Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:24]=[CH:25][C:26]([C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[O:30])=[CH:27][CH:28]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(C(=O)N5CCN(C)CC5)cc4)nnc3c2)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.282 g, 0.94 mmol, 1 equiv), (4-bromo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (0.399 g, 1.41 mmol, 1.5 equiv), cesium carbonate (0.919 g, 2.82 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.109 g, 0.188 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.086 g, 0.094 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot and solvents were evaporated. The residue was diluted with toluene and water (approx. 2:1), and the mixture was heated to 70° C. and stirred for 20 min. The contents were then poured into 250 mL separatory funnel and shaken. The resulting precipitate was filtered off, washed with water and dried to yield a yellow powder (0.275 g, 58% yield). MS (ESI+): m/z=504.1, LC retention time: 1.75 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH2:11][CH3:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH2:11][CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CCOc1c(F)cc(Cl)cc1Br
Agent: O=S(=O)(O)O
Product: CCOc1c(F)cc(Cl)c([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of 30-3 (48.6 g, 192 mmol) in concentrated H2SO4 (240 mL) stirred at room temperature was added HNO3 (19 mL) dropwise. The mixture was allowed to stir at room temperature for two hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate (3×800 mL). The organic layer was combined and concentrated under vacuum to get a crude product which was purified on silica gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 1:1) to afford 30-4 (22.9 g, 40%) as a yellow solid. LRMS: calc 296.9 and found: 297.9 [M+1].
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17](=O)[CH3:18])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.C(OCC)=O.C(CC(N)=O)#N.[O:31]=[C:32]1[NH:39]C=C[CH:36]=[C:33]1[C:34]#[N:35]>O.C(OCC)C>[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17]3[NH:39][C:32](=[O:31])[C:33](=[CH:36][CH:18]=3)[C:34]#[N:35])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)c1cccc(N2CCN(C)CC2)c1
Reactant: N#Cc1ccc[nH]c1=O
Agent: C[O-]
Agent: N#CCC(N)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC=O
Product: CN1CCN(c2cccc(-c3ccc(C#N)c(=O)[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5.3 g. (0.098 mole) of sodium methoxide in 100 ml. ethyl ether under nitrogen is cooled to 3° and treated dropwise with a solution of 18.4 g. (0.084 mole) of m-(4-methyl-1-piperazinyl)acetophenone and 6.25 g. (0.084 mole) of ethyl formate in 100 ml. ethyl ether while keeping the temperature below 5°. When the addition is completed, the mixture is allowed to stir at room temperature overnight. 100 ml. water is then added and the layers separated. The ethyl ether layer is washed with an additional 75 ml. water. The pH of the aqueous layer is adjusted to pH 9 with acetic acid. 10.6 g. (0.126 mole) of cyanoacetamide is then added and the solution heated at 90° for 6 hours. A solid formed which is collected and dried. Recrystallization from DMSO/water gives 14.8 g. (60.2%) of pure 6-m-(4-methyl-1-piperazinyl)-phenyl]-1,2-dihydro-2-oxonicotinonitrile, m.p. 264°-267° d., as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C1COCC1>[F:27][C:25]1[CH:24]=[CH:23][C:22]([N+:28]([O-:30])=[O:29])=[C:21]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:26]=1
Reactant: COc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(Nc2cc(F)ccc2[N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
A solution of 3-methoxyphenylamine (1.58 g, 12.82 mmol) in anhydrous THF (20 mL) was cooled to −70° C. To this was added dropwise 1M LiHMDS in THF (25.14 mL, 25.14 mmol), over 10 minutes. This was stirred at −70° C. for 15 minutes before a solution of 2,4-difluoronitrobenzene (2.00 g, 12.57 mmol) in anhydrous THF (10 mL) was added dropwise. The dark yellow solution was then allowed to reach RT and was quenched with saturated aqueous NH4Cl solution. This was extracted into EtOAc (3×) and the combined organic fractions were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a dark yellow gum, which solidified on standing (3.35 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 9.60 (1H, s), 8.25 (1H, dd, J=9.48, 5.99 Hz), 7.34 (1H, t, J=8.00 Hz), 6.90-6.77 (4H, m), 6.47 (1H, ddd, J=9.47, 7.11, 2.64 Hz), 3.83 (3H, s)
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13](=S)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:23]([NH:27][NH2:28])(=O)[CH2:24][CH3:25]>C(O)C>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13]3[N:14]([C:23]([CH2:24][CH3:25])=[N:27][N:28]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCC(=O)NN
Reactant: CCSc1cccc2c1C(c1ccccc1Br)=NCC(=S)N2
Solvent: CCO
Product: CCSc1cccc2c1C(c1ccccc1Br)=NCc1nnc(CC)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6-ethylthio-1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with propionic acid hydrazide and the resulting product heated to 250° C. to give 7-ethylthio-1-ethyl-6-(o-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=O)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1ccccc1N1CCN(C(=O)OC(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
2.30 ml of a borane-tetrahydrofuran complex (1.2 mol/l) (2.76 mmol) was added to a solution of 303 mg of 4-[2-(3-methoxypropoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10e) (0.77 mmol) in tetrahydrofuran (2.8 ml) under a nitrogen atmosphere and under ice-cooling over five minutes, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled in an ice bath. Then, 2.76 ml of a 1 N sodium hydroxide aqueous solution (2.76 mmol) was slowly added and the mixture was further stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=30/1-10/1) to obtain 276 mg of the title compound (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:46])[C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[O:28]1)=[O:26]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[O:28][CH:27]([C:25]([N:24]([CH3:46])[CH3:23])=[O:26])[CH2:36][CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CN(C)C(=O)C1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide. LCMS (M+H)+=528.0/530.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.77 (s, 1H), 7.87 (s, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.06 (s, 1H), 6.95 (d, J=9.1 Hz, 1H), 5.19-5.14 (m, 1H), 3.99 (s, 6H), 3.12 (s, 3H), 2.89 (s, 3H), 2.15-1.95 (m, 4H).
Reaction SMILES: C(OP([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:20]([C:23]1[N:24]=[C:25]([CH2:28][CH2:29][C:30]2[CH:42]=[CH:41][N:33]3[C:34](=[O:40])[C:35]([CH:38]=O)=[CH:36][N:37]=[C:32]3[CH:31]=2)[S:26][CH:27]=1)([CH3:22])[CH3:21].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[CH:20]([C:23]1[N:24]=[C:25]([CH2:28][CH2:29][C:30]2[CH:42]=[CH:41][N:33]3[C:34](=[O:40])[C:35](/[CH:38]=[C:9](\[CH3:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:36][N:37]=[C:32]3[CH:31]=2)[S:26][CH:27]=1)([CH3:22])[CH3:21]
Reactant: CCOP(=O)(OCC)C(C)C(=O)OC(C)(C)C
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)cnc3c2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C/C(=C\c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
tert-Butyl 2-(diethylphosphono)propionate (70 mg) was dissolved in tetrahydrofuran(5 ml), added with sodium hydride (60% in oil, 40 mg), and stirred for 10 minutes. The reaction mixture was added with 8-(2-(4-isopropyl-1,3-thiazol-2-yl)-ethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (56 mg), stirred for 10 minutes and added with acetic acid (0.2 ml), and then distributed between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (70 mg) as yellow oil.
