Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:34])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]([NH:24]CC4C=CC(OC)=CC=4)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:20]1[N:19]=[CH:18][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:34])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[C:22]([CH3:23])[CH:21]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3cnc(NCc4ccc(OC)cc4)cc3C)CC2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (320 mg) described in Preparation Example 176 was added 4-methoxybenzylamine (1 mL), and the mixture was stirred at 160° C. for 6 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg). The obtained [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give (6-amino-4-methylpyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give the title compound (220 mg).
Reaction SMILES: [OH:1][C:2]1[C:12]2[N:11]=[CH:10][CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17].[CH3:18][OH:19]>>[OH:1][C:2]1[C:12]2[NH:11][CH:10]([O:19][CH3:18])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: CO
Reactant: Cc1ccc2c(c1O)N=CC1CCCN1C2=O
Product: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Reaction time: 72 h

Procedure:
5.5 mg of 2,3,5,11 a-tetrahydro-9-hydroxy-8-methyl-1H-pyrrolo[2,1-C][1,4]benzodiazepin-5-one was dissolved in 0.2 ml of hot methanol and allowed to stand at -20° C. for 3 days. Thus, 3.0 mg of 2,3,5,10,11,11 a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo[2,1-C][1,4]benzodiazepin-5-one was obtained as a colorless crystal. Its infrared absorption spectrum just coincided with that of the product of Example 4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccc(O)cc1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
3-(4-Hydroxyphenyl)propionic acid (202 mg, 1.216 mmol) in DMF (3 ml) was cooled in an ice-bath. 1,2,3,4-Tetrahydroisoquinoline (170 mg, 1.276 mmol) was added and then TBTU (410 mg, 1.276 mmol) followed by DIPEA (330 mg, 2.553 mmol). The mixture was stirred at room temperature overnight. Sodium hydrogencarbonate aqueous solution (sat.) was added. The mixture was extracted with ethyl acetate (×2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 303 mg the desired product, yield 89%.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11][N:10]=1)(C)(C)C>CO>[NH2:8][C:9]1[N:10]=[CH:11][N:12]=[C:13]([CH2:15][OH:16])[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ncn1
Agent: Cl
Solvent: CO
Product: Nc1cc(CO)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 181.6 %

Procedure:
Concentrated hydrochloric acid (0.80 mL) was added to a solution of tert-butyl-6-(hydroxymethyl)pyrimidin-4-ylcarbamate (0.50 g, 2.2 mmol) in MeOH (10 mL). The reaction was stirred at 25° C. for 1 hour and then concentrated under reduced pressure to give the desired compound (0.50 g) as a pale yellow solid, which was used in the next step without further purification. LCMS (ESI) m/z: 126.0 [M+H+].
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:10][S:9][C:8]2[S:11][CH:12]=[CH:13][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH2:17]([Li])CCC.CI>O1CCCC1.CCCCCC>[CH3:17][C:12]1[S:11][C:8]2[S:9][CH2:10][CH:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[CH2:6][C:7]=2[CH:13]=1
Reactant: CCCN(CCC)C1CSc2sccc2C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CCCN(CCC)C1CSc2sc(C)cc2C1
Reaction time: 0.5 h

Procedure:
A mixture of 2.5 g of N,N-dipropyl-5,6-dihydro-4H-thieno[2,3-b]-thiopyran-5-amine in 40 ml of tetrahydrofuran is treated with 4 ml of 2.5 M n-butyl lithium in hexane at 0°. After 30 minutes at 0°, 1.5 g of methyl iodide is added and the mixture is kept at room temperature for 1 hour. Dilution with ether and washing with water followed by drying and removal of the solvent in vacuo affords 2-methyl-N,N-dipropyl-5,6-dihydro-4H-thieno[2,3-b]-thiopyran-5-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][NH2:10])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ccc(Br)cn1
Temperature: 85 °C

Procedure:
A mixture of 2,5-Dibromo-pyridine (13 g, 55.1 mmol) and hydrazine (13 mL, 414 mmol) in pyridine (13 mL) was heated at 85° C. for 48 hours. The reaction was cooled and concentrated in vacuo. The residue was triturated in 1N NaOH (20 mL) and toluene (20 mL). The solid was filtered, washed with water, and dried to give the above named compound (6.43 g, 62%).
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C@@H:23]3[CH2:27][C@H:26]([S:28][C:29]4[C@H:30]([CH3:53])[C@@H:31]5[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]5[C:33]=4[C:34]([O:36]CC4C=CC([N+]([O-])=O)=CC=4)=[O:35])[CH2:25][N:24]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:22])[CH2:17][CH2:16]2)[CH3:14])=O)=CC=1)([O-])=O>O1CCCC1.O>[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:19][CH2:20]1)(=[NH:12])[CH3:14]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CC1
Yield: 23.5 %

