Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([NH:31][CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]>ClCCl>[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([N:31]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(OC)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
Add ethyl chloroformate (0.118 mL, 1.240 mmol), followed by pyridine (0.205 mL, 2.52 mmol), to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol) in dichloromeihane (3 mL). After stirring at room temperature for 12 h remove the solvent in vacuo. Purify using silica gel chromatography, eluting with ethyl acetate/hexane (gradient eluent, 0-30% ethyl acetate in hexane) to afford the title compound (0.218 g, 92%): MS (ES+): 578 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3S(C3C=CC=CC=3)(=O)=O)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10].[OH-].[Na+]>C(O)(C)C.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:44][CH2:45][N:46]([CH:49]([CH3:50])[CH3:51])[CH2:47][CH2:48]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:10])=[O:11]
Reactant: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
2,4-Difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide (81 mg, 0.106 mmol) was suspended in isopropanol (2 ml) and 2M sodium hydroxide (aq) (0.53 ml, 1.060 mmol) was added. The reaction mixture was stirred at RT for 2 h, the solvent removed and the residue dissolved in water (1 ml) and acidified to pH˜6 by the addition of 2M hydrogen chloride (aq). The resultant suspension was extracted with dichloromethane (3×2 ml), the organic layer separated (hydrophobic frit) and concentrated in vacuo to give a brown solid which dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (45 mg).
Reaction SMILES: [Cl:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][NH:5][C:6](=[O:32])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:31])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH3:8].[Li+].[OH-].Cl>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][NH:5][C:6](=[O:32])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:31])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:8]
Reactant: COC(=O)CC[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (S)-methyl 4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoate (400 mg, 0.748 mmol, 1.0 equiv.) in 1,4-dioxane (1 mL) was added LiOH (2 N, 1.5 mL, 2.99 mmol, 4.0 equiv.). The reaction mixture was stirred at RT for 1 h., then was acidified to pH 1-3 with HCl (1 N). The mixture was diluted in EtOAc. The organic layer was washed by H2O and brine, and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoic acid (340 mg, 87%). LRMS (M+H+) m/z 521.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[C:8]([C@@H:15]([N:17]1[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]1=[O:27])[CH3:16])=[CH:7]2.C(=O)(O)[O-].[Na+].[C:33]([NH:36][NH2:37])(=[O:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C.O>[C:33]([NH:36][NH:37][C:12]([C:9]1[C:8]([C@@H:15]([N:17]2[C:18](=[O:27])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]2=[O:26])[CH3:16])=[CH:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)=[O:13])(=[O:35])[CH3:34]
Reactant: CC(=O)NN
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carboxylic acid (100 mg, 0.26 mmol) in DMF (3.0 mL) was added sodium bicarbonate (66 mg, 0.79 mmol), hoat (54 mg, 0/39 mmol), acetic hydrazide (23 mg, 0.31 mmol) and edc (76 mg, 0.39 mmol). The reaction was stirred at r.t. for 2 hours and then it was diluted with ethyl acetate (60 mL) and water (20 mL). The separated aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were washed with LiCl (1.0 M aqueous solution, 30 mL), brine (30 mL) and then dried (MgSO4), filtered and evaporated in vacuo to give (S)—N′-acetyl-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carbohydrazide.1H NMR (400 MHz, CDCl3) δ ppm 10.45 (1H, s), 8.88 (1H, s), 8.64 (1H, s), 7.70-7.84 (4H, m), 7.64-7.66 (2H, m), 7.52 (1H, dd, J=5.3, 2.9 Hz), 6.87 (1H, q, J=7.0 Hz), 2.13 (3H, s), 1.98 (3H, d, J=7.0 Hz). Mass Spectrum (ESI) m/e=437.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]([CH3:48])([CH3:47])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][C:38](=[O:46])[C:37]([CH3:48])([CH3:47])[CH3:36])[CH2:41][CH2:42]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)C(C)(C)C)CC1
Product: Cl

