Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([CH2:13][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]3[C@@H:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:27][N:26]([C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]4[CH2:41][C:42]([O:44]CC4C=CC(OC)=CC=4)=[O:43])[CH2:25]3)[CH2:19][CH2:18]2)[CH2:15][CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([CH2:13][N:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C@@H:24]3[C@@H:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:27][N:26]([C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]4[CH2:41][C:42]([OH:44])=[O:43])[CH2:25]3)[CH2:21][CH2:22]2)[CH2:15][CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1nnn(Cc2ccccc2)n1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccc(OC)cc3)C[C@@H]2c2ccccc2)CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(Cc1nnn(Cc2ccccc2)n1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To 54 mg of 2-(R)-(3-(S)-((4-(N-(2-Benzyl-2H-tetrazol-5-yl)methyl-N-ethylamino)-piperidine-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-Methoxybenzyl ester (from Step E) were added 150 mg of anisole and 3 ml of triflouroacetic acid. The reaction was stirred at room temperature for 1 hour. The trifluoroacetic acid was evaporated under reduced pressure. The residue was purified by flash chromatography with 20% MeOH in EtOAc followed by 20% MeOH+2% NH4OH in EtOAc to give 48 mg of the title compound. ESI−MS 601 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: OC1CCOCC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (ISN): 444.3 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[C@H:58]([OH:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[C@H:58]([OH:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: C[C@@H](O)[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)[C@@H](C)O)ccc1C(=O)N1CCCC1
Yield: 45 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R,2R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxypropylamine in tetrahydrofuran. Yield: 45%; Rf value: 0.36 (silica gel; ethyl acetate/ethanol=9:1); C23H25ClN4O3 (440.93); mass spectrum: (M+H)+=441/443 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](I)[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH3:20][O:21][CH2:22][C:23]#[CH:24]>C1COCC1.CC(OC)(C)C.O.[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>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:24]#[C:23][CH2:22][O:21][CH3:20])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1c(Br)cc(C(=O)O)cc1I
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COCC#Cc1cc(C(=O)O)cc(Br)c1C
Temperature: 65 °C

Procedure:
To a stirred solution of 3-bromo-5-iodo-4-methyl-benzoic acid in THF (0.98 M) was added triethylamine (7.5 equiv.) and copper iodide (0.01 equiv.) followed by PdCl2(PPh3)2 (0.005 equiv). Propargyl methyl ether (1.5 equiv.) was then added and the mixture heated to ˜65° C. for ˜24 h. The mixture was cooled to 20° C. and then diluted with MTBE and water. The layers were cut and the organic washed with further water. The combined aqueous layers were mixed with further MTBE and 5 N HCl. The organic layer was washed with 1M HCl, twice with 3% w/v sodium bisulfite and finally with water. The resultant solution was concentrated to ˜0.38 M and used in the next step as a solution in THF. 1H NMR (400 MHz, Acetone-d6): δ 8.13 (s, 1 H); 8.00 (s, 1 H); 4.40 (s, 2 H); 3.41 (s, 3 H); 2.59 (s, 3 H). FIRMS (ES, M−H) Calcd 280.9813. Found 280.9820.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([NH:34][CH2:35][CH2:36]O)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][CH2:35][CH2:36][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)NCCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-3-[2-(tert-Butylamino)ethyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(N-tert-butylamino)ethanol following General Procedure J.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH:6]=[CH:5]2.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1.C(Cl)Cl>>[C:20]([O:15][CH2:14][C@H:13]([N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[N+:17]([O-:19])=[O:18])[C:8]1=[O:12])[CH3:16])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 45 °C

Procedure:
A mixture of (R)-6-chloro-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (750.0 mg, 0.002653 mol), acetic anhydride (0.325 mL, 0.00345 mol), pyridine (0.322 mL, 0.00398 mol) and methylene chloride (20 mL, 0.3 mol) was heated at 45° C. over night. The solvent was removed under reduced pressure and dried to get pure product as thick yellow oil. MS m/z=325.4 (M+H). 1H NMR (400 MHz; DMSO) δ 8.42 (d, J=8.61 Hz, 1H), 7.47 (d, J=8.61 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 6.29 (d, J=8.03 Hz, 1H), 5.34-5.29 (m, 1H), 4.28-4.20 (m, 2H), 1.94 (s, 3H), 1.40 (d, J=6.96 Hz, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH3:21][O:22][C:23]1[C:31]([CH3:32])=[C:30]2[C:26]([C:27](=[O:33])[O:28][CH2:29]2)=[C:25]([O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[C:24]=1[CH2:41]/[CH:42]=[C:43](\[CH3:46])/[CH:44]=[O:45].[NH4+].[Cl-]>C1COCC1>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][O:34][C:25]1[C:24]([CH2:41]/[CH:42]=[C:43](\[CH3:46])/[CH:44]([OH:45])[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17])=[C:23]([O:22][CH3:21])[C:31]([CH3:32])=[C:30]2[C:26]=1[C:27](=[O:33])[O:28][CH2:29]2
Reactant: COCCOCOc1c(C/C=C(\C)C=O)c(OC)c(C)c2c1C(=O)OC2
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)C(O)/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
Freshly distilled diisopropylamine (0.425 ml) was dissolved in anhydrous THF (10 ml) and cooled to 0° C. n-BuLi (0.63 ml, 2.35M) was added slowly and the reaction was stirred at 0° C. for 20 minutes and cooled to -78°. Ethyl isobutyrate (0.200 ml) was added and the resulting solution was stirred at -78° C. for 40 minutes. A solution of (E)-4-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2-methylbut-2-enaldehyde (365 mg) in THF (10 ml) was added and stirred for 30 min. The reaction mixture was poured to a concentrated solution of NH4Cl, and extracted with ethyl acetate (3×30 ml), the organic layers were dried over Na2SO4, and evaporated to give 420 mg (87%) of ethyl (E)-6-(1,3-dihydro-4-methoxyethoxymethoxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2,2,4-trimethyl-3-hydroxy-4-hexenoate as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([CH3:15])[S:6][C:5]1=[S:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([CH3:15])[S:6][C:5]1=[S:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc(=S)n(CCO)c1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCn1c(-c2ccccc2)c(C)sc1=S

Procedure:
Intermediate 3-(2-hydroxyethyl)-5-methyl-4-phenyl-3H-thiazole-2-thione was treated with acetic anhydride (1 equiv) and TEA (2 equiv) in CHCl3. After 12 h the product mixture was concentrated and chromatographed (silica gel, 0-40% EtOAc/Hex) to afford the title compound. 1H-NMR (CDCl3): δ 7.50-7.55 (3H, m), 7.28-7.32 (2H, m), 4.32 (2H, t), 4.26 (2H, t), 2.03 (3H, s), 1.93 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C@H:15]3[CH2:19][O:18]C(=O)[NH:16]3)[CH:12]=2)[N:7]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:6]=1.[OH-].[Na+]>C(O)C>[NH2:16][C@@H:15]([CH2:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][CH:22]=1)[CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:34])[CH3:1])[CH2:19][OH:18]
Reactant: CN(C)CCc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccc(C[C@H]3COC(=O)N3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccc(C[C@H](N)CO)cc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
(S)-2-Amino-3-[3-(2-(dimethylamino)ethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol (48) was prepared as follows: A mixture of compound 45 prepared in Example 11 (0.2 g, 0.4 mmol), 4 mL NaOH (2N aqueous) and 4 mL of ethanol was shaken at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was extracted with CHCl3, concentrated and purified by column (silica gel, EtOAc/MeOH/NH4OH 80/20/2) to give compound 48 as a sticky oil, which was dissolved in 10 mL of HCl (0.2N aqueous), and freeze dried to afford a white solid (110 mg, HCl-salt, ˜50%): 1H-NMR (400 MHz, CD3OD) δ: 7.72 (s, 1H), 7.49-7.54 (m, 4H), 7.4-7.44 (m, 2H), 7.16-7.22 (m, 4H), 7.07-7.11 (m, 2), 3.73-3.75 (m, 1H), 3.53-3.62 (m, 4H), 3.08-3.12 (m, 2H), 3.1 (s, 6H); LC/MS: m/z=430.1 [M+H]+ (Calc: 429.5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][C:6]([C:15]([O:17]CC)=[O:16])=[CH:5]2.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)c(C(F)(F)F)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(F)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A solution of 1.85 g of ethyl 5-fluoro-6-trifluoromethylindole-2-carboxylate in 60 ml of ethanol was treated with 30 ml of 2N sodium hydroxide solution and stirred at room temperature for 1 hour. The alcohol was evaporated and the solution was adjusted to pH 1 with 2N hydrochloric acid. The separated crystals were isolated, washed with water and dried. There were obtained 1.5 g (90%) of 5-fluoro-6-trifluoromethylindole-2-carboxylic acid as brown crystals with m.p. 178°-180°.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25]([CH2:27][NH2:28])O>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH2:2]([C:1]1[O:24][CH2:25][CH2:27][N:28]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCCCCCCCCCCCCCCCC1=NCCO1

