Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)s1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)s2)cc1
Reaction time: 8 h

Procedure:
Place 5-(4-formylphenoxy)thiophene-2-carboxamide (0.235 g, 0.948 mmol), isoamylamine (0.087 g, 0.996 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.7 mL), cap and stir overnight. Add NaBH4 (0.0359 g, 0.948 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give the title compound: TOF MS ES+ 319.1 (M+H)+, HRMS calcd for C17H23N2O2S 319.1480 (M+H)+, found 319.1488, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.8 min, 100% purity.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]3[O:26][CH2:25][O:24][C@:16]32[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:28])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:27])[CH:6]=[CH:5]1>N1C=CC=CC=1.C(OC(=O)CC)(=O)CC>[OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]3[O:26][CH2:25][O:24][C@:16]32[C:17](=[O:20])[CH2:18][O:19][C:2](=[O:1])[CH2:3][CH3:4])[C@H:12]2[C@H:3]1[C@:4]1([CH3:28])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:27])[CH:6]=[CH:5]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@H]1OCO[C@]12C(=O)CO
Agent: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Product: CCC(=O)OCC(=O)[C@@]12OCO[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]12C
Yield: 182.1 %

Procedure:
A solution of 2.4 g of 11β,21-dihydroxy-16α,17α-methylenedioxy-1,4-pregnadiene-3,20-dione in 24 ml of pyridine and 12 ml of propionic acid anhydride is stirred for one hour at room temperature. After precipitation into ice water-sodium chloride, the mixture is filtered off and worked up as usual. The crude product is purified on 220 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone), thus obtaining 2.5 g of 11β-hydroxy-16α,17α-methylenedioxy-21-propionyloxy-1,4-pregnadiene-3,20-dione, mp 184°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][F:19])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(OCF)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCF)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-fluoromethoxy-pyridine-2-carboxylic acid (CAS1174321-03-9, WO2009091016) following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=413.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: [H][H]
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2ccc(N)cc2)c[nH]1
Yield: 97.2 %

Procedure:
A solution of 2-methyl-4-(4-nitro-phenyl)-1H-imidazole (28 g) in methanol (210 ml) was hydrogenated in the presence of 10% palladium-on-charcoal (1.35 g) at atmospheric pressure and at room temperature. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solution was evaporated to dryness to give 23.2 g of the title compound as a spongy solid. Using the above procedure, and starting from the appropriate nitrophenyl derivative, the following aminophenyl derivatives were also prepared:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][C:36]1[NH:40][C:39]([CH3:41])=[N:38][N:37]=1>>[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[N:35]1[C:17](=[O:18])[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:37]2[N:38]=[C:39]([CH3:41])[N:40]=[C:36]12
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: COC1CCCCC1Nc1nnc(C)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCCCC2OC)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.83 g) and N-(2-methoxycyclohexyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 46%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)C.[H-].[Na+].O[NH:28][C:29](=[NH:31])[CH3:30].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12](=[O:13])[NH:11][C:9]1[S:10][C:6]([C:4]2[O:3][N:31]=[C:29]([CH3:30])[N:28]=2)=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=1)([CH3:17])([CH3:18])[CH3:16]
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccccc1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2sc(NC(=O)OC(C)(C)C)nc2-c2ccccc2)n1
Yield: 36 %