Procedure:
1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-3,3-dimethyl-butan-2-one hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 3,3-dimethyl-1-piperazin-1-yl-butan-2-one (example 16j) in an analogous manner as described in example 25. LR-MS: 677.5 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].[H][H]>CO.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: COC(=O)CN(C(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CN(C(=O)C(F)(F)F)c1ccc(N)cc1
Yield: 100 %

Procedure:
The compound from step b above (3.05 g, 10 mmol) was dissolved in a mixture of methanol (100 mL) and methylene chloride (15 mL) and hydrogenated in the presence of 10% palladium on activated carbon (700 mg) using a hydrogen balloon at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (2.74 g, ˜100%) which was used direct for the next step. 1H NMR (400 MHz, CDCl3) δ: 7.13 (d, 2H), 7.63 (d, 2H), 4.36 (s, 2H), 3.78 (s, 3H), 3.65 (brs, 2H).
Reaction SMILES: Cl.F[C:3]1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([C:59]2[CH:60]=[C:61]3[C:67]([C:68]4[CH:69]=[N:70][N:71]([CH2:73][C:74]5[CH:79]=[CH:78][CH:77]=[C:76]([F:80])[CH:75]=5)[CH:72]=4)=[CH:66][N:65]([S:81]([C:84]4[CH:90]=[CH:89][C:87]([CH3:88])=[CH:86][CH:85]=4)(=[O:83])=[O:82])[C:62]3=[N:63][CH:64]=2)[CH:50]=[CH:51][C:52]=1[CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([C:59]2[CH:60]=[C:61]3[C:67]([C:68]4[CH:69]=[N:70][N:71]([CH2:73][C:74]5[CH:79]=[CH:78][CH:77]=[C:76]([F:80])[CH:75]=5)[CH:72]=4)=[CH:66][N:65]([S:81]([C:84]4[CH:85]=[CH:86][C:87]([CH3:88])=[CH:89][CH:90]=4)(=[O:83])=[O:82])[C:62]3=[N:63][CH:64]=2)[CH:50]=[CH:51][C:52]=1[CH:53]1[CH2:54][CH2:55][N:56]([CH3:3])[CH2:57][CH2:58]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)c(F)c4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C)CC5)c(F)c4)cnc32)cc1
Yield: 20.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(3-fluoro-4-(piperidin-4-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (88 mg, 0.138 mmol) was hydrolyzed with lithium hydroxide (58 mg, 1.381 mmol) in THF/methanol/water (12/4/4 mL) to yield 17 mg (20.7% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.68-8.67 (d, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.60-7.30 (m, 4H), 7.13-7.00 (m, 3H), 5.44 (s, 2H), 3.70-3.50 (m, 2H), 3.30-3.10 (m, 3H), 2.93 (s, 3H), 2.16-2.02 (m, 4H). MS: m/z=484.4 (M+1), HPLC: 97.49% in method A.
Reaction SMILES: [O:1]=[S:2]([Cl:4])Cl.[N+:5]([C:8]1[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:9]=1N)([O-:7])=[O:6].Cl.N([O-])=[O:22].[Na+]>O.Cl[Cu]>[N+:5]([C:8]1[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:9]=1[S:2]([Cl:4])(=[O:1])=[O:22])([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Yield: 105.4 %

Procedure:
In a similar fashion using route 3a general procedure 10, SOCl2 (0.36 ml, 4.95 mmol) in cold water (2 ml), CuCl (5 mg, 0.05 mmol), 2-nitro-4-(trifluoromethoxy)aniline (200 mg, 0.90 mmol), conc. HCl (2 ml), NaNO2 (90 mg, 1.3 mmol) in water (2 ml) gave the title compound (290 mg) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[NH:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[N:10]1)(C)(C)C.Cl>O1CCCC1>[OH:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[NH:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[N:10]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide (0.1 g, 0.15 mmol) in tetrahydrofuran (5 mL) was added aqueous HCl solution (1N, 5 mL, 5 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (silica gel, 25-100% of EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-amide as a white solid (Yield, 45 mg, 54%).
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[C:6](=[O:17])[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=1.Br[CH2:19][CH3:20]>CN(C=O)C.CO.O>[Br:4][C:5]1[C:6](=[O:17])[N:7]([CH2:19][CH3:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=1
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Reactant: CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(-c2ccncn2)cc(Br)c1=O
Temperature: 70 °C

