Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21]C)=[O:20])[C:13]=3[C:12]([CH2:23][CH2:24][NH:25][C@H:26]3[CH:31]4[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]4)[CH2:27]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+:36]>O1CCCC1.O>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O-:21])=[O:20])[C:13]=3[C:12]([CH2:23][CH2:24][NH:25][C@H:26]3[CH:31]4[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]4)[CH2:27]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:36]
Reactant: COC(=O)c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)cn2S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 1-(phenylsulfonyl)-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-4-carboxylate (480 mg, 1.02 mmol) from Step D above in tetrahydrofuran (10 mL) was added lithium hydroxide monohydrate (129 mg, 3.07 mmol) in water (3 mL). The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (S)-1-(phenylsulfonyl)-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-4-carboxylate, which was used in the next step without further purification: MS (ESI+) m/z 454 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][N:14]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: S=C=NCCC1=CCCCC1
Reactant: CC(C)c1ccnc(N)c1
Solvent: CN(C)C=O
Product: CC(C)c1ccnc(NC(=S)NCCC2=CCCCC2)c1
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (0.36 g, 2.2 mmol) and 2-amino-4-isopropylpyridine (0.36 g, 2.2 mmol) in N,N-dimethylformamide (20 mL) was heated at 100° C. for 96 h. The reaction was cooled to room temperature, solvents removed under reduced pressure, taken up in ethyl acetate, washed with 1N aqueous HCl. The organic layer was concentrated and the residue purified by HPLC (elution with hexanes-EtOAc) to afford 169 mg (5.6%) of the titled product: mp 105°-106° C.; IR (KBr, cm-1) 3215, 2931, 1614 1556, 1534, 1487, 1199; 1H NMR (300 MHz, DMSO-d6) δ 11.65 (t, 1H), 10.40 (S, 1H), 8.30 (d, 1H), 7.20 (S, 1H), 6.93 (d, 1H), 5.52 (s, 1H), 3.63 (q, 2H), 2.80 (m, 1H), 2.22 (t, 2H), 1.95 (m, 4H), 1.62-1.42 (m, 4H), 1.18 (d, 6H); MS (FD) m/e 303 (M+); UV (EtOH) 290 nm (ε=17565), 266 nm (ε=18863), 247 nm (ε=15125), 203 nm (ε=23091). Anal. Calcd for C17H25N3S: C, 67.28;H, 8.30; N, 13.85. Found: C, 67.55; H, 8.48; N, 13.94.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]2=[N:6][CH:7]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][C:55]1=[O:59]>O1CCCC1>[O:59]=[C:55]1[CH2:56][CH2:57][CH2:58][N:54]1[CH2:53][CH2:52][O:1][C:2]1[CH:3]=[C:4]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2-c2ncc(O)cc21
Reactant: O=C1CCCN1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2ncc(OCCN3CCCC3=O)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
3-Hydroxy-indeno[1,2-b]pyridin-5-one (0.0500 g), di-t-butyl azodicarboxylate (0.087 g) and triphenylphosphine (0.10 g) were mixed with tetrahydrofuran (1.0 ml), 1-(2-hydroxy-ethyl)-2-pyrrolidone (0.043 ml) was added thereto, and the mixture was stirred at room temperature for 1 day. The mixture was purified by preparative thin layer chromatography (silica gel, eluent:ethyl acetate/methanol=10/1) to give the title compound (0.0386 g, 49%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Br[C:27]1[CH:28]=[C:29]([C:34]([F:37])=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]1[CH:13]=[C:14]([C:27]2[CH:28]=[C:29]([C:34]([F:37])=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:16][C:2]=1[OH:1])=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COC(=O)c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(O)c(CNC(=O)OC(C)(C)C)c2)ccc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
501 mg of t-butyl N-[2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate, 370 mg of methyl 3-bromo-6-fluorobenzoate, 80 mg of dichlorobistriphenyl phosphinoferrocene palladium and 500 mg of potassium carbonate were dissolved in 8 ml of dimethoxyethane and stirred overnight at 80° C. in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column, to give 391 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:20])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Cl:21])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of methyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (3.0 g, 10.29 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (2.75 g, 20.58 mmol) in one portion and the reaction mixture was stirred at 45° C. for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow solid (2.10 g, 62%): mp 119-122° C.; IR (KBr) 1718 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.67 (d, J=4.2 Hz, 1H), 8.22-8.16 (m, 1H), 7.39 (dd, J=7.9, 5.0 Hz, 1H), 3.26 (s, 3H), 1.46 (s, 9H); ESIMS m/z 326 (M+1).
