Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[O:7]([CH:14]1[CH2:17][NH:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+]([NH:21][C:22](N)=[O:23])([O-])=O.C(N(CC)CC)C>CC(C)=O.O>[O:7]([CH:14]1[CH2:17][N:16]([C:22]([NH2:21])=[O:23])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: c1ccc(OC2CNC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)N1CC(Oc2ccccc2)C1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A stirred slurry of 7 g (0.03 mole) of 3-phenoxyazetidine oxalate [1:1] in 100 ml of acetone was treated with 5.3 g (0.05 mole) of nitrourea then after 30 min, treated with 5 ml of water and 5 ml of triethylamine. After stirring for 8 hr, the reaction mixture was diluted with 125 ml of water and stirred until a fine white crystalline solid precipitated. Filtration yielded 3.85 g, m.p. 179°-186° C. The solid was recrystallized from tetrahydrofuran to yield 1.3 g (22.5%) of fine white crystals, m.p. 195°-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([NH:1][C:26]([C:16]2[N:17]([CH3:25])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:15]=2)=[O:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Product: Cn1c(C(=O)Nc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Using essentially the same procedure as Example 4, Step B, but using aniline (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C@H:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1)[CH3:19].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:29](=[O:30])[CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:20][CH2:18][CH3:19])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:33][CH:32]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: Clc1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a suspension of N,N-bis(4-chlorobenzyl)amine (0.958 g, 3.60 mmol) in methylene chloride (30 mL) were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) and N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 1.02 g (62%) of an oil, which solidified upon standing to give white solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:20]([OH:38])=[CH:19][CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:38][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(Cl)ccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
A flask was charged with tert-butylbromoacetate (0.42 ml), dry DMF (20 ml), potassium carbonate (0.36 g) and the product from example 1 step (ii) (0.9 g) and then stirred at room temperature overnight. The mixture was quenched in water and extracted with diethylether, dried (MgSO4) and concentrated under reduced pressure to give an oil. The oil was purified by chromatography on silica eluting with isohexane/diethylether 2:1 to give the sub-title compound as a colourless oil, yield 0.6 g.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]1(OB(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: OB(O)Oc1ccccc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 33.9 %

Procedure:
Scheme VI, Step A′: Into a 10 mL single neck flask was placed [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (113 mg, 0.29 mmol, prepared in example 1), phenyl boric acid (54 mg, 0.44 mmol), potassium carbonate (61 mg, 0.44 mmol), and tetrakis(triphenyl phosphine)Pd(0) (17 mg, 0.02 mmol) in a mixture of dioxane/water (3:1, 7 mL). The mixture was then heated at 100° C. with stirring for 18 hours. The reaction was then cooled to room temperature and poured into H2O. The mixture was extracted with EtOAc and the organic layer was washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via radial chromatography (Chromatotron, Harrison Research Inc., 840 Moana Court, Palo Alto, Calif. 94306) using a 2000 micron rotor (silica gel) and eluting with a solvent of Hexane/EtOAc 4:1 to provide the title compound (33 mg, 34%) as a slowly crystallizing tan oil. Ion spray M.S. 335 (M*+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C@@H:9]2[C:20]([O-:22])=O)[CH:5]=[CH:6][CH:7]=1.ClCCCl.CCN(C(C)C)C(C)C.[NH2:36][C:37]1[CH:46]=[CH:45][C:44]([C:47]([NH2:49])=[O:48])=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2>>[C:47]([C:44]1[CH:45]=[CH:46][C:37]([NH:36][C:20]([CH:9]2[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10]2)=[O:22])=[C:38]2[C:43]=1[N:42]=[CH:41][CH:40]=[CH:39]2)(=[O:48])[NH2:49]
Reactant: NC(=O)c1ccc(N)c2cccnc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)[O-])[C@@H](c2cccc(F)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccc(C(N)=O)c3ncccc23)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(3R,4S)-4-(3-fluoro-phenyl)-pyrrolidine-1,3-dicarboxylate (125.00 mg; 0.40 mmol; 1.00 eq.) in DCE (4.0 ml) bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (102.87 mg; 0.40 mmol; 1.00 eq.) was added. After stirring for 15 mins at RT, DIEA (0.15 ml; 0.81 mmol; 2.00 eq.) and 5-aminoquinoline-8-carboxamide (75.65 mg; 0.40 mmol; 1.00 eq) were added. The reaction mixture was stirred overnight at 60° C. The crude was purified by prep HPLC to yield (4S)-tert-butyl 3-((8-carbamoylquinolin-5-yl)carbamoyl)-4-(3-fluorophenyl)pyrrolidine-1-carboxylate, which was added 1 ml 4.0M HCl and 1 ml methanol, stirred at RT for 3 h. The reaction mixture was concentrated, neutralized to Ph 7 and purified by prep HPLC to afford Example 27. (M+H=479, obsd=479).