Procedure:
A solution of 1.9 g of sodium methoxide in 100 ml of DMF and 30 ml MeOH is added to a suspension of 8.0 g of 3-bromo-5-(4-pyrimidinyl)-2(1H)-pyridone in 100 ml of DMF. Bromoethane (2.7 ml) is added to the mixture, and the mixture is heated to 70° C. for 2 hours. After cooling the mixture to RT, the solvent is evaporated leaving a solid residue which is suspended in 500 ml of distilled H2O, filtered through charcoal and dried. The dried residue is recrystallized from isopropanol with hot filtration to yield 3-bromo-1-ethyl-5-(4-pyrimidinyl)-2-pyridone, M.P. 195°-197° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:23])/[CH:20]=[CH:21]/[CH3:22])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].O1CCCC1>C(O)(C)(C)C.Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:18]2[C:19](=[O:23])[CH2:20][C@@H:21]([CH3:22])[C@H:3]([C:1]#[N:2])[C:4]2=[O:6])=[CH:14][CH:15]=1
Reactant: C/C=C/C(=O)NCCc1ccc(F)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C[C@@H]1CC(=O)N(CCc2ccc(F)cc2)C(=O)[C@H]1C#N
Temperature: 80 °C
Yield: 93.5 %

Procedure:
A solution of ethyl cyanoacetate (4.26 mL, 40 mmol) and trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (4.15 g, 20 mmol) in tert-butanol (60 mL) was treated with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 40 mL, 40 mmol) and the mixture was heated at 80° C. The mixture was cooled to room temperature after 16.5 hours and diluted with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum to remove the organic solvents, providing a suspension of solid in the aqueous residue. This was collected by filtration, dried, and purified by recrystallization from 95% ethanol to provide a white solid (5.13 g, 93%). 1H NMR (300 MHz, CDCl3) δ7.19 (m, 2H), 7.00 (t, J=9 Hz, 2H), 4.02 (m, 2H), 3.41 (d, J=11 Hz, 1H), 2.91 (m, 1H), 2.83 (t, J=8 Hz, 2H), 2.5-2.3 (m, 2H), 1.31 (d, J=6 Hz, 3H). Mass spec (CI) m/z 275.0 (M+H+, 100%).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH:10](Br)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.O.O.O.O.O.O.O.O.[Na+].[Na+].[SH-:28].C(OCC)C.O>CN(C)C=O>[CH2:6]([O:5][C:3]([CH:2]1[CH2:8][CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:28]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(Br)CCC(Br)C(=O)OCC
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(C(=O)OCC)S1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a stirred solution of diethyl 2,5-dibromoadipate (4.5 g) in dimethylformamide (15 ml), sodium sulfide enneahydrate (3.9 g) was added under nitrogen atmosphere and the mixture was stirred for 5 hours under ice-cooling. To the reaction mixture, diethyl ether and water were added. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 2.1 g (72%) of 2,5-diethoxycarbonyltetrahydrothiophene.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:20])(=[O:19])[NH:4][CH2:3]1.[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26]Br>O>[OH:1][CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]([CH3:16])([CH3:17])[CH3:18])(=[O:12])=[O:13])[S:10][C:6]=2[S:5](=[O:20])(=[O:19])[N:4]([CH2:26][CH2:25][O:24][CH3:23])[CH2:3]1
Reactant: COCCBr
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCN1CC(O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
The product from Step F (0.3 g, 0.88 mmol) was added to a suspension of sodium hydride (0.05 g of a 60% suspension in mineral oil, rinsed once with hexane, 1.25 mmol) in DMF (5 mL) at 0° C. The cooling bath was removed and the mixture was stirred for one hour at which point 2-bromoethyl methyl ether (0.09 mL, 0.97 mmol) was added. The mixture was stirred for 18 hr at room temperature, water was added and the mixture extracted with ethyl acetate (3×3 mL). The combined extracts were washed with water (10 mL), dried (MgSO4) and evaporated to provide an oil which was purified by column chromatography (silica, hexane/ethyl acetate gradient) to give the desired product as an oil (0.35 g, 100%) which was used in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=1)[CH3:2].[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][CH:14]([N:19]3[CH2:22][CH:21]([NH:23][C:24](=[O:25])[CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=4)[CH2:20]3)[CH2:13][CH2:12]2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(C2CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CCOC(=O)c1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by the reductive amination of 3-(4-oxo-cyclohexyl)-benzoic acid ethyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[Br:29][C:30]1[N:31]=[C:32]([O:37][CH3:38])[C:33]([NH2:36])=[N:34][CH:35]=1.C(N(C(C)C)CC)(C)C>C(#N)CCC>[Br:29][C:30]1[N:31]=[C:32]([O:37][CH3:38])[C:33]2[N:34]([C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:36]=2)[CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COc1nc(Br)cnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: COc1nc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 125 °C

