Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([O:12][C:13]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][C:16]([C:24]2[C:36]3[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=3[C:31]([Br:39])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:15][C:14]=1[Br:40])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>O1CCCC1.CO>[Br:40][C:14]1[CH:15]=[C:16]([C:24]2[C:36]3[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=3[C:31]([Br:39])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:17]=[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:13]=1[O:12][C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:41])=[O:2]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(C4CCCC4)c3)c2c1C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a solution of (2R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-cyclopentyl-phenoxy]-3-phenyl-propionic acid methyl ester (1.0 g, 1.5 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) at room temperature was added dropwise aqueous potassium hydroxide (3.0 mL of a 1 N solution, 3.0 mmol). After 4 h the reaction mixture was concentrated under reduced pressure. The residue was taken up in water (100 mL) and acidified with aqueous 10% hydrochloric acid. After stirring for 15 min the solid was filtered and washed with water:methanol (95:5). The solid was dried under a vacuum at 50° C. for 18 h to yield the title compound as a white solid (0.99 g, 100%): Opt. Rot. [a]25/D=+38.44° (9.624 mg/mL, MeOH); NMR (DMSO-d6): δ 13.01 (broad s, 1H), 8.19 (d, 1H), 7.67-7.62 (m, 1H), 7.54-7.22 (m, 9H), 4.92 (m, 1H), 3.46 (m, 1H), 3.34 (m, 2H), 2.42 and 2.41 (two singlets, 3H, rotational isomers), 1.99 (m, 1H), 1.98 (m, 1H), 1.72-1.27 (m containing two s at δ 1.57 and 1.53 (rotational isomers), 6H); MS(−ESI): [M−H], 2 bromine isotope pattern, 675 (72%), 677 (100%), 679 (66%); Anal. Calc. for C34H30Br2O3S: C, 60.19, H, 4.46, N, 0.00. Found: C, 59.53, H, 4.35, N, −0.04.
Reaction SMILES: C(OC([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([N:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1>FC(F)(F)C(O)=O>[N:14]1([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:15][CH2:16][C@@H:17]2[CH2:18][NH:11][CH2:12][C@H:13]12
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CN(C(=O)OCc5ccccc5)C[C@@H]43)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Yield: 64.4 %

Procedure:
The product of Example 1D ((3aR,6aR)-1-(4′-Cyano-biphenyl-4-yl)-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid benzyl ester) (750 mg, 1.77 mmole) was refluxed in 10 ml trifluoroacetic acid for 2.5 hours. The solution was concentrated and triturated with dichloromethane. The residue was redissolved in dichloromethane and stirred with sodium bicarbonate powder. The solution was loaded on a silica gel column and purified by chromatography (0.6% ammonium hydroxide and 6% methanol in dichloromethane) to provide the title compound (330 mg, 64%). 1H NMR (CDCl3) δ ppm 7.64 (d, J=2.71 Hz, 4H) 7.51 (d, J=8.81 Hz, 2H) 6.66 (d, J=8.82 Hz, 2H) 4.07-4.17 (m, 1H) 3.50-3.65 (m, 1H) 3.24-3.36 (m, 1H) 2.86-3.10 (m, 5H) 2.15-2.29 (m, 1H) 1.74-1.93 (m, 1H). MS: (M+H)+=290.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7])#[N:2].[CH3:12][Mg]Br>C1COCC1>[F:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:12])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)c(C#N)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
3-Cyano-4-fluorobenzaldehyde (2.17 g, 14.7 mmol) was dissolved in THF (50 mL) then cooled to −70° C. To this mixture was added methyl magnesiumbromide (5.34 mL, 16.0 mmol). The mixture was stirred for 1 h, then was quenched with brine and extracted with ether. The ethereal layer was separated, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by MPLC chromatography through a 120 g Redi-sep column using 0-50% EtOAc/hexane eluent to yield 2-fluoro-5-(1-hydroxyethyl)benzonitrile: LC-MS: M+1=166.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=C(N=C=S)C=CC=1>>[CH3:48][O:52][C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: COc1cccc(N=C=S)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(OC)c4)cc3)ccc2C1=O

Procedure:
The compound of example 262 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-methoxy phenyl isothiocyanate. The compound of example 262 was used directly without isolation for the preparation of compound of example 263.
Reaction SMILES: C([C:10]1[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([N:24]2[N:28]=[C:27]3[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:26]3=[N:25]2)[C:11]=1[OH:37])(C1C=CC=CC=1)(C)C.[Cl:38][O-].[Na+].C(O)C.CCCCCCC.O>>[Cl:38][C:10]1[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:13]=[C:12]([N:24]2[N:28]=[C:27]3[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:32][C:26]3=[N:25]2)[C:11]=1[OH:37]
Reactant: [O-]Cl
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(Cl)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Temperature: 45 °C