Reaction SMILES: Cl.Cl.C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:27]=[C:26]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:32]=4)=[O:30])[CH:25]=[CH:24][C:23]=3[CH3:43])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:44][CH3:45])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:27]=[C:26]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:32]=4)=[O:30])[CH:25]=[CH:24][C:23]=3[CH3:43])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:44][CH3:45]
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Temperature: 25 °C

Procedure:
A mixture of 7-benzyloxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline dihydrochloride (4.45 g) and trifluoroacetic acid (20 ml) was stirred and heated to reflux for 90 minutes. The mixture was cooled to ambient temperature and evaporated. A mixture of a dilute aqueous sodium bicarbonate solution and methylene chloride was added to the residue and the resultant mixture was stirred for 30 minutes at ambient temperature. The precipitated solid was collected, washed with water and dried under vacuum at 60° C. to give 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (3.67 g; NMR: 2.17 (s, 3H), 3.52 (t, 4H), 3.71 (t, 4H), 3.98 (s, 3H), 7.09 (d, 1H), 7.19 (s, 1H), 7.23 (s, 1H), 7.37 (d, 1H), 7.6 (d, 1H), 7.84 (s, 1H), 8.05 (s, 1H), 8.25 (d, 1H), 8.66 (s, 1H), 10.42 (s, 1H), 11.06 (s, 1H); m/s: M+H+ 487.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][CH:69]([CH2:72]O)[CH2:68][CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60]>C(Cl)Cl>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:72][CH:69]4[CH2:70][CH2:71][N:66]([C:64]([O:63][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:65])[CH2:67][CH2:68]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diisopropyl azodicarboxylate (139 μl, 0.71 mmol) was added to a mixture of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 7), triphenylphosphine (186 mg, 0.71 mmol) and 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine, (also known as tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate), (152 mg, 0.71 mmol) in methylene chloride (3 ml), cooled in an ice/water bath. The mixture was allowed to warm to ambient temperature and was stirred overnight. The mixture was concentrated under reduced pressure and the residue purified by column chromatography, eluting with 1% methanol/methylene chloride and 0.1% triethylamine to give tert-butyl 4-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]piperidine-1-carboxylate (293 mg containing 13.5 mmol % triphenylphospine oxide, 86%).
Reaction SMILES: [C:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:27])([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:15]2)[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)(Cl)Cl.CO>C1COCC1>[CH2:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:27])([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH2:15]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2(O)CC[C@H]3CN(C(=O)c4ccccc4)CC[C@@H]3C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CC[C@H]3CN(Cc4ccccc4)CC[C@@H]3C2)cc1

Procedure:
Following the general procedure described in Example 49, trans-2-benzoyl-6-hydroxy-6-(4'-methoxyphenyl)decahydroisoquinoline (219 mg, 0.6 mmol) and lithium aluminum hydride (0.14 g, 3.6 mmol) were reacted in anhydrous THF (10 mL). Column chromatography (chloroform: methanol::9:1) afforded the product, a solid (158 mg): mp 38°-40° C.; NMR (CDCl3, 200 MHz): 7.4 (d, 2H, J=8), 7.35-7.2 (m, 5H), 6.85 (d, 2H, J=8), 3.8 (s, 3H), 3.55 (s, 2H), 2.95 (br d, 1H, J=10), 2.85 (br d, 1H, J=10), 2.05 (br t, 1H, J=8), 1.85-1.7 (m, 4H), 1.6-1.3 (m, 7H); HRMS: Calcd: 351.2198, Found: 351.2193.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([C@@H:7]([OH:12])[CH2:8][C@@H:9]1[CH2:11][O:10]1)[CH:5]=[CH2:6].[CH:13](O)([CH3:15])[CH3:14].O>>[CH3:14][C:13]1([CH3:15])[O:10][C@@H:9]([CH2:11][C:1]#[N:2])[CH2:8][C@@H:7]([CH2:4][CH:5]=[CH2:6])[O:12]1
Reactant: [C-]#N
Reactant: C=CC[C@@H](O)C[C@@H]1CO1
Reactant: CC(C)O
Agent: [K+]
Solvent: O
