Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:51])[CH2:23][C:24]1([CH2:27][CH2:28][CH:29](/[CH:42]=[CH:43]/[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[OH:50])[CH2:30][CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:26][CH2:25]1)[CH3:20]>C(#N)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2/[CH:43]=[CH:42]/[CH:29]([CH2:28][CH2:27][C:24]2([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:51])[CH2:25][CH2:26]2)[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)CCc2ccc(C(=O)OC)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C(=O)OC)cc2)CC1

Procedure:
134.6 mg (0.59 mmol) of 4-(tert-butyl)benzyl bromide and 163.8 mg (1.18 mmol) of anhydrous potassium carbonate are added to a solution of 178 mg (0.395 mmol) of methyl 4-[(4E)-3-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-5-(2-hydroxyphenyl)pent-4-en-1-yl]benzoate in 5 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). This gives 130.6 mg (55% of theory) of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH3:14][O:15][NH2:16]>CO.O>[CH3:14][O:15][N:16]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=2[Cl:11])[CH2:5][CH2:6]1
Reactant: CON
Reactant: O=C1CCc2cc(Cl)cc(Cl)c21
Agent: Cl
Solvent: CO
Solvent: O
Product: CON=C1CCc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a soln. of 5,7-dichloro-1-indanone (0.34 mmol) in 2 mL MeOH was added O-methylhydroxylamine HCl (0.34 mmol). The reaction mixture was stirred at RT for 17 h and then heated to 50° C. for 24 h. The mixture was cooled to RT, diluted with water and extracted 3 times with EtOAc. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired product as white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2/[CH:20]=[CH:21]/[C:22]([CH3:25])([OH:24])[CH3:23])[C@H:12]([CH3:26])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd].C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C@H:12]([CH3:26])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(/C=C/C(C)(C)O)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
Add a solution of (E)-4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-but-3-en-2-ol (68 g, 168.83 mmol) in ethanol (816 mL) to a pressure hydrogenation vessel and add 5% palladium on activated carbon (35.83 g, 16.84 mmol). Purge the vessel with hydrogen gas, pressurise to 470 kPa of hydrogen gas and stir at 25° C. After 16 hours, vent the vessel and filter the reaction mixture through diatomaceous earth. Wash the diatomaceous earth with ethyl acetate and concentrate the filtrate under reduced pressure to give an oil. Dissolve the oil in ethyl acetate (1 L) and concentrate under reduced pressure to give the title compound (64 g, 161 mmol). MS (m/z): 378.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([CH2:16][CH:13]4[O:12][C:8]5=[C:9]6[C:4](=[CH:5][CH:6]=[C:7]5[O:15][CH2:14]4)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]6)[CH2:40]3)=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2c(CC3CCCNC3)c[nH]c2c1
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCCC(Cc2c[nH]c4cc(F)ccc24)C1)O3

Procedure:
This compound was prepared as described for Example 2, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.22 g, 4.9 mmol), 6-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.13 g, 5.9 mmol), to afford 0.11 g (50%) of the (S)-enantiomer of the title compound as a light brown oil. The hydrogen chloride salt was prepared in ethyl acetate and collected as 0.12 g of a yellow solid, m.p. 50° C. (dec).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: ON=C1CCN(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 102.2 %

Procedure:
To a solution of 1-benzylpyrrolidin-3-one (1.0 g, 5.71 mmol) in pyridine (5 mL) is added hydroxylamine hydrochloride (0.59 g, 8.57 mmol). After stirring at 90° C. for 5 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, and brine. The organic layer is dried over MgSO4, filtered, and filtrate concentrated to afford 1-benzylpyrrolidin-3-one oxime (1.11 g) as an oil. MS CI: m/z 191 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH-].[Na+].Cl>C1COCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The title compound 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid (1) was prepared by following procedure: To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (1C) (180 mg, 4 mmol) in THF (4 mL) and MeOH (2 mL) was added 2N NaOH (2 mL). The reaction mixture was stirred at 50° C. for 4 hours and neutralized by slowly adding 5% aq. HCl. The precipitate was then filtered, dried, dissolved in DMSO/MeOH (1:1) and purified by column chromatography on silica gel to provide the desired product 2-(8-(Benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid (1): 1H NMR (300 MHz, DMSO-D6) δ ppm 7.99 (1H, d), 7.76 (1H, d), 7.69 (1H, dd), 7.52 (1H, s), 7.38 (4H, m), 4.91 (2H, s), 3.75 (2H, t), 3.05 (2H, t). MS (ESI(+)): m/z 437 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([Cl:31])[CH:33]=3)=[CH:16][CH:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
To a mixture of 0.150 g (0.453 mmol) of (3′-amino-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (3 mL) is added 0.19 mL (1.4 mmol) of triethylamine followed by 0.069 mL (0.54 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature then an additional 0.21 mL (1.6 mmol) of 3-chlorobenzoyl chloride is added and the mixture is stirred for an additional two days. The mixture is concentrated under reduced pressure and purified by flash silica gel chromatography to provide 0.23 g (quant.) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26](NC(C4C=CC=CC=4)CO)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:42].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26]([OH:42])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)NC(CO)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 90 °C
Yield: 57 %