Procedure:
114 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 6 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 300 mg of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was filtered off and the filtrate was washed with diethyl ether. The resulting solution was concentrated by evaporation under reduced pressure, and the residue was purified by reverse phase column chromatography through 5 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using 20% v/v aqueous methanol as the eluent. Those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure, and lyophilized, to give 13 mg of the title compound as a powder.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[N:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=[O:4].[O-]CC.[Na+].Cl>C(O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:11]2[C@@H:6]3[C@@H:5]([CH2:10][CH2:9][CH2:8][CH2:7]3)[C:3]([OH:4])=[C:13]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[S:16](=[O:30])(=[O:29])[N:15]=3)[C:12]2=[O:31])=[CH:38][CH:37]=1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCCC[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
The crude (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester (0.3 mmol) was dissolved in ethanol (4 mL). A 21% w/w solution of sodium ethoxide in ethanol (0.448 mL, 1.2 mmol) was added into the above solution. The mixture was stirred at 60° C. for 4 h. Upon cooling to 25° C., the mixture was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a light yellow solid. Purification by flash column chromatography (Teledyne Isco RediSep Flash Column; 5% methanol in dichloromethane) afforded the desired product, (4aR,8aS)-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,8a-octahydro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (49.7 mg, 0.09 mmol, 30% over two steps), as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-2.34 (8H, m), 3.06 (3H, s), 3.46-3.69 (1H, m), 4.24-4.66 (2H, m), 4.98 (1H, d, J=16 Hz), 7.16 (2H, t, J=8 Hz), 7.39-7.59 (5H, m), 10.15 (1H, s). LC-MS (ESI) calcd for C24H25FN4O6S2 548.12, found 549.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])[CH:11]=1)=[O:9])(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[CH3:2][C:1]1([CH3:3])[O:5][C:6](=[O:22])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])[CH:11]=2)[O:9]1
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nccn1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1

Procedure:
Prepared from 3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H8) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a beige solid (2.13 g).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.C(OC([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]1)=O)(C)(C)C>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][NH:46][CH2:45][CH:42]3[CH2:43][CH2:44][NH:39][CH2:40][CH2:41]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNCC3CCNCC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:20][CH:19]=1.[ClH:36]>CCOCC>[ClH:36].[NH2:26][CH2:25][C@@H:24]([C:21]1[CH:20]=[CH:19][C:18]([C:4]2[C:5]3[C:6]4[CH:17]=[CH:16][S:15][C:7]=4[C:8](=[O:14])[NH:9][C:10]=3[C:11]([CH3:13])=[CH:12][C:3]=2[O:2][CH3:1])=[CH:23][CH:22]=1)[CH2:34][CH3:35]
Reactant: CC[C@@H](CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1
Agent: Cl
Solvent: CCOCC
Product: CC[C@@H](CN)c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 94 %

Procedure:
Following General Procedure D1, (R)-tert-butyl 2-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)butylcarbamate (100 mg, 0.20 mmol) was reacted with HCl in ether (10 mL) to afford the desired product (75 mg, 94%) as an off-white solid: ESI MS m/z 393 [C23H24N2O2S+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:52]1[CH2:56][CH2:55][CH:54]([CH2:57][OH:58])[CH2:53]1>CN(C)C=O>[OH:58][CH2:57][CH:54]1[CH2:55][CH2:56][N:52]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:53]1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: OCC1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(CO)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.01 mol 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (CAS: 845616-82-2) in 40 ml N,N-dimethylformamide were added successively 3.57 g TBTU, 8.5 ml N-ethyldiisopropylamine and 1 g rac-pyrrolidin-3-yl-methanol (CAS: 5082-74-6). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The mixture was taken in ethyl acetate and washed twice with water and twice with saturated NaHCO3. The organic phase was dried over Na2SO4 and filtered. The solvent was evaporated. The crude oil was purified on silica gel (eluent: ethyl acetate) to yield the title compound as an off white foam. MS (m/e): 396.1 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)[NH:8]2)=[C:4]([O:22][CH2:23][C:24]2[CH:37]=[CH:36][C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[N:3]=1.FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH2:13][NH2:14])[NH:8]2)=[C:4]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([F:32])([F:34])[F:33])=[CH:36][CH:37]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCCc1nc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc2[nH]1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCc1nc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
The tert-butoxycarbonyl derivative 11 (Example 23, 100 mg, 0.19 mmol) is suspended in 10 mL dichloromethane, and 2 mL trifluoroacetic acid are added. The mixture is stirred at room temperature for 30 min and poured into 70 mL of diethyl ether. The precipitate is collected by filtration and purified by flash column chromatography (CH2Cl2/MeOH 5:1) yielding 74 mg (0.17 mmol, 92%) of the title compound. MS (ESI) m/z 424.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Clc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1

