Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][NH:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)=[CH:9][C:8]=1[F:33].[OH-].[Li+].Cl>CO.O>[F:33][C:8]1[CH:9]=[C:10]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)CNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a solution of Example 50 (0.055 g, 0.113 mmol) in methanol (0.5 ml), lithium hydroxide (0.045 g, 1.05 mmol) in water (0.5 ml) was added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale green solid (0.050 g, 96%). M.P.: 252-254° C. 1H-NMR (δ ppm. DMSO-d6, 400 MHz): 12.70 (s, 1H), 9.01 (d, J=3.9 Hz, 1H) 8.73 (d, J=8.7 Hz, 1H), 8.64 (m, 2H), 8.25 (d, J=8.8 Hz, 1H), 8.20 (m, 4H), 7.97 (d, J=8.9 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 7.71 (dd, J=7.8, 4.2 Hz, 1H) 6.27 (s, 2H), 3.96 (d, J=5.8 Hz, 2H), MS (m/z): 456.85 (M+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH2:23][C:24]1[C:29]2=[C:30]([C:42]3[CH:47]=[CH:46][C:45]([NH:48][C:49]([NH:51][C:52]4[CH:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[CH:54][N:53]=4)=[O:50])=[CH:44][CH:43]=3)[C:31]([CH2:40][OH:41])=[C:32]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:28]2[N:27]=[CH:26][N:25]=1>CS(C)=O.CCOC(C)=O>[NH2:23][C:24]1[C:29]2=[C:30]([C:42]3[CH:43]=[CH:44][C:45]([NH:48][C:49]([NH:51][C:52]4[CH:57]=[C:56]([C:58]([F:60])([F:61])[F:59])[CH:55]=[CH:54][N:53]=4)=[O:50])=[CH:46][CH:47]=3)[C:31]([CH:40]=[O:41])=[C:32]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:28]2[N:27]=[CH:26][N:25]=1
Reactant: Nc1ncnn2c(CN3CCOCC3)c(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ncnn2c(CN3CCOCC3)c(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Dess-Martin periodinane (703.6 mg, 1.66 mmol) was added to a stirring solution of Example 62 (600 mg, 1.11 mmol) dissolved in DMSO (3 mL). After 1 hour HPLC indicated that the reaction was complete. The reaction was diluted with EtOAc (200 mL) washed with aq. Sodium thiosulfate solution (2M) (2×), and saturated NaHCO3 solution (2×). The organic layer was dried (Na2SO4) and concentrated to give a brown powder which was triturated with 10% Et2O/Hexanes to afford 450 mg (0.83 mmol, 75.3%) of the title compound. 1H-NMR (DMSO-d6). δ 10.00 (s, 1H), 9.95 (s, 1H), 9.84 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.43 (d, J=5.1 Hz, 1H), 4.18 (s, 2H), 3.57-3.54 (m, 4H), 2.55-2.51 MS [M+H]+=541; LCMS RT=2.50 min.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][CH:3]=1.[C:7]([C:10](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])(=O)[CH3:8]>C(#N)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:17]1[N:6]2[N:5]=[N:4][CH:3]=[C:2]2[NH:1][C:7]([CH3:8])=[C:10]1[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]
Reactant: Nc1cnn[nH]1
Reactant: CC(=O)C(=Cc1ccccc1F)C(=O)OC(C)C
Solvent: CC#N
Product: CC1=C(C(=O)OC(C)C)C(c2ccccc2F)n2nncc2N1
Yield: 23.7 %

Procedure:
A mixture of 0.34 g of 5-amino-1,2,3-triazole and 1.0 g of isopropyl α-acetyl-2-fluorocinnamate in 10 ml of acetonitrile is refluxed under heating for 4 hours. The solvent is distilled off under reduced pressure and the residue is crystallized from a mixture of diisopropyl ether and dichloromethane. The resulting crystals are recrystallized from a mixture of methanol, diisopropyl ether and hexane to give 0.3 g of 7-(2-fluorophenyl)-6-isopropoxycarbonyl-5-methyl-4,7-dihydro-1,2,3-triazolo[1,5-a]pyrimidine, melting at 137°-139° C., as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Cl)nn1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Yield: 69.2 %

