Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].C(O[C:6]([C:8]1[C:9](=[O:34])[C:10]2[CH:15]=[N:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[N:12][C:11]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:7])C>>[CH3:1][NH:2][C:6]([C:8]1[C:9](=[O:34])[C:10]2[CH:15]=[N:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[N:12][C:11]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:7]
Reactant: CN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN(C)C)ncc2c1=O
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN(C)C)ncc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methylamine (1N, 1 mL in methanol) was added to 2-(3-dimethylamino-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 6 Step A, 6 mg, 0.015 mmol). The mixture was kept in a sealed tube at 110° C. with stirring for 2 days. The solution, after cooling down to room temperature, was loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 2-(3-Dimethylamino-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide was obtained as a white solid (4.5 mg, 77%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.70 (br, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.86 (br, 1H), 2.99 (m, 9H), 2.25-2.10 (m, 10H), 1.62 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H28N6O2: 421.23 (M+H). Found. 421.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COc1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 168 h
Yield: 51.7 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 196, 200 mg) in CH2Cl2 (4 ml) were added 4-fluoro-3-methoxyphenylboronic acid (282 mg), copper-(II)-acetate (307 mg), molecular sieve and pyridine (219 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 7 days. The mixture was filtered, diluted with CH2Cl2 and washed with 1M aqueous HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (139 mg) as an off-white solid. MS (m/e)=486.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].Cl.[OH:11][CH:12]1[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]([OH:16])[C@H:13]1[NH2:14].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5]([NH:14][C@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[CH:12]=[O:11])=[O:6]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 8 h
Yield: 90.4 %

Procedure:
2,2,2-Trichloroethoxycarbonyl chloride (200 g, 0.944 mol) is added portionwise to a solution of D-glucosamine hydrochloride (v, 200 g, 0.927 mol) and NaHCO3 (200 g, 2.4 mol) in water (4 L) in a 10 L 3-neck round-bottom flask and the resulting mixture is mechanically stirred overnight at room temperature. The white precipitate that forms is collected by filtration using a 2 L fritted funnel, washed with ether (2 L), and dried at high vacuum for 3 hours to give 297 g (90%) of 2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucose as a white solid (MW 354.57).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[CH:16]([OH:21])[N:15]([CH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1)[CH:14]2[OH:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[CH:16]([OH:21])[N:15]([C@@H:22]1[CH2:26][CH2:25][C@H:24]([O:27][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:23]1)[CH:14]2[OH:28]
Reactant: OC1CCC(N2C(O)c3cc(Cl)c(Cl)cc3C2O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@@H](N2C(O)c3cc(Cl)c(Cl)cc3C2O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a flask was added DCM (40 mL), DIPEA (2.0 mL, 11.48 mmol), c is 5,6-dichloro-2-(3-hydroxy-cyclopentyl)-2,3-dihydro-1H-isoindole-1,3-diol 1.071 g, 3.57 mmol) and methanesulfonyl chloride (0.6 mL, 7.72 mmol) and the mixture stirred overnight at RT. The mixture was concentrated in vacuo, EtOAc (100 mL) and H2O (100 mL) added, filtered off insolubles, separated and extracted the aqueous layer with EtOAc (50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give cis methanesulfonic acid 3-(5,6-dichloro-1,3-dihydroxy-1,3-dihydro-isoindol-2-yl)-cyclopentyl ester as a tan solid (1.5 g, impure as >100% yield).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:32]=[C:33]([O:36][CH3:37])[C:34]=1[OH:35])[CH2:17][N:18]([N:27]1[CH:31]=[N:30][N:29]=[CH:28]1)[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>O.C(OCC)(=O)C.CN(C)C(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:17][N:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[N:27]2[CH:31]=[N:30][N:29]=[CH:28]2)[CH:32]=[C:33]([O:36][CH3:37])[C:34]=1[O:35][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1O