Procedure:
20 mg of the target compound (0.06 mmol, 7.3%) was obtained using 1-(4-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC(Cl)C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[O:14])=[CH:2]1
Reactant: O=C(O)CSc1c[nH]c2ccccc12
Reactant: Cc1cc(N)no1
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Cc1cc(NC(=O)CSc2c[nH]c3ccccc23)no1
Yield: 71 %

Procedure:
2-((1H-indol-3-yl)thio)acetic acid (650 mg, 3.14 mmol) from Step B, 3-amino-5-methyl-isoxazole (616 mg, 6.28 mmol), PyClu (2.00 g, 6.28 mmol), and DIEA (1.36 mL, 7.85 mmol) were added to dichloroethane (25 mL) and microwave irradiated at 110° C. for 20 minutes. The solvent was removed in vacuo and the remaining residue purified on a silica gel column (0-70% ethyl acetate:hexanes over 33 min) to yield the desired product (642 mg, 2.23 mmol, 71% yield). LCMS>99% at 214 nm, RT=1.23 min, m/z=288 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:12](OCC)=[O:13])C>C1COCC1>[CH2:23]([C:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH2:10][OH:9])[CH2:12][OH:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC(CCCCCC)(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC(CO)(CO)CCCCCC
Temperature: 25 °C

Procedure:
A suspension of lithium aluminum hydride (LAH) (2 g, 52.6 mmol) in dry THF (20 mL) was stirred at room temperature, and a THF solution of substituted malonic acid diethyl ester (26.3 mmol, (5)) was added dropwise. The reaction was allowed to reflux for 3 h and was quenched by the addition of cold water. The compound was extracted in ethyl acetate. The organic layer was washed with water, dried over Na2SO4, and evaporated to produce the product (6) as either a sticky liquid or a low-melting solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH:12]=[O:13])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](CCO)CCN1C(=O)OCC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H](CC=O)CCN1C(=O)OCC

Procedure:
A solution of 0.908 g of cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol and 1.14 g pyridinium chlorochromate in 20 ml of methylene chloride is stirred under nitrogen for 4 hours. Mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (1:1) to yield cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C#N)ccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a stirring suspension of 11A (0.34 g, 1.86 mmol) and K2CO3 (0.283 g, 2.05 mmol) in DMF (3 mL) was added iodomethane (0.127 mL, 2.05 mmol). After the addition, the reaction mixture was stirred at rt for 16 h, then partitioned between H2O and CH2Cl2. The separated CH2Cl2 layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 5% to 40% EtOAc/hexane to yield the title compound (0.22 g) as a solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6](=[O:15])[CH2:5][CH2:4]1)[CH3:2].C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C>>[CH2:16]([C:3]1([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6](=[O:15])[C:5](=[CH:21][N:22]([CH3:24])[CH3:23])[CH2:4]1)[CH3:17]
Reactant: CCC1(CC)CCC(=O)c2cc(OC)ccc21
Reactant: CCOC(OCC)N(C)C
Product: CCC1(CC)CC(=CN(C)C)C(=O)c2cc(OC)ccc21

Procedure:
4,4-Diethyl-3,4-dihydro-2-dimethylaminomethylene-7-methoxy-1(2H) naphthalenone was prepared from 4,4-diethyl-3,4-dihydro-7-methoxy-1(2H)naphthalenone (1.50 g, 6.5 mmol) and N,N-dimethylformamide diethyl acetal (3.3 ml, 19.5 mmol) to give the compound as a golden yellow oil (1.72 g) δH (CDCl3) 7.76 (1H, s), 7.63 (1H, d, J 2.9 Hz), 7.11 (1H, d, J 8.6 Hz), 6.96 (1H, dd, J 2.9, 8.6 Hz), 3.84 (3H, s), 3.13 (6H, s), 2.78 (2H, s), 1.66 (4H, q, J 7.5 Hz) and 0.77 (6H, t, J 7.4 Hz). MS (ES+) 288 (MH+, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[C:10]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])(=[O:12])[CH3:11]
Reactant: CCc1ccccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CCc1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Commercial 2-ethylaniline (50 mL, 0.40 mol) was dissolved in acetic anhydride (160 mL, 1.70 mol) and stirred at room temperature for 2 h. Then the reaction mixture was poured into H2O, the whole was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with 5% aqueous NaHCO3, brine, dried (K2CO3), filtered and concentrated to provide the title compound as a white solid (60.0 g, 92%).