Reaction SMILES: [NH2:1][C:2]([C:5]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2S(C)(=O)=O)=[O:12])[C:8]([OH:26])=[C:7]([OH:27])[N:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:35][CH2:36][S:37]([O:26][C:8]1[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])=[N:10][C:5]([C:2]([NH:1][S:37]([CH2:36][Cl:35])(=[O:39])=[O:38])([CH3:4])[CH3:3])=[N:6][C:7]=1[OH:27])(=[O:39])=[O:38]
Reactant: CC(C)(N)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)n1
Reactant: O=S(=O)(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NS(=O)(=O)CCl)c1nc(O)c(OS(=O)(=O)CCl)c(C(=O)NCc2ccc(F)cc2)n1
Reaction time: 8 h

Procedure:
To a solution of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide hydrochloride (prepared as described in WO2003035076 A1) in dichloromethane, triethylamine (4 eq.) was added and the mixture was cooled down with an ice/salt bath. A solution of chloromethanesulfonyl chloride in dichloromethane was added dropwise to the mixture. After 2 hours further triethylamine (1 eq.) and chloromethanesulfonyl chloride (1 eq.) were added at 0° C. and the reaction mixture was aged at room temperature overnight. To allow complete consumption of starting material, additional Et3N (0.5 eq.) and chloromethanesulfonyl chloride (0.5 eq.) were added at 0° C. After one hour, the mixture was poured in dichloromethane and washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain title compound as yellow oil. 1H NMR (300 MHz, d6-DMSO) δ 13.32 (bs, 1H), 9.19 (t, J=6.0 Hz, 1H), 8.03 (s, 1H), 7.37 (dd, J=8.4 Hz, J=5.7 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 5.59 (s, 2H), 4.86 (s, 2H), 4.45 (d, J=6.2 Hz, 2H), 1.64 (s, 6H); MS (ES) C17H19Cl2FN4O7S2 requires 545. Found: 546 (M+H+).