Product: C=CC[C@@H]1C[C@H](CC#N)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium cyanide, 1.3 g (20 mmol), is added to a room temperature solution of (R*,R*)-α-2-propenyloxiraneethanol, 2.56 g (20 mmol), in 25 mL of 4:1 isopropanol-water. The solution is stirred for 20 hours at ambient temperature, concentrated, and partitioned between ethyl acetate and brine. The aqueous layer is extracted 2× with ethyl acetate and the combined ethyl acetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 mL of 2,2-dimethoxypropane, camphorsulfonic acid is added and the solution stirred for 18 hours at room temperature. Concentration and flash chromatography provides 1.30 g of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]([CH:16]=O)=O.O.[OH-].[NH4+]>C(O)(=O)C>[N+:11]([C:8]1[C:9]2[N:10]=[CH:16][CH:14]=[N:1][C:2]=2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=CC=O
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc([N+](=O)[O-])c2nccnc12
Temperature: 22 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
2,3-Diamino-4-nitro-benzonitrile (0.050 g, 0.28 mmol, as prepared in WO-98/32439) was added to solution of glyoxal (40% in water, 0.032 mL, 0.28 mmol) in acetic acid (0.75 mL) and stirred at 22° C. for 3 h. The reaction was cooled to 0° C. and water (2.0 mL) was added and the pH was adjusted to 9.0 by addition of ammonium hydroxide which caused the product to precipitate. The mixture was then filtered and rinsed with cold water. Drying in vacuo gave 0.039 g (70%) of compound 468A as an orange solid. HPLC: 100% at 2.037 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O>[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3([CH3:16])[CH2:7][C:6]4[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=4[O:4]3)[CH2:28][CH2:27]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(COC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.5 g), 4-[(diphenylmethoxy)methyl]piperidine (3.0 g), and triethylamine (7.4 mL) was stirred under argon gas at 180° C. for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) to provide 2.4 g of 2-[[4-[(diphenylmethoxy)methyl]-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine. Yield 95%. This product was treated with 0.45 g of oxalic acid and, then, recrystallized from ethanol to provide 1.8 g of the title compound. Yield 58%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].[OH:11][C@:12]1([CH3:35])[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[O:31][CH2:32][C:33]#[CH:34])[CH2:13]1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:34]#[C:33][CH2:32][O:31][C@H:21]2[CH2:20][CH2:19][C@H:18]3[C@H:17]4[C@H:26]([CH2:25][CH2:24][C@:22]23[CH3:23])[C@:27]2([CH3:30])[C@H:14]([CH2:13][C@@:12]([OH:11])([CH3:35])[CH2:29][CH2:28]2)[CH2:15][CH2:16]4)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: C#CCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)c1ccc(I)cc1
Product: CC(=O)c1ccc(C#CCO[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@](C)(O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
A solution of 4-iodoacetophenone (16 mg, 0.06 mmol), 3α-hydroxy-3β-methyl-17β-(2-propynyloxy)-5α-androstane (22 mg, 0.06 mmol) in dry degassed triethylamine (1 mL) was stirred under argon at 23° C. Bis(triphenylphosphine)palladium chloride (2 mg) and CuI (2 mg) were added and the mixture was stirred at this temp. for 45 min. CH2Cl2 (4 mL) was added and the mixture was stirred at 23° C. for 1 hr. The TLC showed 100% conversion of the starting material, hence, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane:acetone (85:5) gave 17β-[3-(4-acetylphenyl)-2-propynyloxy]-3α-hydroxy-3β-methyl-5α-androstane (19 mg) as a colorless solid; mp 52-55° C.; TLC Rf (hexane:acetone 85:5)=0.5.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH2:20][S:21][CH3:22])=[C:15]([NH:24][CH3:25])[CH:14]=1>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH2:20][S:21]([CH3:22])=[O:6])=[C:15]([NH:24][CH3:25])[CH:14]=1
Reactant: CNc1cc(F)ccc1C(=O)CSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(=O)CS(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (3.49 g) in dichloromethane (80 ml) was added to a stirred solution of 1-(4-fluoro-2-methylaminophenyl)-2-(methylthio)ethanone (4.3 g), prepared in a similar manner to that described in Example 2, in dichloromethane (75 ml) under nitrogen over 15 minutes whilst maintaining the temperature below 25°. The mixture was stirred for a further 2 hours at ambient temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×50 ml) and evaporated in vacuo to give a solid product. Crystallisation from toluene gave 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone, m.p. 137°-138°.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([N+:9]([O-])=O)([CH2:6][NH:7][CH3:8])[CH2:4][OH:5]>CO.[Ni].O>[ClH:1].[NH2:9][C:3]([CH3:2])([CH2:6][NH:7][CH3:8])[CH2:4][OH:5]