Procedure:
2-Tert-butoxycarbonylamino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (1.9 g 5.6 mmol) was dissolved in dry THF (60 mL). Sodium hydride (60% in oil) and N-hydroxy-acetamidine (0.83 g, 11.2 mmol) dissolved in THF (30 mL) was added. The reaction mixture was heated to reflux over night. The reaction mixture was cooled and ethyl acetate (75 mL) glacial acetic acid (0.43 g) were added. The organic mixture was washed with brine (75 mL). The aqueous phase was extracted with ethylacetate The combined organic phases was washed with brine (50 mL) dried with MgSO4 and solvents were removed in vacuo to give a solid. Yield: 36%.
Reaction SMILES: Br.Br[CH:3]1[CH2:13][CH2:12][CH2:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>O>[N:15]1[C:4]2[C:5]3[C:6]([CH2:11][CH2:12][CH2:13][C:3]=2[S:17][C:16]=1[NH2:18])=[N:7][CH:8]=[CH:9][CH:10]=3
Reactant: NC(N)=S
Reactant: O=C1c2cccnc2CCCC1Br
Agent: Br
Solvent: O
Product: Nc1nc2c(s1)CCCc1ncccc1-2
Yield: 92.8 %

Procedure:
A solution of 6.78 g (21.12 mmol) of 6-bromo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one, hydrobromide and 1.93 g (25.35 mmol) of thiourea in 100 ml of water is heated on a steam bath for 2 hours. The mixture is filtered hot through a pad of Celite to remove a small amount of insoluble solid. The filtrate is cooled, basified with ammonium hydroxide, and a precipitate is collected. Recrystallization from acetonitrile affords 4.26 g (92.8%) of the title compound as a tan solid; mp 220°-222° C. (dec.).
Reaction SMILES: [Cl-].[NH4+].C(O)C.O1CCCC1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:28]3[N:29]=[CH:30][N:31]=[C:32]([O:33][C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[C:36]([F:43])[CH:35]=4)[C:27]=3[CH:26]=2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Fe].O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:28]3[N:29]=[CH:30][N:31]=[C:32]([O:33][C:34]4[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([F:43])[CH:35]=4)[C:27]=3[CH:26]=2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ncnc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(F)c3)ncnc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
After adding 400 mg of iron powder, 1 g of ammonium chloride, 20 ml of ethanol, 10 ml of tetrahydrofuran and 10 ml of water to 470 mg of 6-(4-benzyloxyphenyl)-4-(3-fluoro-4-nitrophenoxy)-7-(trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 85° C. for 3 hours. After returning it to room temperature, it was filtered with celite, and ethyl acetate and water were added to the filtrate for liquid separation and extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with plug cotton, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 263 mg of the title compound.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[I:16]CI.N(OCCC(C)C)=O>C1COCC1.[Cu]I>[I:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1C(F)(F)F
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)cc1C(F)(F)F
Temperature: 25 °C
Yield: 74.5 %

Procedure:
Methyl 4-amino-2-(trifluoromethyl)benzoate (˜22 mmol), was dissolved in THF (100 mL) and the mixture was sparged with nitrogen for 15 minutes. Copper (I) iodide (4.14 g, 21.8 mmol) and diiodomethane (8.8 mL, 109 mmol) were added followed by isoamyl nitrite (8.8 mL, 66.2 mmol) and the mixture was stirred at reflux for 4 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution: 1 M sodium thiosulfate (2×) and brine, dried over sodium sulfate, then filtered and concentrated to provide a brown oil which was purified by column chromatography (silica gel, 2-40% dichloromethane in hexanes) to afford methyl 4-iodo-2-(trifluoromethyl)benzoate (5.42 g, 16.4 mmol, ˜75% yield over 2 steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.97 (dd, 1H), 7.52 (d, 1H), 3.93 (s, 3H); GCMS for C9H6F3IO2: 330 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[Se](=O)=[O:16].O1CCOCC1.O>O>[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH:1]=[O:16])[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 90 °C

