Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:8](O)=[O:9])[CH3:3].C1C=CC2N(O)N=[N:29][C:27]=2C=1.C(N(CC)CC)C.CN>C(Cl)Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:8]([NH:29][CH3:27])=[O:9])[CH3:3]
Reactant: CSc1ccc(Oc2ccc(C(=O)O)cc2CN(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc(SC)cc2)c(CN(C)C)c1
Reaction time: 0.5 h

Procedure:
The product from example 158 (480 mg, 1.51 mmol) WSCDI (377 mg, 2 mmol), HOBt.H2) (255 mg, 1.66 mmol) and triethylamine (0.53 mL, 3.78 mmol) were dissolved in DCM (0.03 M). After stirring for 30 min, MeNH2 (condensed, 2 mL) was added and the mixture stirred for a further 12 h. The mixture was then evaporated and the residue partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (3 times). The combined organic layers were dried (MgSO4) and evaporated to a yellow oil, which was purified by flash chromatography [SiO2; DCM/ MeOH/ 880 NH3 (93:7:1)]. The desired title amide was isolated as its hydrochloride salt (285 mg, 63%); Free base: δH(CDCI3, 400 MHz) 2.12 (6 H, s), 2.41 (3 H, s), 2.92 (3 H, d), 3.46 (3 H, s), 6.78 (1 H, brd), 6.84 (2 H, d), 7.20 (2 H, d), 7.63 (1 H, dd), 7.82 (1 H, d); MS m/z (ES+) 331 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1.[CH3:13][NH2:14].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH2:10][CH:11]([NH:14][CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1
Reactant: CN
Reactant: CCCCOc1cncc(Cl)c1
Agent: Cl
Solvent: CO
Product: CNC(C)CCOc1cncc(Cl)c1
Temperature: 100 °C
Yield: 76.6 %

Procedure:
Crude 3-bromo-1-(5-chloro(3-pyridyloxy)butane (1.50 g, 5.67 mmol) from the previous step was dissolved in methanol (10 mL) and added to a 40 wt % aqueous solution of methylamine (40 mL) in a heavy-walled glass pressure-tube apparatus. The mixture was stirred and heated at 100° C. (oil bath temperature) for 14 h. After cooling, the mixture was concentrated by rotary evaporation, and the product was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give a pale-brown oil. The product was dissolved in cold, 15% aqueous HCl (15 mL), stirred at 0° C. for 45 min and extracted with chloroform (50 mL). The aqueous layer was cooled to 0° C., basified with 15% aqueous NaOH solution to pH 8-9 and extracted with chloroform (3×75 mL). The combined extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 0.929 g (76.6%) of a pale-yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([F:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[C:6](=[O:20])[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.[C-:27]#[N:28].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[F:16][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:17][O:18][CH3:19])[C:7]3[C:6](=[O:20])[N:5]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:4]=[C:3]([CH2:2][C:27]#[N:28])[C:15]=3[C:14]=2[CH:13]=1
Reactant: [C-]#N
Reactant: COCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 86.6 %