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1OS(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sulphamoyl chloride solution in toluene (3 mL, 0.7 M, 2.1 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 0.5 mL volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethylacetamide (5 mL) was added. 4-[(3-Chloro-4-hydroxy-5-methoxy-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02179, 212 mg, 0.596 mmol) was added to the colourless solution and the mixture was stirred for 18 hours at room temperature. Ethyl acetate (50 mL) and water (30 mL) were added to the solution, the organic layer was separated, washed with water (2×30 mL) and brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of acetone and precipitated by addition of hexane. The precipitate was filtered off and dried under high vacuum. Yield: 219 mg (84%) white powder. 1H-NMR (400 MHz, d6-DMSO) δ=3.78 (s, 3H, —OCH3), 6.74 (d, J=9.0 Hz, 2H), 7.04 (d, J=2.0 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 7.98 (s, 2H, —NH2), 8.91 (s, 2H). LRMS (FAB+): 435.0 (100, [M+H]+). HRMS (FAB+): 435.06476 C17H16N6O4SCl requires 435.064228.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[O:8][CH3:9].C(O)(=O)C.[BrH:18].N([O-])=O.[Na+]>O>[Br:18][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Br
Reactant: COc1cc([N+](=O)[O-])c(C)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(C)cc1Br
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A slurry of 3-amino-4-methoxy-6-nitrotoluene (18 g) in water (20 ml) containing acetic acid (20 ml) and hydrobromic acid (47%, 35 ml) is stirred until a fine suspension of the hydrobromide is formed, cooled to 0°, and treated with a solution of sodium nitrite (7 g) in water (20 ml) added over 20 min. After a further 10 min., the yellow-brown solution is stirred into a mixture of cuprous bromide (30 g) and hydrobromic acid (47%, 30 ml) in water (50 ml), the mixture warmed on the steam bath until an effervescence commences and then at 70° for 1 hr. The mixture is cooled, diluted with water (500 ml), and the solid collected and recrystallized from aqueous ethanol to give a 3-bromo-4-methoxy-6-nitrotoluene (I) as pale yellow needles (18 g, 72%): mp 91-92°.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>[OH-].[Na+].O1CCOCC1>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(=O)OC1NC(=O)C1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)SC1NC(=O)C1Cc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 0.76 g (10 mmole) of thioacetic acid in 10 ml of 1N sodium hydroxide solution is added dropwise to a solution of 2.19 g (10 mmole) of 4-acetoxy-3-benzylazetidin-2-one (racemic mixture of cis- and trans-isomer in the ratio of 9:13) in 10 ml of dioxan at room temperature under a nitrogen atmosphere, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated bv evaporation in vacuo. The residue is chromatogra.ohed over silica gel with toluene/ethyl acetate (9:1) and yields a cis-trans mixture of the title compound in the ratio of 2:10. By recrystallisation from methylene chloride/hexane at -10° the pure trans-compound having a melting point of 42°-43° is obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[C:24]([NH:29][CH3:30])[N:23]=1.[OH-].[Na+]>>[Cl:21][C:22]1[N:23]=[C:24]([NH:29][CH3:30])[N:25]=[C:26]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:19])[F:20])=[O:12])[CH2:14][CH2:15]2)[N:27]=1
Reactant: CNc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
N-{[2-(Trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (464 mg, 1.63 mmol, 1.00 equiv) was added to the suspension prepared in step b. The resulting mixture was heated to 40° C. and treated with 1 N NaOH to maintain a pH of 9-10. The reaction mixture was stirred for 2 h and then used immediately in the next step without workup or purification. MS (ES+): m/e 428.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16].[OH-].[K+]>C(#N)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:16][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cnc2c(Cl)nccc21
Reactant: OCc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cnc2c(OCc3ccccc3Cl)nccc21

Procedure:
A mixture of 7.5 g of 4-chloro-1-methyl-1H-imidazo(4,5-c)pyridine, 7.1 g of 2-chlorobenzyl alcohol, 3.3 g of KOH and 100 ml of acetonitrile is refluxed for 7 hours. The solvent is removed and the residue is worked up in the customary manner (water/methylene chloride) to give 4-o-Chlorobenzyloxy-1-methyl-1H-imidazo(4,5-c)pyridine, m.p. 132°-135°.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(O)(=O)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:19]([CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[C:5]2=[O:7]
Reactant: NCc1ccc(F)cc1
Reactant: O=C1OC(=O)c2c(F)cccc21
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cccc(F)c2C(=O)N1Cc1ccc(F)cc1
Temperature: 110 °C
Yield: 104.6 %

Procedure:
A mixture of 3-fluorophthalic anhydride (20 g, 120 mmol) and 4-fluorobenzylamine (20 g, 160 mmol) was stirred in 150 mL toluene. Glacial acetic acid (4 mL) was added dropwise, and the reaction was stirred at 110° C. Water was trapped with a Dean-Stark trap for 16 h. The reaction was cooled to 0° C. Product was isolated by filtration as an off-white solid, after washing with hexane. Obtain the title compound (34.3 g, quant.).
Reaction SMILES: C(N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CCC1C=CC(O)=CC=1)C.Cl.ClCCN(CC)CC.[CH2:42]([N:44]([CH2:79][CH3:80])[CH2:45][CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55][N:56]([CH2:77][CH3:78])[C:57]2[CH:62]=[C:61]([O:63]C)[CH:60]=[CH:59][C:58]=2[CH:65]2[CH2:74][CH2:73][C:72]3[C:67](=[CH:68][CH:69]=[C:70]([O:75]C)[CH:71]=3)[CH2:66]2)=[CH:50][CH:49]=1)[CH3:43]>>[CH2:79]([N:44]([CH2:42][CH3:43])[CH2:45][CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55][N:56]([CH2:77][CH3:78])[C:57]2[CH:62]=[C:61]([OH:63])[CH:60]=[CH:59][C:58]=2[CH:65]2[CH2:74][CH2:73][C:72]3[CH:71]=[C:70]([OH:75])[CH:69]=[CH:68][C:67]=3[CH2:66]2)=[CH:50][CH:49]=1)[CH3:80]
Reactant: CCN(CC)CCOc1ccc(CCN(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Agent: CCN(CC)CCCl
Agent: CCN(CCc1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Product: CCN(CC)CCOc1ccc(CCN(CC)c2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1

Procedure:
Synthesized from 4-{2-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol (324 mg) and (2-chloroethyl)diethylamine hydrochloride (168 mg) according to an analogous synthetic method to Preparation Example 40, the total amount of {2-[4-(2-diethylaminoethoxy)phenyl]ethyl}ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine was used according to an analogous synthetic method to Example 111 to provide the title compound (212 mg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Product: Nc1nnc(Oc2ccc(F)c(C(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 35.6 %

Procedure:
6-[4-Fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazin-3-amine (198 mg, 36%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.57 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[C:12]([N+:22]([O-:24])=[O:23])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[N+:22]([C:12]1[C:13](=[O:21])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C:2]2=[O:1])([O-:24])=[O:23]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C([N+](=O)[O-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 17β-hydroxy-4-nitroandrost-4-en-3-one (4-nitrotestosterone, 10.56 g, 31.7 mM) in acetone (900 ml) cooled to -6° C. is treated with Jones reagent (10.0 ml). After the excess reagent is decomposed with methanol, the solids are removed by filtration. The filtrate is concentrated, for example on a rotary evaporator under vaccum, then purified by flash chromatography on silica gel to give 4-nitroandrost-4-ene-3,17-dione, m.p. 205°-205.5° C. dec.(acetone-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](O)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(1R,3S)-3-t-Butoxycarbonylaminocyclopentanecarboxylic acid (229 mg, 1 mmol) was dissolved in THF (10 mL) and borane-THF (1.5 mL, 1M solution) was added drop-wise at 0° C. and stirred overnight at r.t. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ethyl acetate (2×50 mL). The ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and evaporated to yield a semi solid (160 mg, 74%). ESMS (+): 216 (M+1)+, 250 (M+Cl)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.[C:48]([O:51][CH2:52][C:53](Cl)=[O:54])(=[O:50])[CH3:49]>C(OCC)(=O)C>[C:48]([O:51][CH2:52][C:53]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)=[O:54])(=[O:50])[CH3:49]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.6 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (122 μL, 0.880 mmol) and THF (10 mL) was added acetoxyacetyl chloride (47.3 μL, 0.440 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was recrystallized from ethyl acetate-THF to give the title compound (171 mg, 75%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[Na].[CH2:21]([OH:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:21]([O:29][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCO
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Agent: [Na]
Product: CCCCCCCCOc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with the sodium derivative of 1-octanol to obtain 4-octyloxy-7-nitro--cyano-2-trifluoromethylbenzimidazole, m.w., 384.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[O:29][C:30]([F:33])([F:32])[F:31]>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:25])=[CH:22][C:21]=1[O:29][C:30]([F:31])([F:33])[F:32]
Reactant: O=C(Cl)c1ccc(F)c(OC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc(F)c(OC(F)(F)F)c1
Yield: 43 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 4-fluoro-3-(trifluoromethoxy)benzoyl chloride to afford the title compound as a brown solid (25 mg, 43%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=6.0 Hz), 6.93 (d, 1H, Harom, J=8.0 Hz), 7.44 (t, 1H, Harom, J=8.0 Hz), 7.59 (s, 1H, Harom), 7.63 (d, 1H, Harom, J=9.0 Hz), 7.70 (t, 1H, Harom, J=9.0 Hz), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 8-06-8.13 (m, 2H, Harom), 10.47 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:25][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: Cc1ccccc1C1(C)c2ccccc2CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccccc1C1(C)NCCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-Benzyl-1-methyl-1-o-tolyl-1,2,3,4-tetrahydro-isoquinoline (164 mg, 0.50 mmol) and 10% Pd/C (16 mg) in acetic acid (6 ml) is stirred for 5 hours at room temperature under 1 atm of H2. The mixture is filtered through celite and the filtrate concentrated. The residue is diluted with methylene chloride and basified with saturated NaHCO3 to pH 8. The layers are separated and the aqueous layer extracted with methylene chloride. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated to give 1-Methyl-1-o-tolyl-1,2,3,4-tetrahydro-isoquinoline. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=7.2 Hz, 1H), 7.28-6.97 (m, 7H), 6.69 (d, J=8.0 Hz, 1H), 3.43-3.36 (m, 1H), 3.21-3.03 (m, 2H), 2.79 (d, J=16.4 Hz, 1H), 1.99 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[NH:21]([N:22]1[C:5](=[O:13])[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([Br:1])[C:3]1=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccccc1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Br
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)=C(c2ccccc2)C(=O)N1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 g (17 mmol) of 3-bromo-4-phenylfuran-2,5-dione were initially charged in 40 ml of chloroform and, at room temperature, admixed dropwise with stirring with 1.84 g (17 mmol) of phenylhydrazine in 15 ml of chloroform, and the mixture was stirred at room temperature overnight. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate/cyclohexane. Yield: 1.9 g, m.p. 146-147° C.
Reaction SMILES: C(OCC)(=O)C.Cl.COC[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[N:16][CH:17]=1>C(O)C>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][CH2:18][C:15]2[N:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: COCOc1ccc(COCc2ccc(OC(F)(F)F)cc2)nc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(COCc2ccc(OC(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.7 %

Procedure:
2 N hydrogen chloride-ethyl acetate solution (20 ml) was added to an ethanol solution (20 ml) of 5-methoxymethoxy-2-(4-trifluoromethoxybenzyloxymethyl)pyridine (2.3 g) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and a sodium hydrogen carbonate aqueous solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1). The result was concentrated to dryness under reduced pressure to afford the title compound as a white solid (2.4 g).