Procedure:
Following the procedure of Example 2, behenic acid was reacted with ethanolamine in the presence of titanium tetrabutylate as catalyst to form 2-heneicosyl-2-oxazoline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH:22]([NH:35][C:36](=[O:39])[CH2:37]Br)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:37][C:36](=[O:39])[NH:35][CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Reactant: O=C(CBr)NC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(CC(=O)NC(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 60.1 mg (0.23 mmol) of the compound from example 1g in 1 ml of absolute DMF was mixed with 11 mg (0.23 mmol) of sodium hydride (50%) and stirred at RT for 1 h. Then 70.3 mg (0.23 mmol) of the compound from example 10a were added, and the mixture was stirred at RT for 1 h. The reaction solution was mixed with 1 ml of water and extracted several times with EA. The combined EA extracts were dried over Na2SO4, filtered and concentrated. Purification of the resulting residue by chromatography on silica gel with CH2Cl2/methanol (9:1) as mobile phase afforded 71.4 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:16][CH2:15][CH2:14][C:8]=3[C:9](=[O:13])[NH:10][C:11]=2[CH:12]=1.[Mg]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9](=[O:13])[NH:10][C:11]=2[CH:12]=1
Reactant: COc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Agent: [Mg]
Product: COc1ccc2c(c1)NC(=O)C1CCCC21

Procedure:
7-methoxy-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (400 mg, 1.86 mmol) and magnesium (452 mg, 18.6 mmol) are converted into 180 mg (45%) of product analogously to Example 7.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][N:13]([C:24](=[O:46])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:45])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][N:13]([C:24](=[O:46])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:45])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3C(=O)N2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@@H](O)CN3C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of (2R,11aS)-2-(tert-butyldimethylsilyloxy)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one (5.53 g) prepared in Reference Example 68 in tetrahydrofuran (20 ml), there was dropwise added, with ice-cooling, a solution of tetrabutylammonium fluoride (4.54 g) in tetrahydrofuran (50 ml) over 5 minutes and the reaction solution was stirred at room temperature for 30 minutes. After the reaction solution was diluted with ethyl acetate, it was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained after concentration of the reaction solution was subjected to silica gel column chromatography and then eluted with chloroform/acetone (1/1) to give 4.1 g (yield 91.0%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)=[CH2:2].BrN1C(=[O:17])CCC1=O.[OH-].[Na+]>O.CC(O)(C)C>[O:17]1[CH2:2][CH:1]1[C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc(C#N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1ccc(C2CO2)nc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 6-ethenylpyridine-3-carbonitrile (0.742 g, 5.70 mmol) in a 2:1 ratio of H2O:t-BuOH (30 mL) was treated with N-bromosuccinimide in portions over 5 minutes (1.07 g, 5.99 mmol) and stirred at 40° C. for 1 hour. After cooling to 5° C., the reaction was basified with drop wise addition of a solution of sodium hydroxide (0.684 g in 5 mL of H2O, 17.1 mmol) and stirred for another 1 hour. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated aqueous NaCl (1×30 mL) and dried over MgSO4. Evaporation of the solvent and purification over SiO2 (0-30% EtOAc hexanes as eluent) provided 6-(oxiran-2-yl) pyridine-3-carbonitrile.
Reaction SMILES: [C:1]1([C@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=O.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.O>[C:1]1([C@H:11]([NH:13][CH:20]2[CH2:21][CH2:22][C:23]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](NC1CCc2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (R)-1-(naphthalen-1-yl)ethanamine (4.77 ml, 29.5 mmol) in methanol (50 mL) was added 3,4-dihydronaphthalen-2(1H)-one (4.80 g, 32.8 mmol) at 0° C. Acetic acid (2.349 mL, 41.0 mmol) was added and the reaction was stirred for 5 min. After that the reaction was warmed to RT and further stirred for 20 minutes. Again reaction was cooled to 0° C. and sodium cyanoborohydride (3.09 g, 49.2 mmol) was added stirred overnight at RT. After completion of reaction, —NaHCO3 solution (20 mL) and water (50 mL) were added and the mixture was extracted with ethyl acetate (50 mL×2). The extract was washed with saturated brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the crude compound. This was used directly in the next reaction (11.1 g, 36.8 mmol); m/z 302.65.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][N:4]1[C:12]([C:14]1[N:15]=[C:16]([CH3:25])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13].[O:26]1[C:30]2=[CH:31][CH:32]=[CH:33][C:34]([C:35](O)=[O:36])=[C:29]2[CH:28]=[CH:27]1>>[CH3:25][C:16]1[S:17][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]([C:12]([N:4]2[CH2:5][C@@H:6]3[C@H:11]([CH2:10][CH2:9][CH2:8][CH2:7]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[O:26][CH:27]=[CH:28][C:29]=23)=[O:36])=[O:13])[N:15]=1
Reactant: O=C(O)c1cccc2occc12
Reactant: Cc1nc(C(=O)N2CC3CCCCC3C2CN)c(-c2ccccc2)s1
Product: Cc1nc(C(=O)N2C[C@H]3CCCC[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c(-c2ccccc2)s1