Procedure:
A two-phase mixture of 2.8 g (6.7 mmol) of 1-(bromomethyl)-8-fluoro-5-(methoxymethyl)-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 1.3 g (26 mmol) of sodium cyanide and of 0.23 g (0.7 mmol) of tetrabutylammonium bromide in 100 ml of dichloromethane and 100 ml of water is stirred vigorously for 12 h. The organic phase is separated, washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. Diethyl ether is added and the precipitate is collected by filtration and dried under reduced pressure. 2.1 g (5.8 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
174 mg (0.303 mmol) of diastereomer A of (2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 46 mg (1.211 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR55## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.28, FD-MS: M+ =478.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2c(F)cccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
To a solution of 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (1.74 g, 3.60 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (1.64 g, 14.4 mmol) and triethylsilane (1.68 g, 14.4 mL). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was purified by column chromatography and eluted with a gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (1.54 g, 92%) as a colourless solid: mp 115-118° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.42-7.26 (m, 11H), 7.01 (ddd, J=8.2, 8.2, 5.9 Hz, 1H), 6.91 (s, 1H), 6.67 (dd, J=8.8, 8.8 Hz, 1H), 6.27 (s, 1H), 6.23 (d, J=7.9 Hz, 1H), 4.99 (s, 1H), 4.20-4.14 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.2, 157.9 (d, 1JC-F=248 Hz), 147.1, 145.0 (d, 3JC-F=8.7 Hz), 142.7, 137.7 (d, 2JC-F=30.9 Hz), 135.4, 130.1 (d, 3JC-F=8.7 Hz), 128.4 (d, 3JC-F=13.9 Hz), 128.3 (d, 3JC-F=8.4 Hz), 127.5 (d, 3JC-F=11.9 Hz), 119.4, 117.9 (d, 2JC-F=18.9 Hz), 116.1, 109.3 (d, 2JC-F=20.3 Hz), 107.2 (d, 4JC-F=2.1 Hz), 103.1, 73.0, 64.2, 63.7, 57.5; MS (ES+) m/z 467.9 (M+1)
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11]>C(O)(=O)C>[NH:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])[C:2]([NH2:3])=[O:1]
Reactant: NC(=O)c1cccc(N)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cccc(C(N)=O)c1
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
Sodium cyanate (1.3 gm, 20 mMole) in 9.0 ml or water was added over a 15 minute period to a solution of 3-aminobenzamide (1.36 gm, 10 mMole) in acetic acid at 35° C. The mixture was stirred for a further 15 minutes during which time a white precipitate formed. This was filtered off, washed with cold water and crystallized from 25% ethanol to give 1.4 gm (78%) of shiny crystals. m.p. >300° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16])[CH3:10]
Reactant: CCOC(=O)CCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN1C(=O)c2ccccc2C1=O
Yield: 81.4 %

Procedure:
This compound was prepared according to the procedure used to prepare 1,3-dihydro-1,3-dioxo-2H-isoindole octanoic acid ethyl ester. Thus, a mixture of 100 g (0.48 mole) of ethyl 5-bromovalerate (99%, Aldrich) and 94.5 g (0.50 mole) of potassium phthalimide (98%, Aldrich) in 300 mL of dimethylformamide gave 107.6 g (81%) of viscous oil. A 2.0 g sample of this oil was purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:10). Fractions containing title compound were combined and the solvents evaporated under reduced pressure to give 1.9 g (95% recovery) of colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][NH:20][CH2:21][CH3:22])[CH:11]=1)[CH3:2].[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:27]([CH:24]2[CH2:26][CH2:25]2)=[O:28])[CH2:21][CH3:22])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: O=C(O)C1CC1
Product: CCOC(=O)Cc1cncc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-fluoro-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and cyclopropanecarboxylic acid were reacted as described in Example 8, Step 6 to provide (5-{2-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-fluoro-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][OH:15])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=CNc1cccc(C(=NO)C(=O)O)n1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Product: O=CNc1cccc(C(=NOC(=O)C(Cl)Cl)C(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.5 %

Procedure:
A mixture of 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), dichloroacetyl chloride (7.6 g.) and methylene chloride (100 ml.) was stirred at room temperature for 5 hours. The precipitates were collected by filtration, washed with diethyl ether and dried to give 2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (4.6 g.), mp 88° to 90° C.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:30][CH2:31][CH3:32])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCCBr
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 22.3 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and propyl bromide (60 mg, 0.492 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15]([CH2:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:8]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH2:17]([S:15]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3]2)=[CH:8][CH:7]=1)=[O:16])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CS(=O)c1ccc2cc([N+](=O)[O-])c(N)cc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CS(=O)c1ccc2cc(N)c(N)cc2c1

Procedure:
To 0.025 mole of the 2-amino-7-isobutylsulfinyl-3-nitronaphthalene in 100 ml of 95% ethanol is added a solution of 3.4 equivalents of sodium hydrosulfite (Na2S2O4) in a solution of 100 ml of water and 15 ml concentrated (28%) ammonium hydroxide. The mixture is refluxed for 5 minutes and an amount of hydrosulfite solution equal to 10% of the original is added to the refluxing mixture. TLC (silica gel, ether) indicates consumption of starting material. The mixture is concentrated to one-half its original volume under vacuum and the residual mixture extracted with two 150 ml portions of chloroform. The combined chloroform extracts are dried (Na2SO4), filtered, and evaporated to dryness to yield the crude title compound which is used without further purification in Example 10.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[NH:17][C:18]([C:20]1[NH:24][C:23]2[S:25][C:26]([Cl:28])=[CH:27][C:22]=2[CH:21]=1)=[O:19])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[NH:17][C:18]([C:20]1[NH:24][C:23]2[S:25][C:26]([Cl:28])=[CH:27][C:22]=2[CH:21]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 134.1 %

