Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29]>O1CCOCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]=[C:14]1[C:13]2[NH:20][CH:21]=[CH:22][C:12]=2[C:11]2[CH:10]=[C:9]([C:29]#[C:28][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:18]=[CH:17][C:16]=2[NH:15]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
224 mg (1.2 mmol) of copper iodide, 309 mg (3 mmol) of triethylamine and 165 mg (0.23 mmol) of dichlorobis(triphenylphosphine)-palladium (11) are added to a suspension of 898 mg (2.35 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 30 ml of anhydrous dioxan then this mixture is degassed under argon. After 15 minutes, 346 mg (3.52 mmol) of ethynyl-trimethyl-silane is added and the reaction mixture is heated at 100° C. for 3 hours. The raw reaction product is filtered on celite, then the filtrate is evaporated to dryness and the residue is purified on silica (eluent ethyl acetate) to give 400 mg (48%) of 4-oxo-8-trimethylsilanylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([NH:10][C@@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:1][N:2]([S:40]([CH3:39])(=[O:42])=[O:41])[C@H:3]([C:8]([NH:10][C@@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N2-methyl-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Example 164 (122 mg, 0.296 mmol) in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (78 μL, 0.445 mmol) followed by methanesulfonyl chloride (25.4 μL, 0.326 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 0% to 5% methanol (2 N ammonia)/dichloromethane over 20 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.59 (d, J=6.7, 1H), 7.73 (s, 1H), 7.66 (d, J=7.6, 1H), 7.62 (d, J=7.8, 1H), 7.51 (t, J=7.7, 1H), 4.78 (dd, J=6.2, 9.5, 1H), 4.41-4.33 (m, 1H), 3.67 (d, J=13.3, 1H), 3.16 (s, 3H), 3.15 (s, 3H), 2.90 (qd, J=3.3, 7.9, 1H), 2.75 (dd, J=3.3, 9.6, 1H), 2.53-2.44 (m, 1H), 2.38-2.29 (m, 3H), 1.89-1.70 (m, 4H), 1.70-1.58 (m, 3H), 1.36-1.26 (m, 1H), 0.83 (d, J=6.6, 3H), 0.81 (d, J=6.5, 3H); MS (ESI+) m/z 490 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d,15 Hz, 1H), 2.59 (d,15 Hz, 1H), 2.6-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s,1H), 6.72 (d,7 Hz, 1H), 6.98 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.82 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,70%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23].[CH2:24](N(S(F)(F)F)CC)[CH3:25].C(O)C>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][O:23][CH2:24][CH3:25]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO
Reactant: CCN(CC)S(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCN1CCc2c(F)c(F)cc3c(=O)c(C(=O)OCC)cn1c23
Reaction time: 4 h

Procedure:
65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride was added to the solution. The solution was stirred for 4 hours, and 1 ml of ethanol was added to the solution. The deposited solid matter was filtered off and washed with ether to obtain 28 mg of the subject compound (181).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[CH:14]([CH2:15][CH2:16][C:17]3[C:18]4[C@:27]([CH3:35])([CH2:28][CH2:29][C:30]=32)[C@@H:21]([C@@H:22]([CH3:26])[CH2:23][C:24]#N)[CH2:20][CH:19]=4)[C:13]1([CH3:37])[CH3:36].S(=O)(=O)(O)[OH:39]>C1(C)C=CC=CC=1>[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[CH:14]([CH2:15][CH2:16][C:17]3[C:18]4[C@:27]([CH3:35])([CH2:28][CH2:29][C:30]=32)[C@@H:21]([C@@H:22]([CH3:26])[CH2:23][CH:24]=[O:39])[CH2:20][CH:19]=4)[C:13]1([CH3:37])[CH3:36]
Reactant: C[C@@H](CC#N)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reaction time: 2 h

