Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][C:51]1([CH3:68])[C:55]2[C:56]([O:60][C:61]3[N:66]=[CH:65][C:64]([NH2:67])=[CH:63][N:62]=3)=[CH:57][CH:58]=[CH:59][C:54]=2[O:53][CH2:52]1>>[CH3:50][C:51]1([CH3:68])[C:55]2[C:56]([O:60][C:61]3[N:62]=[CH:63][C:64]([NH:67][C:14]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])=[CH:65][N:66]=3)=[CH:57][CH:58]=[CH:59][C:54]=2[O:53][CH2:52]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CC1(C)COc2cccc(Oc3ncc(N)cn3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-D-valine (Intermediate 76, 53.9 mg) in dry N,Ndimethylformamide (1 ml), DIPEA (50.9 μl, 0.292 mmol) and then HATU (102 mg, 0.268 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature under argon. Then 2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine (Intermediate 65, 30 mg) was added and the reaction mixture was stirred at 60° C. under argon during 12 hours. The reaction was quenched with brine (1 ml), diluted with water (2 ml) and extracted with ethyl acetate (2×5 ml). The organic layer was dried over sodium sulphate and evaporated. The residue obtained was purified on silica gel (Companion instrument) with a gradient cyclohexane/ethylacetate 100/0 to 70/30. This afforded the title compound (17 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9](OCC)=[O:10].[CH3:14][CH:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]([O:21][CH:15]([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:10]
Reactant: CCCCCC(C)O
Reactant: CCOC(=O)COc1ccccn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCCC(C)OC(=O)COc1ccccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
5.0 g (28 mmol) of ethyl 2-pyridyloxyacetate were suspended in 100 ml of 2-heptanol, 1 ml of titanium tetraisopropoxide were added, and the mixture was stirred for 4 hours at 120° C. The excess 2-heptanol was subsequently distilled off under an oil pump vacuum, and the residue was purified by column chromatography. 6.2 g (90% of theory) of (1-methyl)hexyl 2-pyridyloxyacetate were obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.O>[CH2:12]([N:1]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of 5-amino-pyridine-2-carbonitrile (37) (800 mg, 6.72 mmol) in DMF (8 mL) was added NaH (60%) (806 mg, 20.2 mmol) portion wise at 0° C. Benzyl bromide (2.3 mL, 20.2 mmol) was subsequently added and the mixture allowed to stir at rt for 3 h. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (2×50 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel column chromatography (100-200 mesh, eluted with 30% EtOAc/pet-ether) to obtain compound 38 (1.3 g, 65%) as a pale yellow solid. Rf: 0.7 (10% MeOH/CHCl3); (m/z): 300 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 8.14 (1H, d, J=2.8 Hz), 7.65 (1H, d, J=9.2 Hz), 7.37-7.25 (10H, m), 7.08 (1H, dd, J=3.6, 9.6 Hz), δ 4.88 (4H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:29]=[C:30]2[N:34]([C:35]=1[S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:32][S:31]2>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:36]([C:35]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[Cl:27])(=[O:37])=[O:38])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1c(Cl)nc2sccn12
Yield: 67.7 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 132 mg, 0.52 mmol) in THF. 172 mg (65%) of 102 was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1)(=[O:21])[CH3:20].N1C=CC=CC=1.N.CO>ClCCCl.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:28]([CH:25]3[CH2:24][CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26]3)=[O:29])=[CH:14][CH:13]=2)[CH2:8]1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Agent: N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)Nc2ccc([C@H]3CCC(N4CCC[C@@H]4C)C3)cc2)CC1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
4-[(S)-3-((S)-2-Methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) was dissolved in DCE (1 mL). To this solution was transferred a solution of 1-acetyl-piperidine-4-carboxylic acid chloride in DCE (1 mL), followed by pyridine (0.5 mL). The solution was stirred at r.t. for 2 h when TLC (5% of 7N NH3 MeOH in DCM) and LC/MS showed that the reaction was complete. The reaction was quenched with polymer bound diethylenetriamine (4 mmol/g) (0.1 g) and the suspension was stirred for 30 min. Then, 10 mL of DCM was added to the suspension and the suspension was filtered through a celite pad, rinsed with DCM and 10% MeOH in DCM. The crude product was purified on a silica gel column eluted with 5% of 7N NH3 MeOH in DCM to obtain 15.9 mg (63%) of the title compound as a gummy solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10](O)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[N:11]=[CH:12][N:13]=[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Nc2ccccc2)ncn1
Product: Clc1cc(Nc2ccccc2)ncn1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
6-(Phenylamino)pyrimidin-4-ol (253 mg, 1.35 mmol) was dissolved in neat phosphorous oxychloride (5 mL) and stirred for 3 h at 95° C. then cooled to room temperature and concentrated. The residue was poured into an ice water slurry and extracted with dichloromethane. The extract was washed saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and the solvent evaporated to afford 6-chloro-N-phenylpyrimidine-4-amine (220 mg) which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[Se:20][C:19]=1[C:27]([NH2:29])=[O:28].CN(C=O)C.[OH-].[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=[C:2]2[NH:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:24])[CH3:25])[Se:20][C:19]=1[C:27]([NH2:29])=[O:28]
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2nc(C)nc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC

Procedure:
The reaction of 4-chloro-6,7-dimethoxy-2-methylquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as an off-white color solid, mp 266-268° C. 1H NMR (400 MHz, CDCl3): δ 11.95 (1H, br s, exchangeable with D2O), 8.97 (1H, s), 7.32 (1H, s), 7.19 (1H, s), 5.38 (2H, br s, exchangeable with D2O), 4.08 (3H, s), 4.01 (3H, s), 2.70 (3H, s), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.63, 168.60, 162.1, 154.8, 154.5, 149.2, 148.2, 148.1, 121.9, 109.0, 107.4, 107.1, 100.1, 56.2, 56.1, 37.1, 32.5, 26.3; LC-MS (negative ion mode): m/z 445, 447 (M−H)−.
Reaction SMILES: [Na].[S:2](=[CH:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=[O:4])=[O:3].[CH3:13]I>>[CH3:13][N:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][CH:5]=[S:2](=[O:4])=[O:3])[CH2:12]1
Reactant: CI
Reactant: O=S(=O)=CCc1cnccn1
Agent: [Na]
Product: CN1C=CN=C(CC=S(=O)=O)C1

Procedure:
5.0 g of 2-(2-sulfonylethyl)pyrazine sodium salt (2500) was added to a solution of 10 ml methyl iodide/50 ml methanol and the mixture refluxed for 4 days. It was then concentrated and purified by gel permeation chromatography (Biogel P-2/water). Freeze-drying gave 4.5 g of product (2600). It was recrystallized from ethanol/water, m.p. 255-60 (dec.). UV H2O max: 281 (3.87). 13C NMR: 162.99, S (C3); 150.63, D (C5); 138.51, D, 136.24, D (C2, C6); 49.66, Q (NCH3); 49.56, T (CH2SO3); 31.44, T (ArCH2). 1H NMR: 9.33, D,T (H6); 8.99, S (H2); 8.82, D (H5); 4.48, S (NCH3); 3.58-3.43, M (--CH2 --).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-])=O)[CH:7]=1)[CH2:2][CH3:3].Cl>C(O)C.[Fe]>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH2:13])[CH:7]=1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCCN(CCC)C(=O)c1ccc(C)c(N)c1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
Crude N,N-dipropyl-4-methyl-3-nitrobenzamide (16.35 g, nominally 61.9 mmol) was dissolved in ethanol (125 mL). To this solution was added iron powder (11.34 g, 200 mmol), then, with rapid stirring, was added 12N hydrochloric acid (42 mL) at such a rate as to maintain a temperature of 75° C. (required 10 minutes). The solution was stirred at 75° C. for an additional 10 minutes, then quenched into water (500 mL). This slurry was made basic (pH 14) by addition of aqueous potassium hydroxide. The resulting pudding-like slurry was stirred with ethyl acetate (300 mL) and filtered (slow). The organic layer of the filtrate was dried (K2CO3) and evaporated to a thick oil that solidified overnight to provide 14.27 g (98.5%) of a wa xy solid that was characterized by proton nmr.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=2F)[C:5](=[S:8])[S:6][CH:7]=1.[CH3:18][NH2:19]>C(#N)C.CO>[CH3:18][N:19]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([F:15])[C:11]=2[F:16])[N:4]2[C:5](=[S:8])[S:6][CH:7]=[C:3]2[CH2:2]1
Reactant: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F
Reactant: CN
Solvent: CC#N
Solvent: CO
Product: CN1Cc2csc(=S)n2-c2ccc(F)c(F)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
4-Chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione (2.5 g) prepared in the same manner as in Reference Example 7 was dissolved in acetonitrile (25 ml) and to the solution was added 40% solution of methylamine in methanol (3.3 g) and the mixture was stirred at 50° C. for 16 hours. The reaction mixture was evaporated to dryness under reduced pressure and to the residue was added water and the solution was extracted with chloroform. The extract was washed with a NaCl solution, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of cyclohexane - ethyl acetate to give the title compound (2.0 g) as pale yellow crystals, m.p. 165°-167° C.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]1([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][O:35][C:36]([C:38]1[N:39]=[CH:40][NH:41][CH:42]=1)=[O:37].