Procedure:
tert-Butyl((1R,2R)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)carbamate (Method 22, 10.6 g, 24.5 mmol) was suspended in DCM (200 mL), TFA (20 mL) added and the reaction stirred at ambient temperature for 20 hours. The volatiles were removed by evaporation under reduced pressure and the residue triturated with DCM (50 mL) then filtered and dried to give the title compound (10.9 g, 100%) as the trifluoroacetic acid salt.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[CH:13]([CH3:15])[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[CH:2].[I:23]I>C([SnH](CCCC)CCCC)CCC.CCOCC.CC(N=NC(C#N)(C)C)(C#N)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[C:3](/[CH:1]=[CH:2]/[I:23])=[C:12]([CH:13]([CH3:15])[CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: II
Reactant: C#Cc1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)c1c(/C=C/I)c(-c2ccc(F)cc2)nc2ccccc12
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 94.7 %

Procedure:
A mixture of 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-quinoline (1.000 gm, 3.64 mmol) (the preparation of which is described in Example 5) and AIBN (13 mg) in 140 ml of tri-n-butylstannyl hydride was rapidly heated to 110° C. After 5 minutes of heating, the mixture was treated with additional Bu3SDE (0.4 ml) and the temperature of the reaction was raised to 130° C. Approximately 10 mg of AIBN was added to the reaction mixture every 0.5 hours. After 4.5 hours, the mixture was cooled to room temperature, diluted with Et2O (25 ml) and treated with solid I2 (3.08 gm, 12.2 mmol). The dark reaction mixture was stirred for 1 hour, then quenched with 10% Na2SO3 in saturated NaHCO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2SO4), filtered and stripped to yield a yellow oil which was triturated with cold hexane to give a precipitate. Recrystallization of the solid from hot hexane gave 1.438 gm (E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)quinoline (917 mg, 64%) as light yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[C:10]3[C:15]([N:16]=[CH:17][C:8]2=[N:7][N:6]=1)=[CH:14][C:13]([Cl:18])=[C:12]([Cl:19])[CH:11]=3)[CH2:2][CH2:3][CH3:4].[OH:20]O>CC(O)=O>[CH2:1]([C:5]1[N:9]2[C:10]3[C:15]([NH:16][C:17](=[O:20])[C:8]2=[N:7][N:6]=1)=[CH:14][C:13]([Cl:18])=[C:12]([Cl:19])[CH:11]=3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2cnc3cc(Cl)c(Cl)cc3n12
Reactant: OO
Solvent: CC(=O)O
Product: CCCCc1nnc2c(=O)[nH]c3cc(Cl)c(Cl)cc3n12
Temperature: 60 °C

Procedure:
The carbonyl compound was prepared by combining 500 mg (1.7 mmol) of the quinoxaline compound (7) and 16 nil HOAc, and then adding 5 ml of 30% H2O2. The mixture was heated to 60° C. for 16 hours, and then cooled. The product was recovered by filtration and dried at 0.5 mm and 60° C. overnight, yielding 150 mg of 1-n-butyl-7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][N:30]=[C:31]=[O:32])[CH3:26].CO>ClCCl>[CH2:25]([O:27][C:28](=[O:33])[CH2:29][NH:30][C:31]([O:24][C@@H:13]([C:9]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[N:12]=[CH:11][CH:10]=1)[C@@H:14]1[N:19]2[CH2:18][CH2:17][C@H:16]([C@@H:21]([CH:22]=[CH2:23])[CH2:20]2)[CH2:15]1)=[O:32])[CH3:26]
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CO
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](OC(=O)NCC(=O)OCC)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
To a solution of 200 mg (0.61 mmol) of quinidine in 5 ml of dry dichloromethane was added 74 ml (0.65 mmol) of ethylisocyanatoacetate. The mixture was allowed to stir magnetically at room temperature for 18 h and concentrated under reduced pressure. The residue was purified on preparative thin layer chromatography (silica, 2 mm) using a mixture of 1:9 ethyl acetate:methanol as the eluent and yielded 130 mg (0.28 mmol, 46%) of (8). MS, IR and NMR data confirmed identity of the compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH:15]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:23][CH:15]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCCCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)NC2CCCCCCC2)c1