Reaction SMILES: [F:1][C:2]([F:30])=[C:3]([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[O:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=1[F:20].[O:31]=O>>[F:30][C:2]1([F:1])[O:31][C:3]1([F:29])[C:4]([F:27])([F:28])[O:5][C:6]([F:26])([F:25])[C:7]([F:23])([F:24])[C:8]([F:21])([F:22])[O:9][C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16]
Reactant: O=O
Reactant: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Product: Fc1c(F)c(F)c(OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C2(F)OC2(F)F)c(F)c1F
Yield: 31 %

Procedure:
A 100-ml metal tube lined with stainless steel and charged with 105.3 g (0.22 mol) of perfluoro(7-phenoxy-4-oxa-1-heptene) was heated at 140° while oxygen was pressured in intermittently until no pressure drop was observed. The liquid product mixture was fractionated to afford 78.5 g of distillate, bp 37°-70° (3 min). The distillation was shaken with 1 liter of ice water, and then 25 ml of CFCl2CF2Cl and some calcium sulfate were added to hasten separation. The lower layer was dried over calcium sulfate and fractionated to give 33.3 g (31%) of perfluoro(7-phenoxy-1,2-epoxy-4-oxaheptane), bp 55° (1.9 mm). IR (CCl4): 6.47 (epoxide ring), 6.58 (aromatic C=C), 8-9μ (CF, C-O). NMR (CCl4): 19F -84.1 (m, 2F, OCF2), -84.6 (m, 2F, OCF2), -129.0 (s, 2F, CF2), -151.8 (m, 2F, arom. CF), -155.1 (t, JFF 21.0 Hz, 1F, arom. CF), -156.6 (t, JFF 17.9 (Hz, ring CF), and -161.7 ppm (m, 2F, arom. CF), with AB groupings at -7382, -7534, -7566, and -7719 Hz (m, 2F) for CF2 adjacent to epoxide ring and at -10381 and -10424 Hz (d of t, JFF 18.8, 9.8 Hz, 1F) and -10600 and -10642 Hz (d, JFF 17.3 Hz, 1F) for epoxide CF2.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([CH2:28]O)=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([N:38](CC)CC)C.CS(Cl)(=O)=O.O.N>C(#N)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([CH2:28][NH2:38])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CC#N
Solvent: O
Product: NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]methanol (1.55 g) and triethylamine (0.4 g) were added to acetonitrile (30 ml), and an acetonitrile solution (10 ml) of methanesulfonyl chloride (0.4 g) was added dropwise thereto under ice cooling. Upon the completion of the dropwise addition, the reaction liquid was stirred at room temperature for 1 hour, and then the resulting solution was added dropwise to a mixture solution containing 28% ammonia water (30 ml) and acetonitrile (50 ml), which had been prepared separately, under ice cooling. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure and the purified by silica gel chromatography to obtain 1-[6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]methanamine (1.0 g).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].CO.CC[O:32]CC>C(O)(=O)C.O.[O-2].[Cr+6].[O-2].[O-2]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:32])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reactant: CCOCC
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 55 °C
Yield: 20 %

Procedure:
37.4 g (0.1 mol) 3β,17β-diacetoxyandrost-5-ene (Steraloids A7850) in 400 ml glacial acetic acid was reacted with 30.06 g (0.3 mol) chromium(VI) oxide (Aldrich 23,265-3) dissolved in 20 ml H2O and 20 ml glacial acetic acid by the method of Butenandt (op. cit.). The CrO3 solution was added dropwise over 4 hours to the 3β,17β-diacetoxyandrost-5-ene solution while maintaining the temperature at 55° C. At the end of that time methanol was added to the reaction mixture in order to decompose any unreacted CrO3, followed by aqueous salt solution and ether. Evaporation of the ether yielded 7.8 g (20% yield) of crude III. Crystallization from 95% EtOH yielded (III) m.p. 214°-215° C. [218°-219° C., Butenandt, op. cit.; 224°-225° C. (from methanol), Pearson et al., J. Chem. Soc. Perkin Trans., I, 267-273 (1985 )] DSC peak 191°-224° C., max at 220° C. Normal phase tlc: EtOAC-cyclohexane-EtOH (45:45:10), Rf=0.86. IR bands: 1737, 1666 cm-1, (Pearson, op. cit. 1728, 1668).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:18]2[NH:22][C@H:21]([C:23]([O:25]C)=O)[CH2:20][CH2:19]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])#[N:2].[NH3:27].CO>>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:18]2[NH:22][C@H:21]([C:23]([NH2:27])=[O:25])[CH2:20][CH2:19]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])#[N:2]