Procedure:
Using 6-chloropyridazine-3-carboxylic acid (1 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.2 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.44 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[B:15](OC)([O:18]C)[O:16]C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([B:15]([OH:18])[OH:16])[CH:3]=1
Reactant: Clc1ccc(Br)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1Cl
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
4-Bromo-1-chloro-2-iodobenzene (10.35 g, 33 mmol) is dissolved in anhydrous tetrahydrofuran (60 ml) and the solution is cooled to −75° C. under an atmosphere of argon. Isopropylmagnesium chloride (17.1 ml, 34 mmol, 2M solution in tetrahydrofuran) is added dropwise over 30 minutes, maintaining the internal temperature below −70° C. by external cooling. Once the addition is complete, the reaction mixture is stirred at approximately −70° C. for 30 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is then cooled to −78° C. and trimethyl borate (7.3 ml, 65 mmol) is added dropwise. The mixture is stirred at −78° C. for 30 minutes and then the cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours. 2M Aqueous hydrochloric acid (30 ml) is added, and the crude product is extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Trituration with hexane gives 5-bromo-2-chlorophenylboronic acid (6.16 g) as an off-white solid.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].[C:7]1([CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:14](=[O:15])[CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nnco1
Product: O=C(Nc1nnco1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, light yellow solid, m.p. 131-132° C. and MS: m/e=279.2 (M+) was prepared in accordance with the general method of example 44a from [1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=3)[C:12]([Cl:29])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (42 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 32 mg of 5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 528.4 (MH+), retention time=0.53 min.; 1H NMR (400 MHz, DMSO-d6) d ppm 1.09-1.34 (m, 4H) 1.35-1.54 (m, 2H) 1.55-1.69 (m, 2H) 1.73-1.89 (m, 1H) 1.94-2.17 (m, 4H) 3.04-3.15 (m, 1H) 3.14-3.20 (m, 2H) 3.20-3.30 (m, 2H) 3.30-3.47 (m, 2H) 3.55-3.72 (m, 1H) 3.84 (dd, J=11.15, 2.54 Hz, 2H) 4.35 (t, J=4.70 Hz, 2H) 6.65 (s, 1H) 6.67-6.83 (m, 2H) 7.05 (br. s., 0H) 7.46-7.68 (m, 0H) 8.06 (s, 0H) 8.82 (d, J=3.52 Hz, 2H)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([CH3:36])[CH:27]=4)=[CH:20][CH:19]=3)[CH2:14]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][C:10]1([CH:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([CH3:36])[CH:27]=4)=[CH:22][CH:23]=3)[CH2:14]2)[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:42]
Reactant: CCOC(=O)CC1(C2CC(c3ccc(OCc4cc(C)nc5ccccc45)cc3)=NO2)CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1(C2CC(c3ccc(OCc4cc(C)nc5ccccc45)cc3)=NO2)CCNC1
Reaction time: 2 h

Procedure:
The intermediate 3-ethoxycarbonylmethyl-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.35 g, 0.61 mmol) from example 41 was dissolved in methylene chloride (5 mL) and TFA (3 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 2 h and was concentrated in vacuo to give (3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-pyrrolidin-3-yl)-acetic acid ethyl ester as a crude oily residue. MS found: (M+H)+=474.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:35][CH2:34][CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: NCC1CCOCC1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCC1CCOCC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 1-tetrahydro-2H-pyran-4-ylmethanamine similar to as described in Example 2 to afford 6 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(tetrahydropyran-4-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 471 (M)+. NMR (400 MHz, DMSO) δ 11.30 (t, J=5.4 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.47 (s, 1H), 5.05-4.97 (m, 2H), 4.59-4.51 (m, 2H), 3.91-3.74 (m, 3H), 3.19 (t, J=6.0 Hz, 2H), 1.82-1.67 (m, 1H), 1.67-1.58 (m, 2H), 1.49 (s, 6H), 1.32-1.18 (m, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12.[O:16]([CH2:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[O:16]([CH2:23][C:24]([NH:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C[C@@]1(C)S[C@@H]2[C@H](N)C(=O)N2C1C(=O)O
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C[C@@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O

Procedure:
6β-Amino-2α-vinyl-2β-methylpenam-3-carboxylic acid is acylated in acetone-water with phenoxyacetyl chloride in the presence of sodium carbonate to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:3]4[O:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1ccoc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A dry flask was charged with 3-Methyl-furan-2-carboxylic acid (0.500 g, 3.96 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (40 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.00 g, 3.96 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.242 g, 3.45 mmol, 87%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[C:9](Cl)(=[O:11])[CH3:10]>>[C:9]([O:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5])(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)C(=O)O
Product: CC(=O)OCC(C)(C)C(=O)O
Yield: 81 %

Procedure:
A solution of 3-hydroxy-2,2-dimethyl-propionic acid (1.5 g, 12.69 mmol) in 5 ml of acetyl chloride was heated at 80° C. under nitrogen for 2 hours. The excess of acetyl chloride was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried and evaporated to get the desired 3-acetoxy-2,2-dimethyl-propionic acid (1.65 g, 81% yield) as a colorless liquid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:34][C@@H:33]2[C@:20]([CH3:37])([CH2:21][CH:22]=[C:23]3[C@H:32]2[CH2:31][CH2:30][C:29]2[C@:24]3([CH3:36])[CH:25]=[CH:26][C:27](=[O:35])[CH:28]=2)[C@H:3]1[C:4](=[O:19])[CH2:5]OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O.[CH2:38]1[CH2:69][O:68][C:40]2([CH2:45][CH2:44][N:43]([C:46]3[N:51]=[C:50]([N:52]4[CH2:57][CH2:56][C:55]5([O:61][CH2:60][CH2:59][O:58]5)[CH2:54][CH2:53]4)[CH:49]=[C:48]([N:62]4[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]4)[N:47]=3)[CH2:42][CH2:41]2)[O:39]1>>[CH2:38]1[CH2:69][O:68][C:40]2([CH2:41][CH2:42][N:43]([C:46]3[N:51]=[C:50]([N:52]4[CH2:57][CH2:56][C:55]5([O:61][CH2:60][CH2:59][O:58]5)[CH2:54][CH2:53]4)[CH:49]=[C:48]([N:62]4[CH2:67][CH2:66][N:65]([CH2:5][C:4](=[O:19])[C@@H:3]5[C@:20]6([CH3:37])[C@H:33]([C@H:32]7[C:23](=[CH:22][CH2:21]6)[C@:24]6([CH3:36])[C:29](=[CH:28][C:27](=[O:35])[CH:26]=[CH:25]6)[CH2:30][CH2:31]7)[CH2:34][C@H:2]5[CH3:1])[CH2:64][CH2:63]4)[N:47]=3)[CH2:44][CH2:45]2)[O:39]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: c1c(N2CCNCC2)nc(N2CCC3(CC2)OCCO3)nc1N1CCC2(CC1)OCCO2
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCC4(CC3)OCCO4)nc(N3CCC4(CC3)OCCO4)n2)CC1
Yield: 77.5 %