Procedure:
A flask containing 2-cumyl-4-(1,1,3,3-tetramethyl-butyl)-6-(5-trifluromethyl-benzotriazol-2-yl)phenol (7.5 g, 0.014 mol), 7% aqueous sodium hypochlorite (125 g, 0.12 mol), ethanol (85 g, 1.83 mol), and heptane (85 g, 0.84 mol) is heated to 45° C. with agitation. After a one hour hold, water (150 g, 8.33 mol) and heptane (150 g, 1.49 mol) are added to the reaction mass to dissolve all solids. The aqueous layer is removed and heptane is distilled off yielding a white residue. The white residue is crystallized from methanol yielding the title compound as a white solid (5.4 g, 91%) melting at 72-81° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:48]1[NH:53][CH2:52][CH2:51][N:50]2[CH2:54][CH2:55][CH2:56][CH:49]12>CN(C=O)C>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:53]3[CH2:52][CH2:51][N:50]4[CH2:54][CH2:55][CH2:56][CH:49]4[CH2:48]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: C1CC2CNCCN2C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN4CCCC4C3)cn2)c1O
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (500 mg, 1.561 mmol), EDC (449 mg, 2.342 mmol) and HOBT (316 mg, 2.342 mmol) in DMF (3122 μl) and treated with DIPEA (818 μl, 4.68 mmol). Octahydropyrrolo[1,2-a]pyrazine (296 mg, 2.342 mmol) was then added. The reaction was allowed to stir for 8 hours and filtered and the filtrate was purified by preparative HPLC (15-40% ACN/water under basic conditions) to give a solid which was recrystallized from MeOH, filtered, and dried in vacuum to give the title compound (286 mg, 0.603 mmol, 38.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (br. s., 1 H) 1.72 (br. s., 3 H) 2.12 (br. s., 1 H) 2.23 (d, J=7.07 Hz, 2 H) 2.42 (s, 3 H) 2.51-2.53 (m, 1 H) 3.06 (t, J=8.08 Hz, 3 H) 3.72 (br. s., 1 H) 4.44-4.56 (m, 1 H) 7.63 (dd, J=8.08, 1.77 Hz, 1 H) 7.69 (d, J=1.26 Hz, 1 H) 7.84 (d, J=8.08 Hz, 1 H) 8.04 (dd, J=8.59, 2.27 Hz, 1 H) 8.09 (s, 1 H) 8.40 (d, J=7.58 Hz, 1 H) 8.52 (d, J=2.27 Hz, 1 H); ESI-MS m/z (M+H)+ calc'd for C24H24N6O2, 429.20; found 429.3.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:28]=[CH:27][C:15]([C:16]([N:18]4[CH2:23][CH2:22][C:21]5[CH:24]=[CH:25][O:26][C:20]=5[CH2:19]4)=[O:17])=[CH:14][CH:13]=3)[S:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[CH2:34]=O>C(O)(=O)C>[C:1]1([C:7]2([C:12]3[CH:28]=[CH:27][C:15]([C:16]([N:18]4[CH2:23][CH2:22][C:21]5[CH:24]=[C:25]([CH2:34][N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)[O:26][C:20]=5[CH2:19]4)=[O:17])=[CH:14][CH:13]=3)[S:8][CH2:9][CH2:10][S:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(C2(c3ccccc3)SCCS2)cc1)N1CCc2ccoc2C1
Reactant: C=O
Reactant: C1CCNC1
Solvent: CC(=O)O
Product: O=C(c1ccc(C2(c3ccccc3)SCCS2)cc1)N1CCc2cc(CN3CCCC3)oc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.719 g (1.764 mmol) of 6-[4-(2-phenyl-1,3-dithiolan-2-yl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.22 ml (2.65 mmol) of pyrrolidine and 0.21 g (2.65 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)(=[O:4])[CH3:3].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].O>ClCCl>[C:2]([O:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:19](=[O:21])[CH3:20])[S:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(=O)OCc1csc(N)n1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(COC(C)=O)cs1
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a mixture of (2-amino-1,3-thiazol-4-yl)methyl acetate hydrochloride (56 g) and pyridine (45 g) in dichloromethane (560 ml) was added acetyl chloride (23 g) over a period of 30 minutes at 5° C., and the reaction mixture was stirred for 10 minutes at the same temperature. The reaction mixture was poured into water (500 ml) and extracted with chloroform (1 L). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residual solid was collected by filtration with isopropyl ether to give (2-(acetylamino)-1,3-thiazol-4-yl)methyl acetate (47 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:41][CH2:42][O:43][CH3:44])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:28][CH:27]=3)[S:25][C:18]=12.O>CS(C)=O.NC1C=CC(O)=C(F)C=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:41][CH2:42][O:43][CH3:44])[C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:28][CH:27]=4)[S:25][C:18]=23)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a solution of 4-amino-2-fluorophenol (4, scheme 1) (14.29 g, 112 mmol 1.2 eq.), in DMSO (117 mL) was added potassium tert-butoxide (13.66 g, 122 mmol, 1.3 eq.), over 5 min. The reaction mixture was stirred at r.t. for 30 minutes. tert-Butyl (6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl) methyl(2-methoxyethyl)carbamate (11) (40.65 g, 94 mmol, 1 eq) was added and the reaction mixture was heated at 100° C. for 1.5 h. Additional amounts of the phenol 4 (0.83 g, 6.53 mmol, 0.07 eq.) in DMSO (5 mL) and potassium tert-butoxide (1.05 g, 9.38 mmol, 0.1 eq.) were added to the reaction mixture which was heated at 100° C. for an additional 30 min. After cooling down to r.t., the reaction mixture was poured into water (900 mL) at 40° C. over 15 min. After stirring for 15 min at 40° C., the mixture was cooled to r.t. over 1 h. The solid was collected by filtration and the cake was washed with water (2×115 mL). The product was dried in vacuum for 16 h then triturated with MTBE (115 mL) for 1 h, collected by filtration and the cake was washed with MTBE (2×20 mL). The product was dried in a vacuum oven (45° C.) to afford title compound 13 as a beige solid (44.02 g, 84 mmol, 90% yield).
Reaction SMILES: C(OC([N:8]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[CH:46][N:45]=1)[C:9]1[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[N:37]=[CH:36][C:35]4[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=4)[C:29]3=[O:43])[C:18]=2[CH2:19][O:20]C(=O)C)[CH:10]=1)=O)(C)(C)C.O.[OH-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:17]([C:11]3[CH:10]=[C:9]([NH:8][C:44]4[CH:49]=[CH:48][C:47]([CH2:50][N:51]5[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]5)=[CH:46][N:45]=4)[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=3)[C:18]=1[CH2:19][OH:20])[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(=O)OCc1c(-c2cc(N(C(=O)OC(C)(C)C)c3ccc(CN4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Acetic acid 2-(5-{tert-butoxycarbonyl-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (1.5 g, 1.92 mmol) was dissolved in 19 ml of dioxane. Lithium hydroxide monohydrate (404 mg, 9.62 mmol) was dissolved in 19 ml of water and added dropwise. The reaction was heated at 50 degrees centigrade for 2 hrs. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (20 ml) and heated in a microwave reactor at 140 degrees for 30 min. The reaction was concentrated and the residue was purified by flash chromatography using a gradient of 0% to 15% methanol in DCM. The residue was diluted with DCM and concentrated again. Isopropyl acetate was added and the mixture was heated in a water bath to form a solution. The solution was cooled to room temperature and allowed to stand at room temperature overnight. The solid that formed was filtered and dried to give 185 mg of 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-phthalazin-1-one. A second crop of crystals yielded 88 mg of product for a combined yield of 273 mg (22.3%). MS: (M+H)+=638; MP=235.0-238.0° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.12 (s, 3 H) 2.19-2.41 (m, 8 H) 3.60 (s, 3 H) 4.32-4.40 (m, 2 H) 4.58-4.63 (m, 1 H) 4.60-4.61 (m, 1 H) 7.25 (d, J=8.59 Hz, 1 H) 7.34-7.44 (m, 3 H) 7.52 (s, 2 H) 7.52-7.54 (m, 1 H) 7.74 (dd, J=13.14, 1.52 Hz, 1 H) 7.87 (d, J=1.52 Hz, 1 H) 8.04 (d, J=2.02 Hz, 1 H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CC(O)=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-morpholin-4-ylmethyl-benzene-1,2-diamine (2.30 g, 11.1 mmol), 4-nitro-1H-pyrazole-3-carboxylic acid (1.57 g, 10.0 mmol), EDC (2.13 g, 11.1 mmol) and HOBt (1.50 g, 11.1 mmol) in dry DMF (25 ml) was stirred at ambient temperature for 24 hours. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (40 ml) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 0-20% MeOH in EtOAc to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)IH-benzimidazole as a yellow solid. (1.0 g, 61%). (LC/MS: Rt 1.83, [M+H]+329).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].[C-:16]#[N:17].[Na+]>CN(C=O)C>[C:2]1([C:13]#[N:14])[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2c(I)cccc12
Reactant: N#C[Cu]
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc2c(C#N)cccc12
Reaction time: 4 h
Yield: 81.2 %