Reaction SMILES: CON(C)[C:4](=[O:16])[CH2:5][C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>CCOCC>[O:16]=[CH:4][CH2:5][C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]
Reactant: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](CC=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of (R)-tert-butyl 4-(methoxy(methyl)amino)-4-oxobutan-2-ylcarbamate (2.48 g, 10.1 mmol) in Et2O (25 mL) cooled to −5° C. was added dropwise a 2.0 M solution of LAH in THF (6.28 mL, 12.6 mmol). After the addition, the resulting slightly milky solution was stirred at 0° C. for 1.5 hr. The reaction mixture was quenched with 1 M aqueous KHSO4 (20 mL) and diluted with water (30 mL). The resulting solution with white milky precipitate was extracted with Et2O (3×). The combined Et2O extracts were washed with 0.5 M aqueous KHSO4 (2×20 mL), saturated aqueous NaHCO3, water, and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was dried under vacuum to give (R)-tert-butyl 4-oxobutan-2-ylcarbamate (1.57 g, 8.40 mmol, 84% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1H), 4.64 (s, 1H), 4.20-4.08 (m, 1H), 2.69-2.52 (m, 2H), 1.43 (s, 9H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH2:16][CH2:15][C:14]=1[CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCC1=C(Cl)C(Cl)=CCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (3.86 g, 20 mmol), (2,3-dichlorocyclohexa-1,3-dienyl)methanamine (3.52 g, 20 mmol) and K2CO3 (4.14 g, 30 mmol) in DMF (100 mL) was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (500 mL). It was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet Ether=1/6 to afford the desired product as a yellow solid (3.37 g, 51%); LC/MS: MS (ES+) m/e 332 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 4.82 (d, J=5.7 Hz, 2H), 6.84 (dd, J=0.9, 6.6 Hz, 1H), 7.28-7.34 (m, 2H), 7.55 (dd, J=2.1, 6.6 Hz, 1H), 8.48 (dd, J=0.9, 6.6 Hz, 1H), 9.22 (t, J=5.7 Hz, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:9][C:10]=1[C:11]#[N:12])C=C.CN1C(=O)[CH2:24][CH2:23][CH2:22]1>>[CH2:24]([C:6]1[C:5]([OH:4])=[C:10]([C:11]#[N:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:23]=[CH2:22]
Reactant: CN1CCCC1=O
Reactant: C=CCOc1cc(NC(=O)C(C)(C)C)ccc1C#N
Product: C=CCc1c(NC(=O)C(C)(C)C)ccc(C#N)c1O
Temperature: 25 °C

Procedure:
A solution of compound 10C (1.5 g, 5.8 mmol) in NMP (7 mL) was heated to 220° C. for 3 h. After cooling to rt, the reaction mixture was poured into ice/water, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was chromatographed (silica gel) eluting with 0% to 50% EtOAc/hexane to furnish the title compound (0.7 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[C:8]([NH:11][CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21](F)=[C:20]([F:25])[CH:19]=2)[CH2:14]1)(=[O:10])[CH3:9]>CN(C)C=O>[F:25][C:20]1[CH:19]=[C:18]([C:15]2[CH2:14][CH:13]([CH2:12][NH:11][C:8](=[O:10])[CH3:9])[O:17][N:16]=2)[CH:23]=[CH:22][C:21]=1[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NCC1CC(c2ccc(-n3cccc3)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
Pyrrole (0.299 ml) is dissolved in 7 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with 60% sodium hydride (132 mg) and the mixture is stirred 20 minutes at room temperature. The solution is treated with (-)-5-(acetamidomethyl)-3-(3,4-difluorophenyl)-isoxazoline (Step 1, Example 11) (763 mg), and the reaction is stirred 2 hours at 50-60° C. The reaction is cooled, the dimethylformamide is removed under a stream of nitrogen, and the residue is washed with water followed by diethyl ether and is dried to give an off-white solid. The crude material is chromatographed over 25 g silica gel (230-400 mesh), eluting with 5% methanol/dichloromethane while collecting 5 ml fractions. Fractions 13-30 are combined and concentrated to give 520 mg (58%) of the title compound as a white solid, mp 176-177° C., [α]25D -73° (c 0.75).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:10]2=[CH:11][C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[N:9]2[CH2:8][CH2:7]1.[OH-].[Na+].CC1C=CC([CH2:27][O:28]C(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CN(C)C=O>[CH2:6]1[C:10]2=[C:11]([CH:27]=[O:28])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[N:9]2[CH2:8][CH2:7]1
Reactant: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Reactant: c1cnc2c(c1)cc1n2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c2n(c3ncccc13)CCC2
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