Reactant: CNCC(C)(CO)[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: CNCC(C)(N)CO
Reaction time: 48 h
Yield: 163.6 %

Procedure:
To a solution of 2-methyl-3-(methylamino)-2-nitropropan-1-ol hydrochloride (5.4 g) in MeOH (32 ml) was added a slurry of Raney Nickel in H2O (1.5 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 48 h. The mixture was filtered through Celite and concentrated in vacuo to give 7.4 g of a crude liquid, which was used directly in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H), 2.26 (s, 3H), 2.99 (s, 2H), 3.41-3.44 (d, J=11.6 Hz, 1H), 3.48-3.51 (d, J=11.6 Hz, 1H). LRMS (ESI/APCI): 145 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:12]1[CH:17]=[C:16](F)[CH:15]=C(F)C=1)(C)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:28][C:29]1([C:36](OC)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=O)(C)(C)C>>[O:10]=[C:9]1[C:8]2([CH2:12][CH2:17][CH2:16][CH2:15]2)[N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])[CH2:36][C:29]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[NH:28]1
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCCCCC1
Product: CC(C)(C)OC(=O)N1CC2(CCCCCC2)NC(=O)C12CCCC2

Procedure:
Essentially following the procedures described for Intermediate 1, but using methyl 1-[(tert-butoxycarbonyl)amino]cycloheptanecarboxylate in place of tert-butyl 2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propanoate, the title compound was obtained. MS: m/z=337 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27]C[CH2:25][CH2:24]1.C([N:32](C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:32]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:25][CH2:24]1
Reactant: Clc1ccccc1N1CCCCC1
Reactant: O=CCCc1cc(-c2cccs2)no1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccccc1N1CCN(CCCc2cc(-c3cccs3)no2)CC1
Yield: 97 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)propanal (27.8 mg, 0. 13 mmol), (2-chlorophenyl)piperidine HCl (26.0 mg, 0.11 mmol), and diisopropylethyl amine (19.5, 0.11 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (71.2 mg, 0.34 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22 hr and followed the same processes as in Example 1 to obtain 41.4 mg (95.4%) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([Cl:11])=[C:9]([CH3:12])[C:8]([Cl:13])=[CH:7][C:5]=2[N:6]=1.[CH2:14]([O:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:15]>>[C:23]1([CH3:26])[CH:22]=[CH:21][C:20]([S:17]([OH:19])(=[O:16])=[O:18])=[CH:25][CH:24]=1.[CH3:1][CH:2]1[N:6]([CH2:14][CH3:15])[C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([CH3:12])=[C:10]([Cl:11])[C:4]=2[O:3]1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2cc(Cl)c(C)c(Cl)c2o1
Product: CCN1c2cc(Cl)c(C)c(Cl)c2OC1C
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
A mixture of 2.1 g. of 2,6-dimethyl-5,7dichloro-benzoxazole and 2 g. of ethyl-p-toluene-sulfonate was heated at 150° C. for 30 minutes. By cooling, a pick cake was obtained. It was ground in a mortar by washing repeatedly with ethyl ether. The product, thus obtained, was dried and used without further purification for the synthesis of dyes.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14]([CH2:16][OH:17])=[CH:13][CH:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CO)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To a solution of 5-[2-[tert-butyl(dimethyl)silyl]oxyethyl]thiophene-2-carbaldehyde (17.8 g, 66.1 mmol) in ethanol (180 mL) at 0° C. was added sodium borohydride (2.5 g, 66.1 mmol). The resulting solution was stirred at 0° C. for 1.5 h. The reaction solution was concentrated in vacuo and partitioned between ethyl acetate (30 mL) and brine (30 mL). The organic phase was over sodium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (17.5 g, 97%) which was used in the next step without further purification.