Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[N:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=2)[N:5]=[C:6]([Cl:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[C:30]([O:9][C:8]([C:7]2[C:6]([Cl:11])=[N:5][C:4]3=[N:12][N:13]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:14]=[C:3]3[C:2]=2[NH2:1])=[O:10])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(Cn2cc3c(N)c(C(=O)O)c(Cl)nc3n2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc3c(N)c(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)c(Cl)nc3n2)cc1
Yield: 89 %

Procedure:
To a cold (0° C.) solution of 4-amino-6-chloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (952 mg, 2.86 mmol) and pentafluorophenol (830 mg) in DMF was added a solution of DCC (620 mg, 3 mmol) in EtOAc (9 mL). After work up the crude product was purified by flash column (silica gel, EtOAc/hexane, 1:1) to give the desired product (1.27 g) as a white solid. LC: 4.64 (Gradient 1), MH+: 499.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:18][C:26](=[O:27])[C:25]1[CH:29]=[C:21]([Br:20])[CH:22]=[CH:23][C:24]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(Br)cc1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Yield: 82.3 %

Procedure:
(2S)-(2-amino-5-bromo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1 mmol) and 5-bromo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described in procedure A.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:14].[ClH:15].C(OC([N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[ClH:15].[F:14][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([F:13])[C:5]=1[O:4][CH2:3][CH2:2][N:27]1[CH2:26][CH:25]2[O:31][CH:29]([CH2:30][NH:23][CH2:24]2)[CH2:28]1)[C:9]#[N:10]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1cc(F)c(OCCBr)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(F)c(OCCN2CC3CNCC(C2)O3)c(F)c1
Temperature: 60 °C
Reaction time: 120 h
Yield: 83.4 %

Procedure:
A suspension of 4-(2-bromoethoxy)-3,5-difluorobenzonitrile (12 g, 45.8 mmol; see step (i) above), 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester HCl-salt (11.5 g, 0.0435 mol; see WO 01/28992) and dry K2CO3 (25.32 g, 0.183 mol) in 140 mL of dry acetonitrile was stirred at 60° C. for five days under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the filtrate was then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, using 20% ethyl acetate in petroleum ether as eluent, to yield 12.55 g of the sub-title compound as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]=[O:21].[OH-].[K+]>CO>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[NH:14][CH:15]=1)[OH:21]
Reactant: c1ccc(Oc2cnc3[nH]ccc3c2)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [5-phenoxy-1H-pyrrolo[2,3-b]pyridine (P-0035, 80 mg, 0.38 mol) in methanol (2.0 mL), 2,4-dichloro-benzaldehyde (32, 133 mg, 0.76 mmol) and potassium hydroxide (74 mg, 1.3 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction mixture resulted in a precipitate, which was collected with vacuum filtration to provide the compound (33, 104 mg, 71%). MS (ESI) [M+H+]+=385.1 and 387.1.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 67.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[C:12](Br)=[CH:11][N:10]=[C:9]([NH:14][C@H:15]3[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17][CH2:16]3)[N:8]=2)[CH2:2]1.[O:22]1[CH2:26][CH2:25][C@H:24]([O:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:23]1>>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[C:12]([C:31]3[CH:32]=[CH:33][C:28]([O:27][C@H:24]4[CH2:25][CH2:26][O:22][CH2:23]4)=[CH:29][CH:30]=3)=[CH:11][N:10]=[C:9]([NH:14][C@H:15]3[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17][CH2:16]3)[N:8]=2)[CH2:2]1
Reactant: CC1(C)OB(c2ccc(O[C@H]3CCOC3)cc2)OC1(C)C
Reactant: C[C@H]1CC[C@@H](Nc2ncc(Br)c(O[C@@H]3CCOC3)n2)CC1
Product: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(O[C@H]4CCOC4)cc3)c(O[C@@H]3CCOC3)n2)CC1

