Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(=O)([O-])O.[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1CCC(CC(=O)c2ccc(N3CCCCC3)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture consisting of 1.84 g of 1-acetyl-4-(4-fluorobenzoylmethyl)piperidine and 5 ml of piperidine was stirred under heating at 100° C. for 20 hours. After completion of the reaction, the reaction mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. After drying, the solvent was ditilled off and the oily residue was purified by silica gel column chromatography (eluent: ehtyl acetate) to give 2.2 g of a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([O:8][CH2:9][C@H:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]2[OH:23])=[O:7])=[C:4]([O:27][CH3:28])[CH:3]=1.Cl.CC(O)C.N>C1COCC1>[NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([O:8][CH2:9][C@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[OH:23])=[O:7])=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)OC[C@H]1CCNC[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A mixture of (±)-1,1-dimethylethyl cis-4-[[(4-amino-5-chloro-2-methoxybenzoyl)oxy]-methyl]-3-hydroxy-1-piperidinecarboxylate (0.053 mol) in THF (250 ml) and a mixture of HCl and 2-propanol (25 ml) was stirred for 2 hours at room temperature, then for 10 minutes at 50° C., then cooled again to room temperature. The mixture was alkalinized with NH3. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated, yielding 4.6 g (29%) (±) cis-(3-hydroxy-4-piperidinyl)methyl 4-amino-5-chloro-2-methoxybenzoate (interm. 6-a).
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21]
Reactant: CCOC(=O)C1=C(O)c2ccc(OC)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 86 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of ethyl 4-hydroxy-7-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.52 g, 1.6 mmol), tert-butyl 2-aminoacetate hydrochloride (0.39 g, 2.3 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.61 g, 4.7 mmol). The mixture was warmed to 86° C. and stirred for 4 hours, M+1=418. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.35 g of the title compound as a pale yellow solid. MS (m/z)=418 (M+H)+.
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][O:15][N:14]=[C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCON=C(c1ccccc1)c1ccccc1
Yield: 73.5 %

Procedure:
Benzophenone oxime (3.94 g, 20 mmol), 1-bromo-2-chloroethane (28.7 g, 200 mmol) and dried, powdered potassium carbonate (5.53 g, 80 mmol) in acetone (60 ml) were heated at reflux for 72 h. The reaction mixture was cooled and filtered and the filtrate was evaporated to an oily residue which was purified by "flash" chromatography (eluting with heptane/ethyl acetate 19/1) to provide diphenylmethanone O-(2-chloroethyl)oxime (3.82 g, 73%) as an oil, tlc rf 0.36 (SiO2, heptane/ethyl acetate 9/1).
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](Cl)=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]>CCOCC.O>[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:1][OH:2])=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: O=C(Cl)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: NO
Solvent: CCOCC
Solvent: O
Product: O=C(Cc1ccc(-c2ccc(F)cc2F)c(F)c1)NO

Procedure:
Hydroxylamine free base was added to a solution of 2,2',4'-trifluoro-4-biphenylylacetyl chloride (obtained as in Example 9) in ether. After stirring for 15 minutes the ether solution was diluted with water, separated, washed again with water, dried and evaporated. The orange residue was recrystallised twice from acetone/40-60 petroleum ether and then from toluene to give fine colourless needles of 2,2',4'-trifluoro-4-biphenylylacethydroxamic acid, m.p. 149°-150° C.
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]([OH:6])=[O:5].[CH2:38](Br)[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40].C(N(CC)CC)C>O1CCCC1>[OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]([O:6][CH2:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40])=[O:5]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCCCCCC=CCCCCCCCC(O)C(CCCCCCCCCCCCCC)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC=CCCCCCCCC(O)C(CCCCCCCCCCCCCC)C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
3-Hydroxy-2-n-tetradecyl-11-icosenoic acid (II)(3.68 g, 7.04 millimole) was dissolved in dry tetrahydrofuran (100 ml), and phenacyl bromide (2.10 g, 10.56 millimole) and triethyl amine (1.47 ml, 10.56 millimole) were successively added thereto with ice cooling. The reaction mixture was allowed to warm to room temperature, and to react for 13.5 hours. The insoluble matter in the reaction mixture was filtered off with suction and the solvent was distilled off from the filtrate. The residue was dissolved in methylene chloride and the obtained solution was successively washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The inorganic salt was filtered off and the solvent was distilled off from the filtrate. The obtained residue was purified over a silicagel column (benzene -→ benzene:ethyl acetate=8:2) to give phenacyl 3-hydroxy-2-n-tetradecyl-11-icosenoate (IV)(998.6 mg, yield 22.1%) in the form of white viscous solid. IR(νmaxKBr, cm-1); 3340, 2900, 2850, 1740, 1705
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][CH3:29])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][CH3:29])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CNS(=O)(=O)c1ccc(Cl)cc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 2.2 %