Procedure:
1,5-Diiodonaphthalene (8.4 g) was reacted with a mixture of 4.2 g CuCN and 40 ml DMF under reflux conditions overnight. The mixture was cooled and poured into 120 ml aqueous solution containing 12.6 g NaCN. The mixture was stirred for four hours and the filtered product was repeatedly washed with copious amounts of water and dried. The isolated crude product (3.6 g, 92% yield, m.pt., 258–260° C.) was recrystallized from toluene to yield 3.2 g of the product (81% yield, m.pt., 260–262° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH2:18])[CH2:7][N:6]1[CH3:19].C(N(CC)CC)C.[CH3:27][C:28]([CH2:34][CH3:35])([CH2:32][CH3:33])[C:29](Cl)=[O:30].O>ClCCl>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:29](=[O:30])[C:28]([CH2:34][CH3:35])([CH3:27])[CH2:32][CH3:33])[CH2:7][N:6]1[CH3:19]
Reactant: Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](N)CN1C
Reactant: CCC(C)(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(C)(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h

Procedure:
A supension of 68 g 2,6-dimethyl-8α-aminoergoline in 1.5 l dichloromethane are pre-cooled to 4° and treated with 78 ml triethylamine. The mixture is treated under stirring dropwise within 25 minutes with 40.5 g 2-methyl-2-ethyl-butyryl chloride. The mixture is stirred for 30 minutes, poured onto 3 l water, the organic phase is dried (Na2SO4) and concentrated. The residue is chromatographed on 800 g silica gel using dichloromethane/methanol (98:2) to yield the title compound, which is crystallised from diethyl ether, m.p. 191°-192°.
Reaction SMILES: [CH2:1]([S:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)=[O:34])[CH3:2]
Reactant: CCS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCS(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 95.4 %

Procedure:
To a solution of (11β,17β)-17-(ethylthio)-9-fluoro-11-hydroxyandrosta-1,4-dien-3-one (700 mg, 1.92 mmole; see example 6) in chloroform (30 ml) was added a solution of 86% m-chloroperbenzoic acid (390 mg, 1.95 mmole) in chloroform (15 ml). An instantaneous reaction was noted (tlc). The solution was then washed with a 10% potassium carbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford the title compound (697 mg) as a solid. One crystallization of this from ethyl acetate followed by drying (100° C., 0.3 mm of Hg, 10 hours) gave the analytical specimen of the title compound (600 mg), melting point 247°-250° C., with consistent spectral data.
Reaction SMILES: [C:1]([CH:6]([C:18]([OH:20])=O)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:27][C:28]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:29]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>C(Cl)Cl.CN(C)C=O>[C:30]([C:29]1[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=1[NH:27][C:18](=[O:20])[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cl)ccc1C(=O)c1ccccc1

Procedure:
A suspension of 45.0 g. of 2-carbethoxy-N-(benzyloxycarbonyl)glycine in 120 ml. of dry methylene chloride, cooled to -20° C., is treated portionwise with 30 g. of phosphorus pentachloride and stirred for 30 minutes at -20° C. to -10° C. To the now clear solution, there is added at the same temperature a solution of 27.7 g. of 2-amino-4-chlorobenzophenone and 1 ml. of dimethylformamide in 120 ml. of dry methylene chloride. The mixture is concentrated under reduced pressure at 40°-45° C. The residue is partitioned between methylene chloride and 10% aqueous soda solution and the methylene chloride phase is dried over sodium sulfate and evaporated to dryness. There is obtained a reddish-colored resin of crude 2'-benzoyl-2-[(benzyloxycarbonyl)amino]-2-carbethoxy-5'-chloroacetanilide, which is then immediately reacted with 130 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After stirring at room temperature for 90 minutes, the obtained solution is concentrated at 45° C. and the oily residue partitioned between water and ether. The aqueous solution is made weakly alkaline with solid sodium bicarbonate while cooling with ice. The separated base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated to dryness. The resulting oil is dissolved in a mixture of 180 ml. of toluene and 180 ml. of glacial acetic acid and heated at 80° C. for 90 minutes. The solution is concentrated to an oil and is crystallized from ether so that there is obtained 8-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester, having a melting point of 214°-217° C. (decomposition). Recrystallization from acetonitrile does not increase the melting point.