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (203 mg, 0.38 mmol, 1.0 eq), 5-bromo-3-methoxypyrazin-2-amine (74.6 mg, 0.38 mmol, 1 eq.; Jiang, B. et al. Bioorg. Med. Chem. (2001), 9, 1149-1154.) and diisopropylethylamine (0.064 mL, 0.38 mmol, 1.0 eq) in 2.3 mL butyronitril was heated to 120° C. for 17 hours and to 125° C. for 6 h. The reaction mixture was concentrated in vacuo. The crude mixture was purified via preparative HPLC under basic conditions (column: Waters X-Bridge, eluent: ACN/water (15/85)→ACN/water 55/45) to deliver 9 mg (4%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:11]>>[NH2:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([NH2:9])=[O:11]
Reactant: Cn1cnc(C#N)c1N
Reactant: O=S(=O)(O)O
Product: Cn1cnc(C(N)=O)c1N

Procedure:
The cyano group of 5-amino-1-methyl-1H-imidazole-4-carbonitrile 1 is hydrolyzed with sulfuric acid to give 5-amino-1-methyl-1H-imidazole-4-carboxamide 2. Cyclization with urea gives 9-methyl-1H-purine-2,6(3H,9H)-dione 3. Chlorination with phosphorus pentachloride and phosphorusoxychloride gives 2,6-dichloro-9-methyl-9H-purine 4 (CAS Registry 2382-10-7).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[NH:14][CH2:13]3)=[O:5])[CH3:2].[H-].[Na+].CI.[C:32](OCC)(=O)C>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([CH3:32])[CH2:13]3)=[O:5])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 17β-N,N-diethylcarbamoyl-6-azaandrost-4-en-3-one (24 mg, 0.065 mmol) in DMF (2 mL) at room temperature is added NaH (16 mg, 80% oil dispersion, 0.5 mmol) and, after 30 min, methyl iodide (50 μL, excess). After stirring for 30 min ethyl acetate (30 mL) is added, the solution washed with H2O and saturated aqueous NACl, dried over MgSO4, concentrated and flash chromatographed on silica gel (100% ethyl acetate to 5% methanol/chloroform) to give 17β-N,N-diethylcarbamoyl-6-methyl-6-azaandrost-4-ene-3-one as a white solid; yield 19 mg (76%). This material is then recrystallized from hexanes/methylene chloride to give 14 mg pure white solid; m.p. 158°-159° C. Anal. Calcd. for C24H38N2O2 ; C, 74.57; H, 9.91; N, 7.25. Found: C, 74.38; H, 9.84; N, 7.18.