Procedure:
(Step 2) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g), 2-(aminomethyl)-4-chloro-N-methylbenzenesulfonamide hydrochloride obtained in Step 1 (0.81 g) and potassium carbonate (0.88 g) were stirred in ethanol (10 ml) overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3->1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (10 mg).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 36.2 %

Procedure:
A mixture of methyl thiosalicylate (0.93 g, 5.5 mmol), 2-cyano-6-methylthiopyridine (0.83 g, 5.5 mmol), triethylamine (1.17 ml, 8.3 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.57 g, 37%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc(Cl)cc2)n1
Yield: 46 %

Procedure:
This compound was synthesized from 4-chlorobenzamide and 1,3-dichloroacetone as described in example 74 step 1 (3.4 g, yield 46%). 1H NMR (300 MHz, CDCl3) δ 8.01-7.98 (d, J=8.8 Hz, 2H), 7.72 (s, 1H), 7.47-7.44 (d, J=8.8 Hz, 2H), 4.59 (d, J=0.9 Hz, 2H).
Reaction SMILES: [CH:1]1([N:7]([CH:28]2[CH2:33][CH2:32][NH2+:31][CH2:30][CH2:29]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH2:19][CH2:18]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH:35]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:1]1([N:7]([CH:28]2[CH2:33][CH2:32][N:31]([C:40]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:41])[CH2:30][CH2:29]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH2:19][CH2:18]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CC[NH2+]CC3)s2)CC1
Reactant: O=C(Cl)C1CCCC1
Agent: [Cl-]
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCN(C(=O)C4CCCC4)CC3)s2)CC1

Procedure:
Prepared in 65% (193 mg) yield as described in general procedure (N) from 4-{1-cyclohexyl-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium; chloride (268 mg, 0.5 mmol) and cyclopentanecarbonyl chloride (80 mg, 0.6 mmol).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:35][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[CH2:19][CH2:20]1)=[O:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-(9H-fluoren-9-ylmethyl) ester (5 g, 14.2 mmol) in CH2Cl2 (50 mL) was added DMF (0.5 mL) and the resulting solution was cooled to 0° C. To this solution oxalyl chloride (3.6 g, 28.44 mmol) was added dropwise and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to afford (9H-fluoren-9-yl)methyl 4-(chlorocarbonyl)-piperidine-1-carboxylate (5 g, 95%) as brown liquid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C(O)C.N1CCCC1>[NH2:9][C:8]1[O:15][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]=1[C:10]#[N:11]
Reactant: N#CC(C#N)=Cc1ccco1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Solvent: C1CCNC1
Product: CCOC(=O)C1=C(C)OC(N)=C(C#N)C1c1ccco1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a solution of (2-furanylmethylene)malononitrile (0.72 g, 5.0 mmole) in hot ethanol (5.0 ml) was added ethyl acetoacetate (0.647 ml, 5.0 mmole) followed by 1 drop of pyrrolidine. The mixture was refluxed for 15 h. Upon cooling the mixture to room temperature a precipitate formed. The mixture was filtered to provide the desired product (0.753 g, 55%) as pinkish powder. Rf=0.4 in 50% ethyl actetate:hexanes. 1H NMR (400 MHz; CDCl3) d 7.295 (m, 1H); 6.27 (dd, 1H, J=3.1, 1.95 Hz); 6.10 (d, 1H, J=3.1 Hz); 4.63 (s, 1H); 4.50 (bs, 2H); 4.22-4.07 (m, 2H); 2.36 (s, 3H); 1.20 (t, 3H, J=7.0 Hz). LC MS shows MH+ at 275.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:27][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1ncc2cc(CN)ccc21
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CCn1ncc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-ethyl-1H-indazol-5-yl)methanamine (step-3 of Example 14).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[CH2:9]([O:11][C:12](=[O:26])[C:13](=O)[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]>O.C(O)C>[CH2:9]([O:11][C:12](=[O:26])[C:13](=[N:7][OH:8])[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(CC)cccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NO)c1c[nH]c2c(CC)cccc12
Yield: 75.7 %