Procedure:
2-Methyl-6-nitroquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide 90.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3×2 ml). The organic extract was then dried in vacuo to give 6-nitro-2-quinolinecarboxaldehyde which was carried forward without further purification. Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 6-nitro-2-quinolinecarboxaldehyde prepared above in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h, the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C87 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 282 as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:13]1[CH:14]=[C:9]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:10]=[CH:11][N:12]=1
Reactant: CC#CCO
Reactant: Fc1ccccc1Cc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccccc2F)ncn1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.08 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2-fluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.19 g of 4-(2-fluorobenzyl)-6-(2-butynyloxy)pyrimidine (the present compound (88)).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(OC)c2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3cccc(OC)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-(3-methoxy-phenoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CC1(C)[O:17][C:16](=O)[CH:15]([CH3:19])[C:14](=[O:20])[O:13]1>C1(C)C=CC=CC=1>[C:14]([CH:15]([CH3:19])[C:16]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:17])([OH:20])=[O:13]
Reactant: CC1C(=O)OC(C)(C)OC1=O
Reactant: Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Product: CC(C(=O)O)C(=O)Nc1ccccc1C(=O)O
Yield: 84.4 %

Procedure:
Anthranilic acid (1.00 g, 7.29 mmol) was added to a solution of 2,2,5-trimethyl-1,3-dioxane-4,6-dione (1.27 g, 8.02 mmol) in toluene (10 mL). The reaction flask was fitted with a Dean-Stark apparatus and the suspension was heated to reflux for 3 h. The suspension was cooled, filtered, washed with toluene and dried. 2-[(2-Carboxy-1-oxopropyl)amino]benzoic acid (1.46 g, 85%) was obtained as a colourless solid; δH (500 MHz, DMSO-d6) 1.31 (d, J=7.2 Hz, 3H, CH3), 3.52 (q, J=7.2 Hz, 1H, CH), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.59 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.98 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.46 (d, J5,6=8.0 Hz, 1H, H6), 11.36 (s, 1H, NH), 12.87 (br s, 1H, CO2H), 13.52 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 13.6, 48.4, 116.7, 120.0, 122.9, 131.1, 134.1, 140.5, 168.2, 169.4, 171.6. νmax 1172, 1251, 1587, 1679, 2553, 2941, 2990, 3332 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]([N:8]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:9]1[C:10]([C:23]([O:25]CC)=O)=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].[O-]CC.[Na+]>C(O)C>[F:34][C:31]1[CH:32]=[CH:33][C:28]([N:8]2[C:9]3[C:10](=[N:11][CH:12]=[C:13]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[CH:14]=3)[C:23]([OH:25])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:35])[C:6]2=[O:7])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC(=O)N(c1ccc(F)cc1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 85.2 %

Procedure:
Ethyl 3-[(3-ethoxy-3-oxopropanoyl)(4-fluorophenyl)amino]-5-(4-fluorobenzyl)pyridine-2-carboxylate (477 mg, 0.99 mmol) was dissolved in ethanol (50 mL) and sodium ethoxide (0.91 mL of a 2.4 M solution) was added. The solution was stirred until reaction was determined complete by LC-MS and the suspension was concentrated under reduced pressure. A small amount of water was added and the mixture was acidified with 1 N hydrochloric acid to a pH of 3 and the resulting white solid was collected by vacuum filtration to yield ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (368 mg, 85% yield). 1H NMR (methanol-d4/CDCl3) δ 8.19 (s, 1 H), 7.17-7.06 (m, 4 H), 6.94-6.83 (m, 4 H), 6.58 (s, 1 H), 4.26 (q, J=7.2 Hz, 2 H), 3.81 (s, 2 H), 1.27 (t, J=7.2 Hz, 3 H); MS m/z 459 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.Cl.[NH2:12][NH:13][C:14]([NH2:16])=[O:15].C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:16][C:14](=[O:15])[NH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]nc(-c2ccc(F)cc2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
4-Fluorobenzoyl chloride (2.50 g, 15.77 mmol) was added to a solution of semicarbazide hydrochloride (2.00 g, 17.93 mmol) and sodium bicarbonate (2.50 g, 29.8 mmol) in water (25 mL) and the mixture was stirred at RT for 2 h. The solids were collected by filtration, and washed and dried under suction to obtain a white solid. MS (ESI) m/z: 198.1 (M+H+). The solid was suspended in water (25 mL), treated with sodium hydroxide (1.50 g, 37.5 mmol) and heated at 100° C. for 5 hours. The reaction mixture was cooled in ice bath, acidified with conc. HCl and stirred for 20 min. The solids were collected by filtration. The white solid was stirred in acetonitrile filtered, washed and dried to provide 3-(4-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one (1.1 g, 38.9% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.03 (s, 1H), 11.65 (s, 1H), 7.81 (m, 2H), 7.31 (m, 2H); MS (ESI) m/z: 180.1 (M+H+).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:21])[C@@H:19]([OH:20])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C@H:8]1[CH2:7][C:5](=[O:6])[CH2:4][CH2:3]2.[F:22][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC(O)C>[F:22][C@@H:7]1[C:5](=[O:6])[CH2:4][CH2:3][C@@:2]2([CH3:1])[CH:8]1[CH2:9][CH2:10][C@@H:11]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]2([CH3:21])[C@H:16]1[CH2:17][CH2:18][C@@H:19]2[OH:20]
Reactant: F[B-](F)(F)F
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(C)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4[C@H](F)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Yield: 4 %