Procedure:
A solution of [2R diastereomer, N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21a in mixture of 1M sulphuric acid (17 mL) and dioxane/water (1:1, 39 mL) was heated at 90° C. for 88 h. The pH of the mixture was adjusted to 3.0 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 mL) and the organic extract as washed with water (50 mL), brine (25 mL), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in pet. ether to afford the title compound (0.2 g, 57%) as a white solid. mp: 77-78° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](O)=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:46]([NH:53][CH3:54])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:44])[N:53]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:54])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)N(C)Cc4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) reacted with benzyl methyl amine to afford the title compound as a yellow oil. Rf=0.11 (EtOAc-heptane 1:1); Rt=5.47.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[O:19]
Reactant: C[C@@H](CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H](CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of tert-butyl {(2S)-1-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate 60 (0.237 g, 0.528 mmol) and Pd/C (0.200 g) in methanol (20 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered through a Celite pad and concentrated to provide 61 (crude, 0.189 g, quant.) as a colorless foam which was used in the next step without purification.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>>[NH2:6][C:7]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 56 %

Procedure:
To 150 mL of conc. H2SO4 was added 42.96 g (334 mmol) of 2-amino-5-chloropyridine in portions with stirring and cooling (ice-water bath). To the resulting solution was added dropwise 22.5 mL of 69-71% HNO3 (355 mmol) at 50° C. (at such a rate that maintain the temperature within 50°-55° C.) over 1 h. The resulting mixture was stirred at 60° C. for 3 h, poured into ice-water (about 1,500 mL) with stirring, then basified to pH 9 by the addition of 40% aq NaOH with stirring and cooling. The precipitate was filtered, washed with water (6×50 mL), and dried to give 32.47 g (56%) of 2 as a yellow powder, mp 190°-191° C. (lit. 191°-2° C. (Israel, M. & Day, A. R., J. Org. Chem. 24:1455-1460 (1959))). 1H NMR (DMSO-d6), 8.044-8.055 (m, 3H), 8.054 (d, 1H, J=3.9).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9].C(O)=[O:12].OO.S([O-])([O-])=O.[Na+].[Na+]>O>[OH:12][CH:5]1[CH:6]2[CH:1]3[CH:2]([CH2:3][CH:4]1[CH2:7]3)[C:8](=[O:10])[O:9]2
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: O=CO
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C1OC2C(O)C3CC1C2C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
With 328.2 g of 5-norbornene-2-carboxylic acid was mixed 240.6 of formic acid. Below 50° C., 254.5 g of 35% aqueous hydrogen peroxide was added dropwise to the mixture over 6 hours. After the completion of addition, the reaction mixture was poured into a mixture of 1.5 liters of water and 0.8 kg of sodium sulfite. After three times of extraction with 1 liter of ethyl acetate, the organic phase was washed with water, dried, and concentrated in vacuum. The residue was dissolved in 1.2 liters of methanol, to which a catalytic amount of potassium carbonate was added. This was agitated for one hour at room temperature. The methanol was distilled off under vacuum, followed by conventional extraction and washing. There was obtained 247.6 g of 2-hydroxy-4-oxatricyclo[4.2.1.03,7]nonan-5-one. The yield was 65.5%.
Reaction SMILES: [NH2:1][C@@H:2]([CH:19]([CH3:21])[CH3:20])[C:3]([NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:20][CH:19]([CH3:21])[C@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2)[C:3]([NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(C)[C@H](N)C(=O)Nc1cccnc1Nc1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of (S)-2-amino-3-methyl-N-(2-phenylaminopyridin-3-yl)butyramide (3.0 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (720 mg, 3.0 mmol) and DIPEA (2.6 mL, 15.0 mmol) in n-butanol (12 mL) was heated at 100° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound (821 mg, 68% over two steps). LCMS (Method J): RT 1.75 min [M+H]+ 403.2.