Procedure:
Solutions of sodium acetate (43.7 g, 0.53 mol) in water (100 mL) and hydroxylamine hydrochloride (37 g, 0.53 mol) in water (100 mL) were added to 7-ethyl-α-oxo-1H-indole-3-acetic acid ethyl ester 4 (17.4 g, 0.07 mol), in ethanol (250 mL) and the mixture was heated at reflux for 12 hours. The ethanol was removed by distillation and the resultant precipitate was filtered and recrystallized from hot ethanol to give the product (13.8 g, 75%), m.p. 167°-169° C. as a mixture of isomers.
Reaction SMILES: O1[C:3]23[C@:16]([CH3:22])([C:17]([CH3:21])=[CH:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:23])[C@H:9]([F:24])[CH2:8]2)[C:5](=[CH2:25])[C@H:4]3[CH3:26].[ClH:27]>C(O)(=O)C>[Cl:27][C:2]1[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[C@@:16]2([CH3:22])[C:3]=1[C@H:4]([CH3:26])[C:5](=[CH2:25])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][C@@H:9]([F:24])[C:10]2=[O:23]
Reactant: C=C1[C@H]2[C@@H]3C[C@@H](F)C(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C(C)=CC(=O)C3OC32[C@@H]1C
Reactant: Cl
Solvent: CC(=O)O
Product: C=C1[C@@H](C)C2=C(Cl)C(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12

Procedure:
A solution of 4,5-epoxy-16α-fluoro-1,6β-dimethyl-7-methylenandrost-1-ene-3,17-dione (359 mg) in glacial acetic acid (5 ml) is treated with gaseous hydrogen chloride for about 30 min at room temperature. The precipitate is filtered off, washed with diethylether and then chromatographed on silica gel to give pure 4-chloro-16α-fluoro-1,6β-dimethyl-7-methylen-androsta-1,4-diene-3,17-dione (245 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)c3ccc(F)cc3)c2)cc1Cl
Yield: 40 %

Procedure:
According to general General Sulfonylation Procedure 2 in example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added 4-fluoro-benzenesulfonyl chloride (18.6 mg, 96 μmol, 1.1 eq). The product was purified by precipitation in methanol and lyophilized to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-fluoro-benzenesulfonamide (13.5 mg, >95% purity, yield: 40%).
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1(/[CH:28]=[CH:29]/[CH:30]=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:28][CH:29]2[C:30](=[O:31])[O:13][C:12]3[NH:11][C:10]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[F:21])=[N:9][C:8]=3[CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C/C=C/C1CCCCC1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1CC1CCCCC1
Reaction time: 72 h
Yield: 56 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-cyclohexylacrylaldehyde. After 72 h, the reaction only reached 64% conversion by 1H NMR. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 19 as an off-white solid (71 mg, 56%). Analytical data for 19: 1H NMR (500 MHz, CDCl3) δ 9.45 (d, J=8.3 Hz, 1H), 7.90 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.36-7.27 (m, 3H), 7.13-7.04 (m, 3H), 7.01-6.93 (m, 1H), 4.24 (d, J=6.9 Hz, 1H), 3.29 (q, J=6.9 Hz, 1H), 1.74-1.61 (m, 6H), 1.49-1.40 (m, 1H), 1.29-1.18 (m, 2H), 1.18-1.04 (m, 2H), 0.91-0.81 (m, 2H); 13C NMR (CDCl3, 126 MHz) δ 169.5, 159.1 (d, JCF=243.4 Hz), 155.4 (dd, JCF=240.8, 2.1 Hz), 149.3, 137.3, 136.3, 129.2, 128.1, 127.7, 118.5 (dd, JCF=12.9, 9.1 Hz), 117.1 (dd, JCF=25.7, 8.7 Hz), 116.5 (dd, JCF=24.7, 9.5 Hz), 114.5 (dd, JCF=27.0, 3.8 Hz), 110.6 (d, JCF=3.9 Hz), 43.0, 39.6, 34.6, 34.4, 33.4, 32.8, 26.4, 26.2, 26.1; IR (film) cm−1 2923, 2851, 1770, 1637, 1619, 1529, 1481, 1463, 1450, 1387, 1172, 1115, 1094, 881, 812, 766, 737, 700; LRMS (ESI): Mass calcd for [M+H]+ C25H25F2N2O2: 423.2. found 423.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 15% IPA/hexanes 0.7 mL/min, 280 nm), Rt1 (major)=9.1, Rt2 (minor)=25.0 min; er=98:2.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]3[C:13]([CH:19]=[O:20])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=3)[C:5]=12.Cl[C:22]([F:27])([F:26])C([O-])=O.[Na+]>CC#N>[F:26][CH:22]([F:27])[O:18][C:15]1[CH:14]=[C:13]([C:12]([O:11][CH2:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][N:16]=1)[CH:19]=[O:20]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=Cc1cc(=O)[nH]cc1OCc1cccn2ccnc12
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cc(OC(F)F)ncc1OCc1cccn2ccnc12
Temperature: 25 °C
Yield: 5.1 %