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH3:34][O:35][C:36]([C:38]1[N:39]([CH:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][C:3]2([CH3:14])[CH3:13])[CH:40]=[N:41][CH:42]=1)=[O:37]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)NC(=O)c2ccccc2C1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)NC1(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (1.15 g, 6.0 mmol) in THF (85 mL) is added triphenylphosphine (2.7 g, 10.2 mmol), and methyl-4-imidazolecarboxylate (1.3 g, 10.2 mmol). The heterogeneous reaction mixture is cooled to 0° C. and di-tert-butyl azodicarboxylate (2.4 g, 10.2 mmol) is added. The reaction is allowed to warm to room temperature and stirred for 45 min, and then heated at 40° C. for an additional 75 min, at which time the reaction is cooled to 0° C. and 4M HCl in dioxane (20 mL, 80 mmol) is added. The reaction is brought to room temperature and allowed to stir for 45 min. The reaction mixture is then basified to a pH of ca. 8 via the cautious addition of saturated aqueous NaHCO3. The resulting mixture is further diluted with ethyl acetate and saturated aqueous NaHCO3 and the layers are separated. The aqueous layer is extracted 3 times with ethyl acetate and the organic layers are combined, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is adsorbed onto silica gel and submitted to silica gel flash chromatography [35 to 60% of a stock solution in hexanes (stock solution is made of 17% v/v reagent alcohol in ethyl acetate)] to provide 3-(3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester as an off-white solid. HRMS (ESI) m/z 300.1354 [(M+H)+; calculated for C16H18N3O3: 340.1348]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (s, 3 H), 1.45 (s, 3 H), 3.94 (s, 3 H), 5.72 (br. s., 11 H), 6.59 (s, 1 H), 7.32-7.38 (m, 1 H), 7.41 (s, 1 H), 7.50-7.61 (m, 2 H), 7.78 (s, 1 H), 8.19-8.28 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14][N:25]=[N+:26]=[N-:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](CCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCN=[N+]=[N-])N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 96 h
Yield: 106.6 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-bromopropyl]-benzenesulfonamide (1.74 g, 3.58 mmol) in THF/H2O (20/4, 24 mL) was added sodium azide (2.33 g, 35.8 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 4 days. The mixture was extracted with ether (3×60 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 1.53 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzenesulfonamide as a colorless oil in 95% yield.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9](OC(=O)NC3C=CC=CC=3)[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](OC(OC)=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)Nc3ccccc3)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Yield: 43.4 %

Procedure:
The procedure of Example 17 was repeated except that 48.4 mg (0.0798 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-phenylcarbamoyloxy)pregn-5-en-3β-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregna-5-en-3β-yl acetate to give 16.3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate. In addition, 17.4 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-phenylcarbamoyloxy)pregn-5-en-3β-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was 68% based on consumed 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-phenylcarbamoyloxy)pregn-5-en-3β-yl acetate. The 1H-NMR spectrum of the product 20-(5,5-dimethyl-1,3-dioxan-2-yl)- 1α,2α-epoxypregna-5,7-dien-3β-yl acetate was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan- 2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate obtained in Example 17.
Reaction SMILES: C([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[S:9][C:8]=1[C:19](O)([CH3:21])[CH3:20])C=C>C1COCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[S:9][C:8]3[C:19]([CH3:20])([CH3:21])[O:23][C:5](=[O:4])[NH:6][C:7]=3[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C=CCOC(=O)Nc1cc(-c2cccc(Cl)c2)sc1C(C)(C)O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2cc(-c3cccc(Cl)c3)sc21
Reaction time: 0.25 h