Procedure:
Using the procedure of Example 1, Step 3, 4-((R)-tetrahydrofuran-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine was reacted with 2-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to provide the title compound as a free base.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH3:16][N:17](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:17][CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)COc1ccc(Br)cc1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
To a solution of (4-bromophenoxy)acetic acid (500 mg, 2.10 mmol) in N,N-dimethylformamide (15 mL) was added methylamine hydrochloride (320 mg, 5.10 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (570 mg, 3.00 mmol), 1-hydroxybenzotriazole (400 mg, 3.00 mmol) and N-methyl-morpholine (600 mg, 6.00 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), and then washed three times with ethyl acetate (20 mL). The combined organics was dried and concentrated to give the title compound (580 mg, 90% yield) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H), 6.79 (d, 2H), 6.56 (s, 1H), 4.46 (s, 2H), 2.91 (d, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:22](I)[CH:23]=[CH2:24].CCOC(C)=O>CN(C=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=2[N:3]1[CH2:24][CH:23]=[CH2:22]
Reactant: C=CCI
Reactant: COC(=O)c1cnc2ccc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ncc(C(=O)OC)cc21
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
A solution of methyl 6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (1.963 g, 5.36 mmol) in DMF (32 ml) was treated with K2CO3 (2.95 g, 21.3 mmol), stirred for 10 mins and then treated with allyl iodide (0.535 ml, 5.88 mmol), heated for 7 h at 75° C., further allyl iodide (0.15 ml, 0.89 mmol) was added and the reaction heated for a further 2 h. The reaction was treated with EtOAc, washed with water three times. The combined aqueous phases were then re-extracted with EtOAc and this washed with water twice. The combined organic phases were dried, evaporated and the residue was subjected to column chromatography on silica gel using a 1:1 EtOAc:hexane gradient to provide the desired compound (0.809 g, 62%).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O.[BH4-].[Na+]>>[O:7]=[C:5]1[N:1]([CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: O=Cc1ccccn1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
D-glutamic acid (2.21 g, 15 mmol) was dissolved in 2N aqueous sodium hydroxide (15 ml, 30 mmol) at 0° C. and then treated with pyridine-2-carboxaldehyde (1.43 ml, 15 mmol). The mixture was stirred at room temperature for 45 minutes and then cooled to 0° C. and treated with sodium borohydride (0.189 g, 5 mmol). The mixture was allowed to warm to room temperature with stirring over 4 hrs then after washing twice with diethyl ether it was acidified to pH5-6. The aqueous layer was concentrated then azeotroped three times with toluene and then with a 1:1 ethanol:toluene mixture and finally with ethanol. The residue was then taken up in ethanol (50 ml) and refluxed for 8 hrs. Concentration gave an oil which when dried in vacuo gave 5-oxo-1-(2-pyridinylmethyl)proline (2.60 g) as a foam which was used without any further purification.
Reaction SMILES: Cl[CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>>[O:18]1[CH2:19][CH2:20][N:15]([CH2:2][CH:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C(CCl)c1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(CN1CCOCC1)c1ccccc1
Temperature: 110 °C
Yield: 53.1 %

Procedure:
A mixture of ethyl 3-chloro-2-phenylpropionate (1 g, 4.72 mmol) prepared in the above (1) and morpholine (470 mg, 5.4 mmol) was stirred to cause reaction for 6 hours under heating at 110° C. To the resulting solution, saturated aqueous sodium bicarbonate was added. After the prepared solution was extracted with ethyl ether, the extract was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography using acetone/hexane=1/6 to obtain 660 mg of the titled compound as a colorless oil (yield: 53.2%).
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCCl>[CH2:20]([O:19][C:17]([C:13]1[NH:12][CH:16]=[C:15]([C:2](=[O:7])[CH2:3][CH2:4][C:5]([OH:1])=[O:6])[CH:14]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)CCC(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
Into a 3000-mL 4-necked round-bottom flask was placed a solution of oxolane-2,5-dione (100 g, 999.27 mmol, 2.00 equiv) in 1,2-dichloroethane (690 mL) and AlCl3 (400.5 g, 3.00 mol, 6.00 equiv), followed by the addition of a solution of ethyl 1H-pyrrole-2-carboxylate (69 g, 495.86 mmol, 1.00 equiv) in 1,2-dichloroethane (660 mL) dropwise with stirring at room temperature over 20 min (FIG. 14). The resulting solution was stirred at room temperature for 3 h and quenched by the addition of 3 kg of water/ice. The solids were collected by filtration, washed with 1×1000 mL of water and dried in a vacuum oven to afford 105 g (89%) of 113g as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:3][CH2:4][C:5]([NH:43][CH:40]1[CH2:41][CH2:42][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:23]3[N:22]([CH3:21])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH:32]=2)[CH2:38][CH2:39]1)=[O:7])[CH3:2]
Reactant: CCOCC(=O)O
Reactant: Cn1c(-c2cccc(N3CCC(N)CC3)c2)nc2ccccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCC(=O)NC1CCN(c2cccc(-c3nc4ccccc4n3C)c2)CC1
Temperature: 70 °C
Yield: 435 %