Procedure:
To 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (100 mg, 0.37 mmol, 1 equiv) in CH3CN (10 mL) was added sodium 2-chloro-2,2-difluoroacetate (84.5 mg, 0.56 mmol, 1.5 eq.). The mixture was stirred at rt O/N and concentrated. The crude was purified on silica gel using 10% MeOH/DCM as eluent to give 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde (6.0 mg, 5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.14 (s, 1H), 8.10 (d, J=7.0 Hz, 1H), 7.61 (s, 2H), 7.44 (t, J=60.0 Hz, 1H), 7.24-7.27 (m, 2H), 6.79 (t, J=7.0 Hz, 1H), 5.63 (s, 2H). LRMS (M+H+) m/z 320.0.
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@H:16]([CH2:17][C:18]([CH3:26])=[CH:19][CH2:20]1)[CH2:15][CH2:14]3)(=O)C.O>CO>[CH3:26][C:18]1[CH2:17][C@H:16]2[C@:21]([CH3:22])([CH2:20][CH:19]=1)[C@@H:23]1[C@H:13]([C@H:10]3[C@@:8]([CH2:25][CH2:24]1)([CH3:9])[C@@H:7]([OH:6])[CH2:12][CH2:11]3)[CH2:14][CH2:15]2
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(C)=CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1

Procedure:
Aqueous sodium hydroxide solution (50 ml; 4N) was added to a solution of 3-methyl-5α-androst-2-en-17β-ol acetate (50 g) in methanol (400 ml) and the solution was heated under reflux for 1 h. The solution was cooled and water was added to precipitate the product (43 g). Recrystallisation of a sample from ether gave pure 3-methyl-5α-androst-2-en-17β-ol, m.p. 128°-130°; [α]D +68° (c 0.31 in EtOH).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[NH:18][C:19]([O:21][CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][C:26]=2[CH:27]=1)=[O:20])=[O:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[C:32]1([C:29]2[CH:30]=[CH:31][C:25]3[O:24][C:23]([CH2:22][O:21][C:19]([NH:18][C:9]4[CH:10]=[CH:11][C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:8]=4[C:6]([OH:7])=[O:5])=[O:20])=[CH:27][C:26]=3[CH:28]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[Si](C)(C)CCOC(=O)c1c(NC(=O)OCc2cc3cc(-c4ccccc4)ccc3o2)ccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2ccccc2c1C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
To a solution of 2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester (574 mg, 1.07 mmol) in DMF (5 mL) was added 1.0M tetra-n-butylammonium fluoride (1.1 mL, 1.07 mmol) under a nitrogen atmosphere. The mixture was stirred for 1.5 h. Water was added and the mixture was extracted, washed with water and brine, dried and concentrated to ca. 3 mL. The suspension was cooled at 0-5° C. for 40 min and filtered. Recrystallization of the obtained white solid gave 224 mg of 2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-naphthalene-1-carboxylic acid, 201, mp: 174.5-177.2° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6]#[CH:7])[CH3:2].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26](I)[S:27][C:20]=12)[NH2:14]>>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6]#[C:7][C:26]1[S:27][C:20]2[C:21](=[N:22][CH:23]=[CH:24][C:19]=2[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2[F:10])[CH:25]=1)[CH3:2]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCCN(CC)CC
Product: CCN(CC)CCC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 50 °C
Yield: 6 %

Procedure:
Prepared from N,N-diethylbut-3-yn-1-amine (30 mg, 1.04 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 200 mg, 0.518 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated to 50° C. for 7 hours. The crude was purified by preparative TLC (10% MeOH/EtOAc). The product was obtained as a waxy solid (12 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=6 Hz, 1H), 7.52 (s, 1H), 7.03 (m, 1H), 6.52 (m, 3H), 3.85 (s, 2H), 2.88 (m, 2H), 2.67 (m, 6H), 1.12 (m, 6H).