Procedure:
To a solution of [5-(3-Chloro-phenyl)-2-(1-hydroxy-1-methyl-ethyl)-thiophen-3-yl]-carbamic acid allyl ester (0.12 g, 0.34 mmol) in anhydrous THF (5.0 mL) was added KOtBU (0.076 g, 0.068 mmol) and stirred for 15 minutes, quenched with H2O, and in situ crystallization was carried out by adding minimal amount of MeOH to the solution. The white crystals were collected on a Büchner funnel, mp 123-125° C. 1H NMR (DMSO-d6) δ1.64(s, 6H), 7.05(s, 1H), 7.37-7.48(m, 2H), 7.53-7.56(s, 1H), 7.67-7.68 (m, 1H), 10.41(s, 1H); MS(EI) mlz 293/295(M+H); Anal. Calc. For C17H18CINO3S: C, 57.24; H, 4.12; N, 4.77. Found: C, 56.93; H, 3.92; N, 4.97.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([OH:12])[CH3:11].Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1>>[Br:20][C:18]1[N:19]=[C:14]([O:12][CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: CC(O)c1c(F)ccc(F)c1Cl
Reactant: Nc1ncc(Br)nc1Br
Product: CC(Oc1nc(Br)cnc1N)c1c(F)ccc(F)c1Cl

Procedure:
5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2-chloro-3,6-difluoro-phenyl)-ethanol and 3,5-dibromo-pyrazin-2-ylamine.
Reaction SMILES: [C:1](/[C:3](=[N:10]\[O:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19]C(=O)OC(C)(C)C)[CH:16]=[CH:15][CH:14]=1)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C:17]1[N:18]=[C:13]([CH2:12][O:11]/[N:10]=[C:3](/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)\[C:1]#[N:2])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO/N=C(\C#N)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C/C(=N\OCc1cccc(N)n1)c1ccccc1
Yield: 99.9 %

Procedure:
To a solution of tert-butyl {6-[({[(Z)-cyano(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (5.4 g, 15.32 mmol, 1 eq.) in DCM (200 ml) was added TFA (17.47 g, 153 mmol, 10 eq.). The solution was refluxed for 12 h. The reaction was quenched by addition of aq. sat. NaHCO3 and extracted with EtOAc (3×50 ml). The organics were combined, dried over MgSO4 and concentrated to give (2Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)acetonitrile (3.86g, 89% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[C@@H:10]([CH3:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P([N:68]=[N+:69]=[N-:70])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:68]([CH2:11][C@H:10]([CH3:13])[C@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:69]=[N-:70]
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (2S,3R)-3-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol (1.0 equiv.), DIAD (2.0 equiv.), and PPh3 (2.0 equiv.) in THF (0.18 M) was added DPPA (1.0 equiv., 1M solution in THF). The reaction mixture was stirred at room temperature overnight. Upon removal of the volatiles under vacuo, the residue was purified by silica gel column chromatography (2-3-5% EtOAc/n-heptanes) yielding ((1R,2S)-3-azido-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)(tert-butyl)dimethylsilane (62%). 1H-NMR (400 MHz, CDCl3): δ 4.04-4.10 (m, 1H), 3.94 (dd, J=8.0, 6.4, 1H), 3.72 (d, J=7.2, 1H), 3.53 (t, J=8.0, 1H), 3.36 (dd, J=12, 8.0, 1H), 3.19 (dd, J=12.0, 6.7, 1H), 1.52-1.60 (m, 1H), 1.41 (s, 3H), 1.34 (s, 3H), 0.92 (d, J=7.2, 3H), 0.90 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>CO>[CH2:3]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 175.4 %

Procedure:
To a solution of L-phenylalaninol 3c (where W=H, W=OH, R1=H, R2=Bn, R3=H) (5 g) in MeOH (150 ml) benzaldehyde (3.3 ml) were added. The reaction mixture was stirred at r.t. for 1 h, then 1.2 g of NaBH4, were added in small portions in 2 hr at 0° C. The solvent was evaporated and the residue extracted with 50 ml of HCl at pH=2. The aqueous solution was extracted with Et2O, treated with Na2CO3 until pH=9 and then extracted with CHCl3. The organic phase evaporated gave N-benzyl-(L)-phenylalaninol as white solid (7 g) 3c (where W=H, W=OH, R1=H, R2=Bn, R3=Bn)