Procedure:
Method N—Step e To a solution of ethoxyacetic acid (0.05 mL, 0.49 mmol) in acetonitrile (3 mL) was added CDI as a stock solution (0.80 g, 0.49 mmol) and the resulting suspension was stirred at room temperature for 3 h. {1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-ylamine hydrochloride (0.13 g, 0.41 mmol) and DIPEA (0.07 mL, 0.41 mmol) were added and the resulting solution heated at 70° C. overnight. The reaction was then cooled to room temperature, the solvent removed under reduced pressure. The crude product was redissolved in dichloromethane (4 mL) and washed with saturated Na2CO3 solution (2 mL) and water (2 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: dichloromethane:MeOH, gradient from 100% dichloromethane to 95% dichloromethane:5% MeOH) to afford 0.70 g (44%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C)C1C=CN=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 279.8 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (0.31 g, 0.70 mmol), cyclopropanecarbonyl chloride (0.42 g, 4.0 mmol) and N,N-dimethylpyridine-4-amine (0.49 g, 4.0 mmol), and in the same manner as in Example A29(vi), the title compound (1.00 g, 45%) was obtained as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2cccc(Cl)c2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(OCc4cccc(Cl)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (71 mg, 0.40 mmol) was reacted with the product from Example 144a (143 mg, 0.41 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (122 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 5.16 (s, 2H) 6.25 (d, J=6.98 Hz, 1H) 6.66 (d, J=8.83 Hz, 2H) 7.07-7.25 (m, J=8.46 Hz, 5H) 7.38-7.53 (m, 3H) 7.80 (d, J=8.45 Hz, 1H) 8.40 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.83 HZ, 1H) 9.79 (s, 1H) 11.02 (br s, 1H) 14.38 (br s, 1H); MS (ESI+) m/z 500 (M+H−TFA)+; (ESI−) m/z 498 (M−H−TFA)−.
Reaction SMILES: Br[C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C@H:7]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:6][CH2:5][C:4]=2[CH:3]=1.[C:21](OC)(=[O:23])C>[Cu]Br.C[O-].[Na+]>[CH3:21][O:23][C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C@H:7]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: COC(C)=O
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(Br)c3c(c21)CCO3
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Product: CCC(=O)NCC[C@@H]1CCc2cc(OC)c3c(c21)CCO3
Yield: 60.2 %

Procedure:
A solution of sodium methoxide (200 mL, 28% solution in methanol) was added dropwise into a mixture of (S)—N-(2-[4-bromo-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl)propionamide (5.00 g, 14.8 mmol), copper(I) bromide (2.12 g, 14.8 mmol) and methyl acetate (3.29 g, 44.3 mmol). The mixture was refluxed for 5 hours. The mixture was cooled, which was quenched with 1N HCl, followed by extracting with methanol-chloroform. The extracted solution was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography and recrystallized from ethyl acetate to afford the title compound (yield 2.58 g, 60%) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[C-:12]#[N:13].[K+]>O1CCOCC1.O>[S:7]1[C:3]([CH2:2][C:12]#[N:13])=[CH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]1=2
Reactant: ClCc1cc2ccccc2s1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1cc2ccccc2s1