Procedure:
The pair of stereo isomers Examples 70 and 71 were isolated by preparative HPLC from the coupling reaction according general procedure A (1-(aminomethyl)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and benzofuran-4-carboxylic acid. The assignment of stereochemistry is not verified. MS (ESI) 500 (M+H).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=[O:21])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>CO.O>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH2:20][OH:21])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCn1c(=O)c(CO)c(OC)c2cc(C)ccc21

Procedure:
A solution of 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 10 g) in methanol (80 ml) was cooled in an ice-bath and stirred while adding, in small lots, solid sodium borohydride (0.5 g). After stirring for an additional 5 mins the reaction mixture was carefully diluted with water and extracted with methylene chloride. The extracts are dried and evaporated under reduced pressure. The crude product is chromatographed on silica-gel. Elution with 30% acetone-hexane gave 1-hexyl-3-hydroxymethyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 303 (M+); NMR (CDCl3): δ4.0 (s, H, OCH3), 4.75 (d, 2H, CH2O).
Reaction SMILES: [Br:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[C:2]([Br:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(N)c1Br
Temperature: 80 °C
Yield: 84.8 %

Procedure:
To a stirred solution of methyl 2-bromo-3-nitrobenzoate (4 g, 15.38 mmol) in ethanol (20 mL), ammonium chloride (4 g, 74.07 mmol) dissolved in water (20 mL) and iron powder (6.88 g, 123 mmol) were added under stirring. Resulting reaction mixture was heated at 80° C. for 1 h. On completion, water was added to the mixture and filtered through celite. The filtrate was extracted with ethyl acetate and the combined organic layers washed with water and sodium bicarbonate solution, dried and concentrated under reduced pressure giving the desired methyl 3-amino-2-bromobenzoate (3 g, 85%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[CH:3]=1.[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:12][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: OC1CCNC1
Reactant: FC(F)(F)c1cc(Cl)cc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: OC1CCN(c2cc(Cl)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 1-bromo-3-chloro-5-(trifluoromethyl)benzene (5.0 g), 3-hydroxypyrrolidine (1.85 g), palladium(II) acetate (217 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.2 g) and cesium carbonate (18.8 g) in toluene (96 mL) was stirred under an argon gas atmosphere at 85° C. for 16 hr. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20-10:90) to give the title compound (4.11 g, yield 80%) as a brown oil.