O)(C#Cc1ccccc1)CO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a solution of ethyl 2-oxo-4-oxa-8-azaspiro[4.5]decane-8-carboxylate (Edwin S. C. Wu, Ronald C. Griffith, James T. Loch III, Alex Kover, Robert J. Murray, George B. Mullen, James C. Blosser, Anthony C. Machulskis, Sally A. McCreedy, J. Med. Chem., 1995, 38 (9), pp 1558-1570, 82 mg, 0.362 mmol) in THF (4 mL) was added dropwise a 1M solution of phenylethynylmagnesium bromide in THF (0.724 mL, 0.724 mmol), stirring at r.t. under anhydrous nitrogen atmosphere. The reaction mixture was stirred at r.t. for 4 h, then at 60° C. for 6 h, then it was quenched with a saturated aqueous solution of ammonium chloride, extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 75:25 to 4:6) affording the title product as yellow solid. Yield: 87.2%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[C:3]=1[Cl:10].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:18])[CH:5]=[C:4]([Br:9])[C:3]=1[Cl:10]
Reactant: Cc1cc(Br)c(Cl)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: Clc1c(Br)cc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To 1,3-dibromo-2-chloro-5-methylbenzene (1000 mg, 3.52 mmol) was added NBS (688 mg, 3.87 mmol) and AIBN (57.7 mg, 0.352 mmol). The mixture was stirred at room temperature for 30 minutes and then heated to 80° C. overnight. The solution was evaporated and the residue was purified by silica gel chromatography (0-5% EtOAc/heaxnes) to provide the title compound (740 mg) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][NH:5][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Cl)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNc1ccc(Cl)cc1OCc1ccccc1

Procedure:
A solution of [(2-benzyloxy-4-chlorophenyl)-tert-butoxycarbonylamino]-acetic acid methyl ester (14.95 g, 36.8 mmol) in 180 mL of TFA/methylene chloride (1:2) is stirred at RT for 45 min. The solvent is removed under reduced pressure and the residue is dissolved in EtOAc (500 mL). To this solution is added diisopropylethylamine (13.11 g) and the resulting precipitate is filtered. The filtrate is evaporated to give the title compound as a tan solid. (M+1)=306.
Reaction SMILES: S([C:5]1C=[CH:10][C:8](C)=[CH:7][CH:6]=1)(O)(=O)=O.[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:20][C:19]=2[Br:29])=[O:15].CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]1[N:28]=[C:7]([C:8]3[N:27]=[CH:26][N:25]([CH3:21])[CH:10]=3)[CH:6]=[CH:5][N:27]=1)=[CH:20][C:19]=2[Br:29])=[O:15]
Reactant: CN(C)C(=O)c1cc2cc(NC(=N)N)cc(Br)c2[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cc(Nc3nccc(-c4cn(C)cn4)n3)cc(Br)c2[nH]1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.6 g 4.6, 2.2 g 7.12 and 2.5 g potassium tert-butoxide in 30 ml N,N-dimethylformamide was stirred at 150° C. for 1.5 h under microwave irradiation. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (dichloromethane/methanol 100:0→90:10) to give intermediate 10.1/Example 15.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>C1COCC1.BrC1C=CC(OC(F)(F)F)=CC=1>[F:11][C:10]([F:13])([F:12])[O:9][C:6]1[CH:7]=[CH:8][C:3]([B:14]([OH:19])[OH:15])=[CH:4][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of magnesium (3.25 g) in THF (25 mL) at room temperature was treated with several drops of 1-bromo-4-(trifluoromethoxy)benzene, stirred for several minutes, treated with THF (100 mL), treated with 1-bromo-4-(trifluoromethoxy)benzene (30.8 g), heated to reflux, stirred for 16 hours, treated with triisopropyl borate (34 mL) over 10 minutes, stirred for 1 hour, cooled to 0° C., treated with 6M HCl (50 mL), stirred for 45 minutes, and extracted with isopropyl acetate. The extract was washed with brine, filtered, and concentrated to provide 21.5 g of 4-(trifluoromethoxy)phenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](C(N)=O)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of trans-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (119 mg, 0.333 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (133 mg, 0.402 mmol), Na2CO3 (88.3 mg, 0.833 mmol), Pd(PPh3)4 (23.1 mg, 0.0200 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 22 h. To the cooled reaction solution was added water (10 mL), the mixture was extracted with EtOAc (3×15 mL), the combined organic layers were washed with water (2×10 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as light yellow solid. Chromatography of the mother liquor on silica gel (8 g, eluting with 2%→4%→6%→8%→10% MeOH in CH2Cl2) gave an additional batch. Both batches contained a small amount of the corresponding cis isomer (see below for its independent synthesis). 1H NMR (CDCl3, 400 MHz): δ=2.70-2.78 (m, 2 H), 2.97-3.08 (m, 2 H), 3.21-3.26 (m, 1 H), 5.66-5.72 (quintet, 1 H, J=8.4 Hz), 6.54 (brs, 2 H), 7.08 (s, 1 H), 7.59 (s, 1 H), 7.68-7.78 (m, 3 H), 7.94-7.98 (m, 1 H), 8.12 (s, 1 H), 8.26-8.28 (d, 1 H, J=8.4 Hz), 8.32-8.37 (m, 3 H), 8.48-8.53 (m, 2 H), 8.66-8.68 (d, 1 H, J=8.8 Hz). MS (ES+): 435.2 [MH+]. HPLC: tR=2.3 min (polar—5 min).
Reaction SMILES: C(=O)=O.C(O)C.Cl[C:8]([F:12])=[C:9]([F:11])[F:10].Cl[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16].C([Li])CCC>C1COCC1>[CH2:15]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:8]([F:12])=[C:9]([F:11])[F:10])[CH3:16]
Reactant: FC(F)=C(F)Cl
Reactant: CC[Si](Cl)(CC)CC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Product: CC[Si](CC)(CC)C(F)=C(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A reactor flushed with argon gas was cooled with a dry ice-ethanol cooling medium, and 2.03 g (0.0174 mol) of chlorotrifluoroethylene was introduced into the reactor. To this reactor, 17 ml of THF was introduced to bring the chlorotrifluoroethylene concentration to 1 mmol/ml, and then 2.35 g (0.016 mol) of chlorotriethylsilane was added. The reactor was cooled to -78° C., and 12 ml (0.018 mol) of butyllithium (1.47M hexane solution) was added in 1 hour. The mixture was stirred at 78° C. for 4 hours and at room temperature for about 1 hour. Workup was conducted in the same manner as in Example 1, whereby 2.64 g (86.2%) of triethyltrifluorovinylsilane was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=2)[CH:8]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Oc2cnc3ccccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-hydroxyphenoxy)quinoline (2.4 g), ethyl 2-bromopropionate (2.1 g), anhydrous potassium carbonate (3.3 g) and dimethylformamide (50 ml) was stirred and heated at 80° C. for 4 hours. The mixture was poured into water (500 ml) and extracted with diethyl ether (2×100 ml). The ether extracts were dried, evaporated to dryness and then chromatographed on silica gel (100 g) with dichloromethane elution. Ethyl 2-[4-(3-quinolinyloxy)phenoxy]propionate was obtained as a pale yellow oil (1.9 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.75 (1H, d); 8.1 (1H, bd); 7.7-7.3 (4H, m); 7.0 (4H, s, phenoxy protons); 4.75 (1H, q, CH-CH3); 4.25 (2H, q, OCH2 -CH3); 1.65 (3H, d, CH-CH3); 1.25 (3H, t, OCH2 -CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25]([O:27]C(C)(C)C)=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[CH:10]=[CH:9]2.C(O)(C(F)(F)F)=O.[Cl:40][C:41]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:50])[C:42]=1C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25](=[O:27])[C:42]1[C:41]([Cl:40])=[CH:49][N:48]=[CH:47][C:46]=1[Cl:50])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[CH:10]=[CH:9]2
Reactant: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cncc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
Methyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate (compound No 26, international patent application WO 03/093237) (500 mg, 1.05 mmol) was dissolved in DCM (5 ml) and a solution of TFA (0.8 ml, 10.5 mmol) in DCM (2 ml) was added drop wise over 10 minutes. After addition was complete the reaction was stirred at RT over night. The reaction was cooled to 0° C. and TEA (2.1 ml, 15.8 mmol) in DCM (2 ml) was added drop wise over 10 minutes. The reaction was cooled to −10° C. and 3,5 dichloro-isonicotinoylchloride (Bioorg. Med. Chem. Lett. 2002, 12, 1591-1594), (663 mg, 3.0 mmol) was added drop wise over 10 minutes, before allowing the reaction to warm to RT. After 1 hour the reaction was washed with aqueous HCl (1N, 10 ml), followed by washing with aqueous NaHCO3 solution (saturated, 10 ml). The DCM layer was dried over MgSO4, filtered and the solvent removed in vacuo to yield an off white solid. The solid was purified using flash chromatography (eluent EtAc) to yield the title compound as a white powder (432 mg, 75%) LCMS M+1 (552, 550, 548), Retention Time 3.82 min, 1H NMR, 300 Mz, d6-DMSO-9.50 (1H, d), 8.63 (2H, s), 8.42 (1H, d), 7.98 (1H, d), 7.94 (1H, d), 7.78 (1H, dd), 7.65 (2H, d), 7.55 (2H, m), 4.95 (1H, m), 3.74 (3H, s), 3.45 (1H, dd), 3.20 (1H, dd).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:17]1[C:22]([NH:23][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Oc2ncccc2N)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1cccnc1Oc1cccc(CCNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 54.3 %

Procedure:
A mixture of tert-butyl[2-[3-(3-amino-2-pyridyloxy)phenyl]ethyl]carbamate (3.3 g, 10 mmols), ethyl 4-bromobutyrate (2.8 ml, 20 mmols), potassium carbonate (1.4 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[3-[2-(tert-butoxycarbonylamino)ethyl]phenoxy]-3-pyridyl]aminobutyrate (2.41 g, 54.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH:24]=[CH2:25].O>CN(C)C=O>[CH2:23]([NH:26][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:28])[CH:24]=[CH2:25]
Reactant: C=CCN=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in N,N-dimethylformamide (5 ml), allyl isocyanate (0.2 ml) was added, and the admixture was stirred at 80° C. for 15 hours with heat. Water was added to the reaction mixture, the admixture was extracted 2 times with ethyl acetate, and the organic layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 61 mg of the title compound (yield: 96%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][C:6]=1[CH:7]=O)([O-:4])=[O:3].N1CCCCC1.C(O)(=O)[CH2:26][C:27]([OH:29])=[O:28]>N1C=CC=CC=1>[N+:2]([C:5]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][C:6]=1[CH:7]=[CH:26][C:27]([OH:29])=[O:28])([O-:4])=[O:3]
Reactant: O=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Yield: 87.6 %

Procedure:
2-Nitro-5-piperazinylbenzaldehyde hydrochloride (47 g) was dissolved in 500 ml of pyridine and 5 g of piperidine and 100 g of malonic acid were added to the solution followed by heating under reflux for 5 hours. After cooling, crystals which formed were collected by filtration to give 42 g of 2-nitro-5-piperazinylcinnamic acid, m.p. 229°-237° C.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:13](C(OCC)=O)=[O:14])[CH2:11][CH3:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:30]([NH2:32])[CH3:31]>C(Cl)(Cl)Cl.CO>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:13]([NH:32][CH2:30][CH3:31])=[O:14])[CH2:11][CH3:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCN
Reactant: CCOC(=O)C(=O)[C@H](CC)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCNC(=O)[C@H](CC)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 64 %

Procedure:
This compound was synthesized from protected α-ketoester derived from Z-Leu-Abu-CO2Et and ethylamine in 64% yield by the procedure described in Example PKC47. Single spot on TLC, Rf =0.36 (CHCl3 /CH3OH 50;1); mp 130°-132° C. Anal. calcd. for C21H31N3O5 : 405.45; C, 62.20; H, 7.71; N, 10.36. Found: C, 61.92; H, 7.62; N, 10.31. NMR (CDCl3) ok. MS (FAB) m/e=406 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[S:5][C:6]=1[Br:7].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15])[S:5][C:6]=1[Br:7]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(Br)c(Br)s1
Product: CN(C)C=CC(=O)c1cc(Br)c(Br)s1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A mixture of 1-(4,5-dibromo-2-thienyl)ethanone (9.7 mmol) and N,N-dimethylformamide dimethyl acetal (44.8 mmol) was refluxed for 3 h and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 3.24 g (94% yield) of 1-(4,5-dibromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccccc1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)c1nc(Oc2ccccc2)c2ccccc2c1O
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 1.399 g of 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (5 mmol) and 2.86 g of phenol was heated at 145° C. to 150° C. for 24 h. After cooling to ambient temperature the mixture was suspended in 50 ml of aqueous 2N NaOH and the mixture was extracted with 4×25 ml of ethyl acetate. The combined organic phases were washed with 3×25 ml of aqueous 2N NaOH, 50 ml of brine, dried over MgSO4, and evaporared in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (9:1) and (95:5). 0.650 g of the title compound were obtained; 1H NMR (CDCl3): δ=11.52 (s, 1H), 8.32 to 8.39 (m, 2H), 7.72 to 7.86 (m, 2H), 7.13 to 7.42 (m, 5H), 4.31 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=2[S:5][CH:6]=1.[C:12]([Cu])#[N:13]>N1C=CC=CC=1>[C:12]([C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=2[S:5][CH:6]=1)#[N:13]
Reactant: N#C[Cu]
Reactant: Cc1cccc2c(Br)csc12
Solvent: c1ccncc1
Product: Cc1cccc2c(C#N)csc12

Procedure:
3 g of 3-bromo-7-methylbenzo[b]thiophene and 1.1 g CuCN are dissolved in dry pyridine and heated at 220° in an autoclave for 12 hours. The mixture is cooled, concentrated, the residue partitioned between dichloromethane and dilute HCl and the organic phase washed, dried and concentrated. Chromatography of the residue over silica gel (toluene) yields the title compound as pale-yellow crystals. M.p.=82°-84°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:20])[N:9]=2)[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccc(Cl)c2[nH]ncc12
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cl)c2nn(C)cc12
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a solution of methyl 7-chloro-1H-indazole-4-carboxylate (5.40 g, 25.6 mmol) in ethyl acetate (150 mL) was added trimethyloxonium tetrafluoroborate (5.69 g, 38.5 mmol) at room temperature, and the mixture was stirred for 5 hr. The is reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (4.10 g, yield 71%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:39])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][CH:37]([CH3:39])[CH3:36])[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1C(C(C)C)CC2
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
A stirring solution of (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine (0.250 g, 0.43 mmol) in DCE (3 mL) was treated with acetone (0.159 mL, 2.17 mmol). The reaction was allowed to stir for 20 minutes, followed by the addition of NaBH(OAc)3 (0.184 g, 0.87 mmol). The reaction was stirred at room temperature overnight. An additional 2.5 equivalents of acetone and 1.0 equivalent of NaBH(OAc)3 were added to the reaction and stirred an additional 2 hours. The reaction was quenched by the addition of saturated NaHCO3 and diluted with DCM. The combined organics were washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure to give N-((1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (0.185 g, 84%), which was used without further purification. LCMS (APCI+) m/z 536.4 [M+H]+; Rt=3.61 min.