Procedure:
To a solution of 2-chloromethyl-benzo[b]thiophene (1 eq.) in dioxane/water (2/1) was added KCN (1.5 eq.). The reaction was refluxed for 4 h. The crude was partitioned between water and EtOAc. The organic layer was washed with water, then brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 95/5 to 90/10) to afford benzo[b]thiophen-2-yl-acetonitrile.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][NH:8][CH:9]=[O:10]>C(Cl)(Cl)Cl>[CH3:7][N:8]([CH:9]=[O:10])[C:3](=[O:4])[CH:2]([Cl:6])[Cl:1]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CNC=O
Solvent: ClC(Cl)Cl
Product: CN(C=O)C(=O)C(Cl)Cl
Yield: 86 %

Procedure:
25 g of dichloroacetyl chloride (1.25 eq.) was added to a solution of 50 g N-methylformamide (NMF) in chloroform at ambient temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried with magnesium sulfate and the solvent was evaporated off in vacuum to give N-methyl-N-formyl-α,α-dichloroacetamide (86% yield) in high purity as a yellow oil. The chemical structure was confirmed by APCI-MS, FT-IR, 1H and 13C magnetic resonance spectroscopy.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH2:19]([O:21][C:22](=[O:29])[C@:23]([F:28])([CH3:27])[C:24](O)=[O:25])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:29])[C@:23]([F:28])([CH3:27])[C:24]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:25])[CH3:20]
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 1 a), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester yielded the title compound as a colourless oil;
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CO.Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C=NO)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
4-Nitrobenzaldehyde (40 g, 264.49 mmol) was added to MeOH (100 ml) followed by hydroxylamine hydrochloride (22.9 g, 330.9 mmol) in H2O (100 ml). The solution was then cooled to 0° C. Sodium carbonate (16.9 g, 159.5 mmol) in H2O (100 ml) was added and the reaction was allowed to stir overnight. The MeOH was removed under vacuum and then H2O (400 ml) was added. The precipitate was filtered and dried under vacuum to yield the product (39.65 g, 238.68 mmol).
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])/[C:6](/[CH3:7])=[CH:39]/[C:38]1[CH:41]=[CH:42][C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:36][CH:37]=1)[CH3:5]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
Carbethoxyethylidene triphenylphosphorane (1.02 g, 2.81 mmol) was dissolved in anhydrous THF (25 mL), and 4-benzyloxy-benzaldehyde (0.5 g, 2.36 mmol)/THF (10 mL) solution was added dropwise thereto at −78° C. The mixture was heated slowly to room temperature and then stirred for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure. The residue was added with water and then extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex=1/9) to obtain the title compound (0.68 g, 97.4%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]>N1C=CC=CC=1>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:28][CH2:29]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
2-Thiophene carbonyl chloride (0.16 mL, 1.5 mmol) was added to a stirred solution of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (5) (392 mg, 1 mmol) in pyridine (5 mL) at 0° C. under inert atmosphere. The solution was allowed to come at room temperature and further stirred for 18 h. The solution was poured into ice water, the solids formed were filtered, washed by water, dried, and recrystallized by ether and ethyl acetate to yield 256 mg (51%) of 1-benzyl-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (6) as white solids. MP: 168° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=6.9 Hz, 3H), 3.16 (m, 4H), 3.88 (m, 4H), 4.31 (q, J=6.9 Hz, 2H), 5.56 (s, 2H), 7.15 (dd, J=3.5, 4.9 Hz, 1H), 7.20-7.29 (m, 5H), 7.38 (dd, J=4.6, 8.2 Hz, 1H), 7.97 (d, J=4.9 Hz, 1H), 8.35 (dd, J=1.5, 7.5 Hz, 1H), 8.66 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 503 (M+1), 525 (M+23). Anal. C27H26N4O4S (C,H,N).