Reactant: N
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)c(C#N)c2)N1
Solvent: CO
Product: N#Cc1cc([C@H]2CC[C@@H](C(N)=O)N2)ccc1OCc1ccccc1F
Yield: 72 %

Procedure:
A solution of methyl (5R)-5-(3-cyano-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinate (D73, 64 mg, 0.180 mmol) in 7M NH3/MeOH (2 ml) was stirred 10.5 h at 40° C. The solvent was evaporated and the residue purified via flash chromatography using a DCM/MeOH (98:2 to 8:2) to afford (5R)-5-(3-cyano-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (44 mg, 72%) as the free base. The title compound (32 mg) was prepared as described for example 4 in procedure 2. MS: (ES/+) m/z: 340 [MH+], C19H18FN3O2 requires 339. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.37 (br. s., 1H), 8.54 (br. s., 1H), 8.04 (br. s., 1H), 7.97 (dd, 1H), 7.85 (dd, 1H), 7.74 (br. s., 1H), 7.63 (td, 1H), 7.50 (d, 1H), 7.43-7.55 (m, 1H), 7.25-7.36 (m, 2H), 5.32-5.44 (m, 2H), 4.56-4.82 (m, 1H), 4.21-4.42 (m, 1H), 2.22-2.43 (m, 2H), 1.94-2.26 (m, 2H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:24][C:23]([NH:25]CC5C=CC(OC)=CC=5)=[N:22][N:21]=4)[CH:18]=3)[N:13]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:12]=2)[N:6]=1)([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[CH:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:24][C:23]([NH2:25])=[N:22][N:21]=4)[CH:18]=3)[N:13]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:12]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(NC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(NC(C)C)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A solution of 5-(3-(4-(isopropylamino)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (220 mg, 0.36 mmol) in TFA (1.1 mL) was heated at 100° C. in a microwave for 30 min. The mixture was cooled to RT and TFA was removed in vacuo. The residue was washed with Et2O to give the crude material (150 mg, 85%). MS (ESI, pos. ion) m/z: 489.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3S[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12.ClC1C=CN=C2C=C(C3[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])C=CN=3)SC=12>>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1cc2nccc(Cl)c2s1
Product: C[Si](C)(C)CCOCn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1

Procedure:
Following the procedure described above for the synthesis of compound 11 (example 12, step 3, scheme 2) but substituting compound 10 for compound 109, title compound 110 was obtained as a yellow solid (104 mg, 50% yield). MS (m/z) 487.3 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]3)[CH:35]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:41][CH2:40][S:39](=[O:42])(=[O:43])[CH2:38][CH2:37]4)[CH:35]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CCS(=O)(=O)CC3)c2)OC1(C)C
Agent: Cl[Pd+]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: NCCc1[c-]cccc1
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CCS(=O)(=O)CC4)c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Temperature: 80 °C
Yield: 46.2 %

Procedure:
A mixture of (S)-cyclobutyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.098 g, 0.267 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide (0.097 g, 0.296 mmol), XPhos Precatalyst 2nd Generation (0.021 g, 0.027 mmol), cesium carbonate (0.261 g, 0.801 mmol), 1,4-dioxane (1.2 mL) and water (0.2 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 10-100% ethyl acetate-hexane). The resulting off-white solid was further purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 2-5% methanol-dichloromethane) to afford cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1λ6-thian-4-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (60 mg, 47%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.07 (d, J=7.04 Hz, 3 H), 1.61-1.74 (m, 1 H), 1.76-1.91 (m, 1 H), 2.05-2.19 (m, 2 H), 2.21 (s, 3 H), 2.34-2.48 (m, 2 H), 2.52-2.76 (m, 4 H), 3.12 (ddd, J=13.63, 8.79, 4.25 Hz, 2 H), 3.41-3.57 (m, 3 H), 4.07 (dd, J=12.61, 6.45 Hz, 1 H), 4.48 (tt, J=7.66, 3.92 Hz, 1 H), 5.05 (quin, J=7.55 Hz, 1 H), 5.17 (br s, 1 H), 7.09-7.23 (m, 2 H), 7.68 (s, 1 H), 7.77 (s, 1 H), 8.08 (s, 1 H). MS (ESI, pos. ion) m/z 487 [M+H]+.