Procedure:
16 ml diisobutylaluminiumhydride (20% in toluene) were added dropwise to a solution of 920 mg (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbonitril in 60 ml toluene at a temperature of −72° C. The mixture was stirred for 2 h at the same temperature, poured into 2N sulfuric acid, extracted with ethyl acetate, washed with 2N sulfuric acid and then washed with a half saturated solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 750 mg (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde as a white solid, which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][C@H:30]([O:32][Si](C(C)(C)C)(C)C)[CH2:29][C:28]4=[O:40])[CH2:23][CH2:22]3)=[CH:16][NH:17]2)=[CH:13][CH:12]=1.Cl>CO.C(Cl)Cl.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][C@H:30]([OH:32])[CH2:29][C:28]4=[O:40])[CH2:23][CH2:22]3)=[CH:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)N(C2CCN(Cc3c[nH]c4cc(Oc5nc6ccccc6s5)ccc34)CC2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1C[C@@H](O)CN1C1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
To a solution of (R)-1-{1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidin-4-yl}-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-2-one (200 mg, 0.35 mmol) in MeOH:DCM (1:1, 15 mL) was added 4 M HCl in dioxane (5 mL) and the resulting reaction mixture was stirred (rt, 3 h). The reaction mixture was concentrated in vacuo to provide the title compound as a tan solid (112 mg, 70%). MS (ESI): mass calcd. for C25H26N4O3S, 462.5; m/z found, 463.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.00 (br s, 1H), 7.73-7.71 (m, 2H), 7.62 (d, J=7.9, 1H), 7.39-7.33 (m, 2H), 7.28-7.23 (m, 1H), 7.12-7.07 (m, 2H), 4.35 (t, J=8.4, 1H), 3.95-3.90 (m, 1H), 3.69 (s, 2H), 3.37-3.33 (m, 1H), 3.21-3.15 (m, 1H), 3.04-3.02 (m, 2H), 3.41-3.38 (m, 1H), 2.10-2.04 (m, 2H), 1.94-1.89 (m, 1H), 1.77-1.73 (m, 2H), 1.64-1.60 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10]Br)=[C:6]([O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:14]([N:16]([CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]2[C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15].[CH:41]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42]1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][NH:46][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[C:6]([O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:14]([N:16]([CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]2[C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15]
Reactant: NC1CCCC1
Reactant: COc1ccccc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OCCBr)c2Cl)nc2ccccn12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OCCNC3CCCC3)c2Cl)nc2ccccn12
Temperature: 90 °C

Procedure:
To 0.1 ml of a 0.2 M solution of (2-chloro-3-bromoethoxy-4-methoxyphenyl)-N-({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)-N-(3-methylbutyl)carboxamide in N-methylpyrrolidinone is added 0.1 ml of a 1 M solution of cyclopentylamine. The mixture is heated at 90 ° C. for 15 h in a sealed vial. After cooling to room temperature, the reaction mixture is diluted with 0.5 ml of ethyl acetate and washed with 0.5 ml of 1 N aqueous sodium hydroxide. The organic layer is separated and purified by preparative TLC eluting with 9/1/0.5 ethyl acetate/methanol/triethylamine to obtain 11 mg of the title compound. Mass Spec m/z (M++1) 633.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([NH:17][S:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:12])(=[O:10])=[O:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1F
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 5-chloro-2-fluorobenzene-1-sulfonyl chloride (2.0 g) in tetrahydrofuran (30 ml) was added to a solution of tert-butylamine (9.15 ml) in tetrahydrofuran (70 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give N-tert-butyl-5-chloro-2-fluoro-benzenesulfonamide (2.2 g, 95% yield) as a white solid.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25].[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C(Cl)c1cccs1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2cccs2)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.05 g) as starting compound was reacted and treated in the same manner as in Example 1 using 2-thiophenecarbonyl chloride (0.48 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.82 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(2-thiophenecarbonylamino)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:30][CH:29]=1>>[O:23]=[S:22]1(=[O:24])[C:8]2[C:7]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:32][CH:33]=3)=[N:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:19][CH2:20][CH2:21]1
Reactant: O=S1(=O)CCCc2nc(-c3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: NC(=O)Cc1ccc(N)cc1
Product: NC(=O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 60.8 %

Procedure:
Following general procedure G, 5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.125 g, 0.31 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.051 g, 0.34 mmol) to afford the desired product (0.077 g, 61%) as a white solid. MW=408.47. 1H NMR (DMSO-d6, 500 MHz) δ 8.74 (s, 1H), 8.30-8.25 (m, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.59-7.50 (m, 3H), 7.48 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 3.77-3.71 (m, 2H), 3.40 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 409 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]([O:39][Si](C(C)(C)C)(C)C)[CH3:38])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH2:7][O:8]2)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(=O)C.C1COCC1.O>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH:37]([OH:39])[CH3:38])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O[Si](C)(C)C(C)(C)C)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Yield: 65 %

Procedure:
A solution (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(4-(2-(tert-butyldimethylsilyloxy)propoxy)benzyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (350 mg, 0.46 mmol) in Acetic acid:THF:Water (3:1:1, 5.0 mL) was stirred at r.t. for 48 h. After completion of the reaction, as confirmed by TLC, sat. solution of NaHCO3 (10 mL) was added dropwise to the reaction mixture and organic layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1:1 Ethyl acetate:Pet. Ether) to afford title compound (190 mg, 65.7%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:20]([O:19][C:17]([CH:16]1[C:15](=[O:14])[C:7]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:8]=2)[N:6]=[CH:22]1)=[O:18])[CH3:21]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2c(cc(F)cc2[N+](=O)[O-])C1=O
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 2 in the section relating to the preparation of starting materials 4-fluoro-2-nitroaniline and diethyl ethoxymethylenemalonate were reacted, and then refluxed in diphenyl ether to give 3-ethoxycarbonyl-6-fluoro-8-nitro-4-oxo-3,4-dihydroquinoline in 45% yield, mp 278-280° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[C:44]1([CH2:54][C:55](O)=[O:56])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:55](=[O:56])[CH2:54][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:47]=[CH:46][CH:45]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccc2ccccc12)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-naphthylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-naphthalen-1-yl-acetamide (0.7 g, 74%) as a white solid: mp 187-189° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.70 min. (98%); 1H NMR (DMSO-d6) δ 1.98-2.06 (m, 1H), 2.54-2.63 (m, 2H), 2.83-2.96 (m, 1H), 4.03 (s, 2H), 4.74 (d, J=5.8 Hz, 2H), 5.11-5.17 (dd, J=5.2 and 12.8 Hz, 1H), 7.43-8.11 (m, 10H), 8.71 (t, J=4.6 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.89, 48.82, 121.86, 124.17, 125.52, 125.64, 125.95, 127.11, 127.15, 127.92, 128.37, 131.48, 131.90, 132.47, 133.23, 133.33, 134.56, 139.23, 166.89, 167.42, 169.77, 170.60, 172.72; Anal. Calcd. for C26H21N3O5: C, 68.56; H, 4.65; N, 9.23. Found: C, 68.24; H, 4.54; N, 9.19.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:20])=[C:15]([CH3:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH2:27])=[O:20])=[C:15]([CH3:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1CNC(=O)OC(C)(C)C
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1CN

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-[(2R/S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C23H26ClN5O2 (439.94); mass spectrum: (M+H)+=440/442 (chlorine isotope).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=CC=CN=1.[CH:10]#[C:11][CH2:12]C.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:15]([C:14]1[CH:2]=[C:7]([O:8][CH3:9])[CH:18]=[CH:17][N:16]=1)#[C:10][CH2:11][CH3:12]
Reactant: CCNCC
Reactant: C#CCC
Reactant: COc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CCC#Cc1cc(OC)ccn1
Reaction time: 20 h

Procedure:
After adding dichlorobis(triphenylphosphine)palladium (II) (671 mg) and copper iodide (91 mg) to a solution of 2-bromo-3-methoxypyridine (18.0 g) in diethylamine (250 mL), 1-butyne (15.5 g) was bubbled through at room temperature, and the mixture was stirred for 20 hours. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, extraction was performed with ethyl acetate, the extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (500 g), and 2-(1-butynyl)-4-methoxypyridine (10.0 g) was obtained from the n-hexane:ethyl acetate (2:1) fraction as a brown oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C@H:16]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:53]1([NH:59][C:60]2[CH:69]=[C:68]3[C:63]([C:64](=[O:77])[C:65](CO)=[CH:66][N:67]3[CH:70]3[CH2:74][CH2:73][CH2:72][CH2:71]3)=[CH:62][C:61]=2[F:78])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>O.ClCCl>[CH:53]1([NH:59][C:60]2[CH:69]=[C:68]3[C:63]([C:64](=[O:77])[C:65]([O:15][C@@H:16]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[CH:66][N:67]3[CH:70]3[CH2:71][CH2:72][CH2:73][CH2:74]3)=[CH:62][C:61]=2[F:78])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=c1c(CO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)Oc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
213 μl of diisopropyl azodicarboxylate was added to a 5.0 ml dichloromethane solution of 263 mg of benzyl (2R)-2-hydroxy-3-phenylpropanoate and 270 mg of triphenylphosphine at 0° C., followed by stirring for 15 minutes. Then, 177 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(hydroxymethyl)quinolin-4(1H)-one was added thereto, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with EtOAc and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 160 mg of benzyl (2S)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-3-phenylpropanoate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:32])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[Cl:31])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:30]1[CH:29]=[CH:28][S:27][C:26]=1[C:24]1[CH2:23][C:22](=[O:32])[NH:21][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2sccc2Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc2c(c1)NC(=O)CC(c1sccc1Cl)=N2

Procedure:
Prepared from {3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K16) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (60 mg).