Procedure:
25.5 g of 4-chloro-3-chlorosulfonylbenzoic acid were reacted as prescribed in Example 75a) with 45 g of cyclooctyl amine and worked up. The crystallized 4-chloro-3-cyclooctylsulfamoylbenzoic acid so obtained was dried end reacted without further purification in thionyl chloride as prescribed in Example 74a). Colorless crystals, melting point: 134° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1)(=[O:3])[CH3:2].[Br:20]Br>C1COCC1>[Br:20][CH2:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(C(=O)CBr)c2ccccc21

Procedure:
To a stirred solution of 3-acetyl-1-(tert-butoxycarbonyl)-indole, which may be prepared as described in Step (b) above, (0.01 mol), in THF at a temperature of about −80° C. to about 25° C. is added bromine (0.01 mol), and the mixture is stirred from about 5 minutes to about 24 hours. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of desired product is formed, the mixture (or, optionally, the residue which is obtained after first rotary evaporating off the reaction solvent) is partitioned between ethyl acetate and an excess of an aqueous solution of sodium bisulfite or an aqueous solution of sodium thiosulfate. The organic layer is washed with water, then brine, dried over sodium sulfate, and rotary evaporated to give 3-bromoacetyl-1-(tert-butoxycarbonyl)-indole, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=O)[CH2:12]3)([O:3][CH3:4])=[O:2].Cl.[NH2:28][OH:29].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=[N:28][OH:29])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=NO)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
A suspension of 17β-Carbomethoxy-6-oxo-3β,5α-dihydroxy-androstane, 8 g, as prepared in example 17, hydroxylamine hydrochloride (12 g) and sodium acetate trihydrate (16 g) in ethanol (100 mL) is heated at reflux for 1 h. The reaction mixture is cooled to ambient temperature and filtered to afford 17β-carbomethoxy-6-oximino-3β,5α-dihydroxyandrostane as a white solid, mp 234°-237° C. dec. Anal. Calcd. for C21H33NO5.H2O: C, 63.34; H, 8.88; N, 3.53. Found: C, 62.91; H, 8.98; N, 3.27.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]#[C:8][CH2:9][OH:10]>C(OCC)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCC#Cc1ncccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCc1ncccn1
Reaction time: 6 h

Procedure:
3-(2-pyrimidyl) prop-2-yn-1-ol (4.45 g; 0.033 M) was dissolved in ethyl acetate (140 mL), 10% Pd/C (890 mg) was added and the mixture stirred under an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through Celite and the filtrate evaporated to give 3-(2-pyrimidyl) propan-1-ol as a yellow oil, 4.15 g (91%). NMR (CDCl3) 2.1 (2H, m), 3.2 (2H, t), 3.8 (2H, t), 7.2 (1H, t), 8.7 (2H, d) MS found MH+139.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[N:21]=[C:20]([F:22])[C:19]([NH2:23])=[CH:18][CH:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:20]1[C:19]([NH2:23])=[CH:18][CH:17]=[C:16]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)[N:21]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: Nc1ccc(Br)nc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(N)c(F)n3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
5-Methoxybenzofuran boronic acid (345 mg, 1.80 mmol), 6-bromo-2-fluoro-pyridin-3-ylamine (286.5 mg, 1.50 mmol), Pd(PPh3)2Cl2 (25.2 mg, 0.036 mmol) and Et3N (475.5 μL, 3.41 mmol) were mixed in EtOH (10 mL) in a microwave vial. The reaction mixture was stirred at 140° C. for 10 minutes in a microwave reactor. The volatiles were then removed under reduced pressure and water was added (20 mL). The product was extracted with ethyl acetate (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of the crude product by flash column chromatography using 25% ethyl acetate in hexane gave 2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-ylamine (268 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.58 (d, J=7.6 Hz, 1 H), 7.39 (d, J=9.0 Hz, 1H), 7.15 (m, 1H), 7.14 (s, 1H), 7.04 (d, J=2.6 Hz, 1H), 6.88 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H). ESMS: m/z 259.47 [M+1]+