Procedure:
The reaction of 16α-methyl-21-(4-nitrobenzenesulfonyloxy)pregna-1,4,9(11)-triene-3,20-dione with 2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-(1-piperazinyl)pyrimidine as described in Example 5 leads to the title compound in a yield of 77.5%, m.p.:156°-174° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].C(N(CC)CC)C.[O:11]1[CH:16]2[CH:12]1[C:13](=O)[CH2:14][C:15]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:17][Si](C)(C)C.[Cl-].[NH4+]>CO>[CH3:1][S:2][C:13]1[C:12](=[O:11])[CH2:16][C:15]([OH:17])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:14]=1
Reactant: C[S-]
Reactant: CCCCCCCCC1(O[Si](C)(C)C)CC(=O)C2OC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCCCCC1(O)C=C(SC)C(=O)C1

Procedure:
A solution of 910 mg of sodium thiomethoxide dissolved in 100 ml of methanol was stirred under ice-cooling and stirring for 15 minutes. Triethylamine (6 ml) was added, and after the mixture was stirred for 10 minutes, a solution of the above crude oil of 2,3-epoxy-4-octyl-4-trimethylsilyloxycyclopentanone in 15 ml of methanol was added dropwise. After the mixture was stirred for 6 hours, the reaction mixture was poured onto saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude oil of 2-methylthio-4-hydroxy-4-octyl-2-cyclopentenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[F:1][C:2]1[C:3]2[C:9]([CH3:10])=[C:19]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)CBr
Reactant: CC(=O)c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)C)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a solution (25 mL) of 1-(2-fluoro-6-hydroxyphenyl)ethanone (1.3 g) in N,N-dimethylformamide were added potassium carbonate (3.5 g) and 1-bromo-3-methylbutan-2-one (1.7 g) synthesized in Example A75(1) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (15 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL) was added to the mixture, and the mixture was stirred at 110° C. for 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (1.4 g, 77%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)Cl.C(O)(=O)C>[Br:23][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of the crude 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene of Example 2a (12.6 g, up to 30 mmole) in methylene chloride (100 ml) was diluted with 75 ml of acetic acid and cooled to about 5°. A 1M solution of bromine in acetic acid (33 ml, 1.1 equiv) was added and the reaction stirred at about 5°. After 1 hour, additional bromine solution (5 ml) was added. After 2 hours total reaction time, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated in vacuo. Recrystallization from ethanol gave the title compound (7.9 g), m.p. 122°-124°. Infrared and NMR spectral data were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N:11]([CH2:13][CH2:14][NH:15][C:16](=O)[CH3:17])[C:12]=3[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][C:8]3[CH:9]=[C:10]4[C:16]([CH3:17])=[N:15][CH2:14][CH2:13][N:11]4[C:12]=3[C:4]=2[CH:3]=1
Reactant: CC(=O)NCCn1ccc2c1-c1cc(Cl)ccc1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1cc1c2-c2cc(Cl)ccc2CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
N-[2-(8-Chloro-4,5-dihydro-1H-benzo[g]indol-1-yl)-ethyl]acetamide (2.9 g) was treated with 20 ml of phosphorus oxychloride under argon and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was poured on to 1500 g of ice-water and treated with 100 ml of 2N sodium hydroxide solution and 150 ml of 28% sodium hydroxide solution. The mixture was extracted once with 250 ml of methylene chloride and twice with 150 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue (2.7 g) was dissolved in a 20-fold amount of ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 3.2 g (83%) of 2-chloro-5,6,10,11-tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 172°-174° C. (dec.).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])[CH2:48][CH2:49]C3C=CC=CC=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])[CH2:48][CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(CCc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-3-phenylpropanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.049 g, 48% yield over 2 steps): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.40 (br s, 2H), 8.16 (s, 1H), 8.10 (d, 1H), 7.77–7.67 (m, 3H), 7.50 (t, 1H), 7.28 (d, 4H), 7.18 (sextet, 1H); ES-MS (m/z) 409.