Procedure:
A mixture of dihydrotestosterone (1.00 g), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) or SELECTFLUOR® (1.92 g) in i-PrOH (35 ml) was refluxed for 18 h. After cooling, the resulting precipitate was filtered and the organic phase was washed with H2O and brine, dried over Na2SO4 and was evaporated to dryness. The crude reaction mixture was purified by flash chromatography (SiO2, n-hexane/acetone/EOAc 75/12.5/12.5) to give 4α-fluoro-17β-hydroxyandrostan-3-one (43 mg, 4% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Nc1ccc(C2CCC(=O)CC2)cn1
Product: Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-3-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:11][C:10]([NH2:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[N:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:21]([O:28][C:29](=[O:30])[NH:33][C:32]([C:31](=[O:36])[NH:20][C:10]1[N:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1)([CH3:34])[CH3:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)N=C(OCc2ccccc2)OC1=O
Reactant: Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Solvent: Cc1ccccc1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1-Benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-amine (4.15 g, 15.47 mmol), 2-(benzyloxy)-4,4-dimethyloxazol-5(4H)-one (4.07 g, 18.56 mmol) were stirred in 5 ml of toluene in a 100 ml prbf. The white suspension was allowed to stir at 50° C. for over weekend. It was then cooled to r.t. The volatiles were removed in vacuo and the resulted solid was dissolved in EtOAc (130 mL) and heptane (50 mL) with heating. It was cooled to r.t. and let sit overnight. The resulted precipitates were collected and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6) 1.41 (s, 6H) 5.01 (s, 2H) 5.43 (s, 2H) 7.12 (d, J=6.82 Hz, 2H) 7.23-7.43 (m, 11H) 7.64-7.74 (m, 2H), 10.05 (br. s., 1H). MS (m/z) 488.1 M(+1), tR=1.60, Method A.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.O.[Pd]>[F:15][C:14]([F:17])([F:16])[CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][NH:11]1
Reactant: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)C1CNCCN1

Procedure:
1-Benzyl-3-(trifluoromethyl)piperazine (0.74 g, 3.0 mmol; Intermediate 44) was dissolved in acetic acid (70 mL) and water (5 mL). Pd, 5% on carbon, (0.074 g) was added and =hydrogenation was performed at 3 bar and 70° C. overnight. The reaction mixture was filtered through Celite and the pad was rinsed with water (5 mL). Solvents were removed in vacuo, toluene (20 mL) added to the residue, followed by re-concentration in vacuo to remove residual water. The desired product sublimated on the evaporator and 0.15 g (32%) was collected as a white powder. 1H NMR (270 MHz, methanol-d4) δ ppm 2.67-2.87 (m, 3H) 2.91-3.05 (m, 2H) 3.12-3.21 (m, 1H). MS (ESI+) m/z 155. *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.