Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[O:50]1[CH2:55][CH2:54][N:53]([C@H:56]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:57](O)=[O:58])[CH2:52][CH2:51]1>>[CH3:46][O:45][C:44]([NH:43][C@H:3]([C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[C@@H:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:57](=[O:58])[C@H:56]([N:53]3[CH2:54][CH2:55][O:50][CH2:51][CH2:52]3)[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[CH:23][CH:22]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:16][CH:17]=1)=[O:41])=[O:42])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:47]
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCOCC3)cc2)c2ccccc2)cc1)C(C)(C)C
Yield: 66.9 %

Procedure:
The product from Example 10A (40 mg, 0.060 mmol) and the product of Example 57A (19.9 mg, 0.090 mmol) were processed using the method described in Example 43 to afford 35 mg (67%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.80 (s, 1H), 9.78 (s, 1H), 7.35 (m, 3H), 7.28 (m, 2H), 7.14 (m, 3H), 6.97 (m, 4H), 6.88 (m, 3H), 6.46 (d, J=8.1 Hz, 2H), 6.37 (t, J=7.2 Hz, 1H), 4.40 (bs, 4H), 4.22 (m, 1H), 4.11 (m, 1H), 4.05 (m, 2H), 3.67 (m, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.34 (s, 3H), 3.30 (m, 3H), 3.24 (m, 2H), 2.49 (s, 8H), 2.22 (m, 2H), 2.12 (m, 2H), 1.92 (m, 1H), 1.79 (m, 3H), 1.62 (m, 4H), 0.77 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]([CH3:25])[CH3:26])[C:16]2=[O:27])=[CH:13][CH:14]=1
Reactant: CC(C)n1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reaction time: 5 h
Yield: 59.6 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) and 10% Pd—C (0.444 g) in EtOH (40 ml) was hydrogenated under balloon pressure at room temperature for 5 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (670 mg) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)c1ccc(F)cc1
Yield: 88.1 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)butyrate (45.3 g, 0.215 mol), 85% potassium hydroxide (14.22 g, 0.215 mol, Mallinckrodt) in 200 ml of deionized water was refluxed for 2 h, concentrated by spin evaporation in vacuo, made acidic (pH 3) with 12N hydrochloric acid (Mallinckrodt), and extracted with dichloromethane (4×200 ml). The dichloromethane layers were combined, washed with deionized water (50 ml), and concentrated by spin evaporation in vacuo. The residue was crystallized from dichloromethane-hexanes to give 34.5 g (88%) of 3-(4-fluorophenyl)butyric acid as a white crystalline solid;
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[C:12](=[CH2:15])[CH2:13][CH2:14][C:3]=12.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C(O)(C)C>O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[CH:12]([CH2:15][N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1ncc[nH]1
Reactant: C=C1CCc2c(C)c3ccccc3n2C1=O
Solvent: O
Solvent: CC(C)O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cn1ccnc1C)CC2
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-methylenepyrido[1,2-a]indol-6(7H)-one (142 mg), 2-methylimidazole (180 mg), isopropyl alcohol (1 ml) and water (0.4 ml) was heated at 100° C. for 3 hours. The reaction mixture was purified by a procedure analogous to that of Example 74 to give 8,9-dihydro-10-methyl-7-[(2-methyl-1H-imidazol-1-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (60 mg).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: CC(C)OC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-chlorobenzenesulfonic acid chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.O[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:22][CH:23]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.7 %

Procedure:
To a stirred mixture of 4-(1-(4-hydroxylphenyl)-2-phenylbut-1-enyl)phenol (500 mg, 1.0 eq), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (480 mg, 1.5 eq) and PPh3 (625 mg, 1.5 eq) in 25 mL anhydrous THF under nitrogen was added DIAD (480 mg, 1.5 eq) dropwise at 0° C. The reaction was stirred for 48 h at rt. Then the reaction was quenched with water and extracted with EtOAc. The extract was dried, concentrated and purified by column chromatography to give the desired product (400 mg, 51% yield, Z/E=1/1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:23]=[C:22]([C:24]2([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[C:20]([C:33]([F:36])([F:35])[F:34])[N:19]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:23]=[C:22]([C:24]2([C:29]([F:30])([F:31])[F:32])[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]4[CH2:15][CH2:14]4)=[O:12])[CH3:9])=[CH:4][CH:3]=3)[CH2:25]2)[CH:21]=[C:20]([C:33]([F:34])([F:35])[F:36])[N:19]=1
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(Br)cc1
Reactant: FC(F)(F)c1cc(C2(C(F)(F)F)CCNC2)cc(C(F)(F)F)n1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)C1CC1)c1ccc(N2CCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
To the solution of N-[(1S)-1-(4-bromophenyl)ethyl]cyclopropanecarboxamide (0.134 g) and 2,6-bis(trifluoromethyl)-4-[3-(trifluoromethyl)pyrrolidin-3-yl]pyridine (0.195 g) in toluene was added sodium tert-butoxide (0.096 g), tris(dibenzylideneacetone)dipalladium chloroform complex (0.010 g) and xantphos (0.017 g) and the vessel was applied by Ar gas. The vessel was sealed and applied to microwave reactor at 120° C. for 10 min. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-[(1S)-1-(4-{3-[2,6-bis(trifluoromethyl)pyridin-4-yl]-3-(trifluoromethyl)pyrrolidin-1-yl}phenyl)ethyl]cyclopropanecarboxamide (0.272 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[N:17]=1>CN(C=O)C.O>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:19][N:20]=3)[N:17]=2)=[N:5][CH:4]=[N:3]1
Reactant: Clc1ccc2nnc(-c3ccccc3)n2n1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1ccc2nnc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-methyl-2 H-1,2,4-triazol-3-yl)methanol (0.9 g, 8.0 mmol) (prepared using the conditions described in EP-A-421210) in DMF (30 ml) was added sodium hydride (0.32 g of a 60% dispersion in oil, 1.6 mol eq.) and the reaction mixture was stirred at room temperature for 30 minutes. After this time the product from Example 88 Step a) (1.15 g, 5.0 mmol) was added as a solution in DMF (20 ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (200 ml) and the aqueous extracted with dichloromethane (4×150 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using 4% MeOH in dichloromethane as eluent to give the required product, (1.5 g, mp=254° C.). 1H NMR (360 MHz, CDCl3) δ3.98 (3 H, s), 5.61 (2 H, s), 6.90 (1 H, d, J=9.8 Hz), 7.51-7.60 (3 H, m), 7.94(1 H, s), 8.12 (1 H, d, J=9.8 Hz), 8.39 (2 H, dd, J=9.6, 1.5 Hz); MS (ES+) m/e 308 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:22])=[O:21]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(F)c1F
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(F)c1F
Reaction time: 8 h
Yield: 57.4 %

Procedure:
2-Aminobenzenesulfonamide (26 mg, 0.15 mmol) was dissolved in pyridine (1 ml) and 2,3-difluorophenylsulfonyl chloride (19 μl, 0.15 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (30 mg, 58%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)C.B(Cl)(Cl)Cl.CO>ClCCl>[OH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[N:11]=[C:10]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2ccccc2)c2cccc(OC(C)C)c2n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccccc2)c2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 8-isopropoxy-2-methyl-4-phenyl-quinazoline (36) (0.34 mmol) in dichloromethane (2 mL) at −78° C. was added BCl3 (1.36 mL of a 1 M solution in dichloromethane, 1.36 mmol). The reaction mixture was allowed to warm to RT (over 2 h) and stirred for a further 2 h. MeOH (5 mL) was added and the mixture was concentrated to dryness. The process was repeated four times. Further washing of the remaining residue with diethyl ether (2 mL×3) provided 8-hydroxy-2-methyl-4-phenyl-quinazoline (A24).
Reaction SMILES: [Li].N.[CH2:3]([OH:6])[C:4]#[CH:5].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH3:11]>O.CCOCC>[CH2:3]([OH:6])[C:4]#[C:5][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CCO
Reactant: CCCCCBr
Agent: N
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: CCCCCC#CCO
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Under argon atmosphere, a small amount of lithium pieces was added to liquid ammonia (250 ml). The reaction mixture became dark blue in color. A catalytic amount of ferric nitrate nonahydrate was added and the mixture was stirred until the dark blue color disappeared. Lithium pieces (2.75 g, 396 mmol) were further added and the reaction mixture was stirred for one hour. Subsequently, propargyl alcohol (8.16 g, 146 mmol) was added and the mixture was stirred for 30 minutes. Then, n-pentyl bromide (20 g, 132 mmol) was added, and the mixture was stirred for 10 minutes and allowed to stand overnight at room temperature. Water-containing ether (50 ml) and water (200 ml) were added and the resulting mixture was extracted with ether (200 ml, 100 ml, 50 ml×3). The organic layers were combined, washed with water (400 ml) and with brine (400 ml), dried over anhydrous sodium sulfate (50 g) to concentrate. The residue was distilled (b.p.=58°-61° C. at 0.3 mmHg), yielding a colorless oil, 2-octyne-1-ol (9.5758 g, 52% yield). The above described structure of this product was confirmed by the following data.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([CH:7]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[CH2:8]1)(=O)[CH3:5]>N1C=CC=CC=1>[CH2:12]([N:10]1[CH2:11][CH:7]([C:4](=[N:2][OH:3])[CH3:5])[CH2:8][C:9]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)C1CC(=O)N(Cc2ccccc2)C1
Reaction time: 18 h
Yield: 104.2 %

Procedure:
Hydroxylamine hydrochloride (5.58 g, 0.076 mole) was added to a solution of 4-acetyl-1-benzyl-2-pyrrolidinone (15.0 g, 0.069 mole) in pyridine (250 mL) and the reaction mixture was heated at 40° with stirring under nitrogen for 18 hours. The solvent was removed under reduced pressure at 65° and the residue was dissolved in chloroform (900 mL), washed with water (500 mL), 0.5M HCl (3×500 mL), and dried (MgSO4). The solvent was removed under reduced pressure to give 1-benzyl-4-(1-hydroxyiminoethyl)-2-oxo-pyrrolidine (16.7 g, quant) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, light brown solid, m.p. 121° C. and MS: m/e=324.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9]C)=O)[CH:3]=[N:2]1.[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([C:7](=[O:9])[CH2:6][C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[C@@H:26]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cc1cn[nH]c1
Product: COc1ccc(N2CCN(C(=O)Cc3cn[nH]c3)[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Yield: 58 %

Procedure:
Prepared by the method outlined for Example 275 using methyl 1H-pyrazol-4-ylacetate and (S)-1-(3-cyclobutoxy-4-methoxyphenyl)-3-(4-fluorobenzyl)piperazine as starting materials. Product was obtained as a colorless solid (58%). LC/MS 3.44 min, [M+1]+ 479.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C[C@H](N)C(=O)O
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](C)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.1 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and L-alanine (45 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μl, 1.0 mmol). The mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off and the residue was chromatographed on a Sephadex LH20 column under the same conditions as above. The eluate was evaporated to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-alanine (23 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
An additional trial performed under the same operating conditions but in tert-butanol with another nitrated aromatic aldehyde i.e. 4-nitrobenzaldehyde provided tert-butyl 4-nitro-benzoate in a yield of only 13.5%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.C(N1CCOCC1)C.[NH2:56][CH2:57][C@H:58]([OH:61])[CH2:59][OH:60].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:56][CH2:57][C@H:58]([OH:61])[CH2:59][OH:60])=[O:19])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NC[C@H](O)CO
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC[C@H](O)CO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
A solution of 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4) (90 mg, 0.211 mmol) in DMF (2 mL) was treated with EDC (48.5 mg, 0.253 mmol), HOBT hydrochloride (38.8 mg, 0.253 mmol) and N-ethylmorpholine (0.080 mL, 0.633 mmol) and after 3 min with (S)-3-aminopropane-1,2-diol (38.5 mg, 0.422 mmol). The resulting mixture was stirred at room temperature for 5 h then EDC (48.5 mg, 0.253 mmol), N-ethyl morpholine (0.080 mL, 0.633 mmol), HOBT (38.8 mg, 0.253 mmol) and further (S)-3-aminopropane-1,2-diol (38.5 mg, 0.422 mmol) were added and the corresponding mixture was stirred for 16 h then concentrated in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N—((S)-2,3-dihydroxypropyl)benzamide (30 mg, 29%) as a white solid. LCMS (HpH, 2 min), Rt=0.75 min, MH+=500.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)o1
Yield: 97.5 %

Procedure:
1.88 g (5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature over the weekend with 1.12 g (11 mmol) of dipropylamine and 10 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed twice with water and dried over magnesium sulfate. After evaporating the solvent and crystallizing the residue from ethyl acetate and hexane there were obtained 2.15 g (98%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 134°-136°, which was converted into the hydrochloride of melting point 235°-237°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25])#[N:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25])#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C#N
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
40% Methanolic Triton B (0.24 mL, 0.53 mM) was added to a solution of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (140 mg, 0.41 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (130 mg, 0.82 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate/THF) to afford 116 mg (68%) of the {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.75 (d, 1H, J=8 Hz), 7.5-7.2 (m, 6H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 2H, J=8 Hz),), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.75 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 2228, 1732, and 1675. MS (ES) m/e 412, 414.