Phosphorus oxychloride (3.85 ml) was added dropwise to N,N-dimethylformamide (25 ml) cooled in an ice-bath. The mixture was stirred 10 min before the addition of 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene (4.40 g) in N,N-dimethylformamide (7 ml). The mixture was stirred 45 min at 40° C., cooled to room temperature and concentrated aqueous sodium hydroxide added dropwise to pH10. The mixture was heated at 50° C. 10 min, cooled to room temperature and poured onto crushed ice. The organics were extracted with ethyl acetate (2×), the combined organic phases washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1 to 1:0) to afford 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene-8-carbaldehyde (2.4 g, 46%) as a light orange oil which solidified on standing. Mp. 137-141; MS (EI): 187 (M+H)+, 143, 100; 1H NMR (δ, CDCl3) 10.01 (s, 1H), 8.45 (dd, 1H, J=1,8 Hz), 8.32 (dd, 1H, J=1,5 Hz), 7.23 (dd, 1H, J=5,8 Hz), 4.31 (t, 2H, J=6 Hz), 3.38 (t, 2H, J=8 Hz), 2.76 (dt, 2H, J=6,8 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[CH3:26]S(C)=O.CI.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24]
Reactant: CS(C)=O
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc2c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(C)c(-c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
6-Bromo-3-methyl-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (15.6 g, 38.0 mmol), dimethyl sulfoxide (DMSO) (190 ml), methyl iodide (4.76 mL, 76 mmol) and cesium carbonate (12.39 g, 38.0 mmol) were added to a 500 mL flask The mixture was stirred at RT for 2 h. Water (200 mL) was added to the resulting slurry, and the mixture was stirred for 10 min, the solid was collected by filtration, and the filter cake was washed with 500 mL of water. The resulting solid was dried under reduced pressure to afford the desired product as a tan solid (15.75 g, 98%). MS (m/z) 426.0 (M+H+).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:17]([CH2:18][CH:19]=1)=[C:16]1[C:12]([N:13]([CH2:20][CH:21](O)[CH3:22])[N:14]=[CH:15]1)=[CH:11]2.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:31]([CH:21]([CH3:22])[CH2:20][N:13]1[C:12]2=[CH:11][C:10]3[C:17]([CH2:18][CH:19]=[C:8]([O:7][CH3:6])[CH:9]=3)=[C:16]2[CH:15]=[N:14]1)=[N+:32]=[N-:33]
Reactant: COC1=CCC2=c3cnn(CC(C)O)c3=CC2=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC1=CCC2=c3cnn(CC(C)N=[N+]=[N-])c3=CC2=C1
Yield: 82.4 %

Procedure:
1.15 ml (14.2 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.74 g (7.12 mmol) of (RS)-1-(6-methoxy-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 3.85 ml (28.5 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 50 minutes. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.92 g (14.2 mmol) of sodium azide and the reaction mixture was heated to 90° for 5 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.58 g (82%) of (RS)-1-(2-azido-propyl)-6-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(C=O)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(CO)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 0.10 g (0.227 mmol) of the product of Example 335 in 5 mL of methanol and 2.0 mL of THF was added 8.6 mg of sodium borohydride. The reaction was stirred for 1 h at room temperature and then concentrated in vacuo. The residue was diluted with dichloromethane, washed with water, and the organics were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting tan solid was washed with ether and dried in vacuo to give 0.086 g (86%) of the alcohol. Electrospray Mass Spec: 442.9 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[N:9]=[CH:8][N:7]=1)=[O:5].[C:33]1([Mg]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>C1COCC1>[C:4]([C:6]1[N:7]=[CH:8][N:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:11]=1)(=[O:5])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(C)OC)ncn3)CC1)C(=O)N2
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4ccccc4)ncn3)CC1)C(=O)N2
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 100 mg (0.227 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acidmethoxy-methyl-amide were cooled to −10° C. in 5.00 mL THF and combined with 0.400 mL (0.400 mmol) phenylmagnesium bromide solution (1M in THF). The mixture was stirred for 1 h at −10° C. and then heated to 0° C. Then 0.200 mL (0.200 mmol) phenylmagnesium bromide solution (1M in THF) were added, the mixture was stirred for 1 h and then heated to RT. The reaction mixture was combined with a saturated ammonium chloride solution and extracted with EtOAc. The combined organic phases were dried and evaporated down i. vac. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and evaporated down by half. The precipitate formed was suction filtered and dried.