Reaction SMILES: C[Si](C)(C)[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13]([N:14]([Si:24]([CH3:27])([CH3:26])[CH3:25])[C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][C:11]3=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[OH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13]([N:14]([Si:24]([CH3:26])([CH3:25])[CH3:27])[C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][C:11]3=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C=C1C=C2N([Si](C)(C)C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O[Si](C)(C)C)CC[C@H]3[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1C=C2N([Si](C)(C)C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The diene disilane prepared above is redissolved in THF (300 mL) and treated with tetrabutylammonium fluoride (1.0 M in THF; 35.0 mL, 35.0 mmole). The desilylation reaction occurs over 20 minutes with stirring at ambient temperature. The reaction mixture is then diluted with EtOAc (500 mL) and washed with brine (3×400 mL). The crude product solution is dried over MgSO4, filtered and evaporated to dryness. The crude product is purified by flash chromatography (1:1 EtOAc/CH2Cl2) to afford 17β-hydroxy-4-trimethylsilyl-7-ethyloxycarbonylmethylene-4-aza-androst-5-en-3-one as a mixture of the E and Z isomers (diolefin). The diolefin is then hydrogenated in a manner similar to that described in Example 7H to give 7β-ethoxycarbonylmethyl-17β-hydroxy-4-aza-5α-androstan-3-one. The compound has the following structure:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH:19]=O)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:19][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])[C@H](NC(=O)C(F)(F)F)CCC2
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCCc2cc(CN3CCCCC3)c([N+](=O)[O-])cc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((R)-2,2,2-trifluoro-N-(6-formyl-7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (350 mg, 1.1 mmol) in 6 mL of 1,2-dichloroethane was added piperidine (187 mg, 2.2 mmol) and NaBH(OAc)3 (350 mg, 1.65 mmol). After stirring at RT overnight, the reaction was quenched with Sat. NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, and evaporated to dryness. Flash chomatography (SiO2, EtOAc/hexane=1:1) afforded (R)-2,2,2-trifluoro-N-(7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide as a white solid.
Reaction SMILES: Br[CH:2]([PH3+])[CH2:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:23]([Si:27]([CH3:46])([CH3:45])[O:28][C:29]1[C:30]([CH3:44])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:43])([CH:41]=O)[CH2:33][CH2:32]2)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([Si:27]([O:28][C:29]1[C:30]([CH3:44])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH:41]=[CH:2][CH2:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])([CH3:43])[CH2:33][CH2:32]2)([CH3:46])[CH3:45])([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)CCCC(C)CC([PH3+])Br
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(C=O)O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(C=CCC(C)CCCC(C)C)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 1-bromo-3,7-dimethyl octanyl phosphonium (1.05 mmol) in 20 mL of anhydrous THF at 0° C. was added 1.05 mL of 1 M lithium bis(trimethysilyl)amide in THF. The mixture was stirred at 0° C. for 30 min, and compound iii (1 mmol) in 10 mL of THF was slowly added over a period of 1 h. After being stirred at room temperature for 1 h, the solution was concentrated, diluted with 20 mL of ethyl acetate, and washed, in tandem, with H2O and brine. The residue was purified by flash silica gel chromatography to afford t-butyl-[2-(4,8-dimethyl-non-1-enyl)-2,5,7,8-tetramethyl-chroman-6-yloxy]-dimethylsilane (iv) as colorless oil in 80% yield. 1H NMR (300 MHz, CDCl3) δ 0.11 (s, 6H), 0.86-0.95 (m, 6H), 1.04 (s, 9H), 1.39 (s, 1H), 1.49-1.56 (m, 1H), 1.76-1.86 (m, 1H), 2.01-2.06 (m, 2H), 2.11 (s, 3H), 2.17 (s, 6H), 2.25-2.32 (m, 1H), 2.62 (t, J=6.60 Hz, 2H), 5.30-5.44 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][O:20][CH3:21])[C:10]=12.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][O:20][CH3:21])[C:10]=12)[NH2:22]
Reactant: COCCc1c[nH]c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
63 mg (0.18 mmol) of N-(3-fluoro-4-{[3-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)acetamide are dissolved in 5 ml of ethanol. 2 ml of 20% strength aqueous sodium hydroxide solution are added, and the mixture is stirred at 90° C. overnight. The reaction mixture is then partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The aqueous solution is extracted with ethyl acetate and the combined organic phases are washed with 1N aqueous sodium hydroxide solution. The organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The product is reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+:31]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([O-:28])=[O:27].[Na+:31]
Reactant: COc1cc(C=C2C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=C2C(C)=C(CC(=O)[O-])c3cc(F)ccc32)cc(OC)c1OC
Reaction time: 0.33 h

Procedure:
5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenyl-acetic acid (1.79 g, 4.65 mmol) in methanol (10 ml) is added to a solution of sodium methoxide (0.25 g, 4.65 mmol) in methanol (5 ml). The reaction mixture is stirred for 20 minutes and evaporated to dryness to yield sodium 5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetate.