Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)=[CH:14][C:13]=1[CH2:23][NH2:24]>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)=[CH:14][C:13]=1[CH2:23][NH:24][CH:5]=[O:7]
Reactant: NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Product: O=CNCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of acetic anhydride (0.82 mL, 9.7 mmol) and formic acid (0.4 mL, 9.7 mmol) was heated to 50° C. for 30 minutes and then cooled to 0° C. 2-Chloro-5-(1H-pyrazol-3-yl)benzenemethanamine (i.e. the product of Step C) (1.0 g, 4.8 mmol) was added, and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was then diluted with dichloromethane, washed with saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated. The crude residue was purified by preparative thin layer chromatography (TLC) (2% methanol in chloroform as eluant) to provide the title product as a solid (0.5 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][CH:49]([S:51](Cl)(=[O:53])=[O:52])[CH3:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([S:51]([CH:49]([CH3:50])[CH3:48])(=[O:53])=[O:52])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and propane-2-sulfonyl chloride as starting materials in 27% yield. LCMS for C28H34ClN6O3S (M+H)+: m/z=569.2.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:1][CH:2]([S:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:22]=[O:23])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: O=Cc1ccc(OCCc2ccc(O)cc2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 72.9 %

Procedure:
3.77 g (13 mmole) 2-propanesulfonyl chloride dissolved in dichloromethane was slowly added to a solution of 3.2 g (13 mmole) 4-[2-(4-hydroxyphenyl)ethoxy]benzaldehyde and 2.63 g (26 mmole) triethylamine in 80 ml dichloromethane at 0° C. The temperature was slowly allowed to rise to room temperature and when the starting material was consumed the reaction mixture was poured on to ice. The phases were separated and the organic phase was washed with sodium carbonate, dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane as eluent to give 3.3 g (yield 72.8%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 2-propanesulfonate.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].Cl.[CH3:7][N:8]=[C:9]([NH2:18])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=1>Cl>[CH3:7][N:8]=[C:9]([NH2:18])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:5][CH2:4][CH2:3][NH2:2])[N:15]=1
Reactant: CN=C(N)Nc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Product: CN=C(N)Nc1nc(CSCCN)cs1
Yield: 82.2 %

Procedure:
Cysteamine hydrochloride (1.89 g; 16.6 mmoles) and 2-(2-methylguanidino)-4-chloromethylthiazole hydrochloride (4.0 g; 16.6 mmoles) [prepared from (N-methylamidino)thiourea and 1,3-dichloro-2-propanone] were combined in 20 ml of concentrated hydrochloric acid and the solution was heated at an oil bath temperature of 100°. After 2 hours the mixture was evaporated under reduced pressure and the residue made basic with 40% aqueous NaOH solution. The aqueous phase was extracted several times with methyl acetate and the organic phase was dried, filtered and evaporated to give 3.35 g of the title compound. The NMR spectrum (60 MHz) in D2O gave the following characteristic resonances δ: 6.52 (s, 1H), 3.60 (s, 2H), 2.70 (m, 7H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17](OC(C)(C)C)=[O:18].[O-]CC.[Na+]>CCO>[OH:18][N:17]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:9]
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: CC(C)(C)ON=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(=O)C(=NO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 2-phenyl-1-p-tolylethanone (5.0 g, 23.78 mmol) in EtOH (475.0 mL) at room temperature was added dropwise tert-butyl nitrite (5.5 mL, 46.2 mmol) followed by sodium ethoxide (4.07 g, 59.8 mmol). The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with H2O, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an orange oil (5.31 g). LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (35 mg, 0.125 mmol) from Example 5 step 3 was dissolved in DMF (0.62 mL), cesium carbonate (203 mg, 0.62 mmol) was added, stirred at room temperature for 10 minutes. 2-bromo-5-(methylsulfonyl)pyridine (32.4 mg, 0.137 mmol) was added. Reaction was run at room temperature for 1 hour, then heated to 50° C. for 5 hours. Water (10 mL) was added, extracted with EtOAc (10 mL×2), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by preparative-TLC (Analtech Silica Gel GF 1500 μM, 20×20 cm) using 30% acetone/hexane to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CC(O)C.[CH2:32]([CH:34]1[O:36][CH2:35]1)[Cl:33]>O>[Cl:33][CH2:32][CH:34]([OH:36])[CH2:35][NH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCC(O)CCl)no2)cc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a flask containing (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (84 mg, 0.23 mmol) was added 2 mL of IPA. The cloudy, white mixture was cooled to 0° C. and epichlorohydrin (20.7 μL, 0.26 mmol) was added and the reaction mixture stirred at room temperature overnight. The IPA was removed by concentration in vacuo and water (500 μl) and aliquots of epichlorohydrin (20.7 μL, 0.26 mmol) were added every hour (4 total) at room temperature until conversion was complete. The reaction mixture was concentrated, dissolved in DCM and purified by chromatography (MeOH/DCM) to provide 19.3 mg (18%) of 5-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile INT-15 as a white solid. LCMS-ESI (m/z) calculated for C24H25ClN4O3: 452.9. found 453.1 [M+H]+, tR=2.62 min.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.P(Br)(Br)[Br:25].N1C=CC=CC=1>CCOCC>[Br:25][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Br)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 116.7 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (1.0 g), phosphorus tribromide (0.70 g) and pyridine (0.05 g) in dry ether was stirred at 0° C. for 1.5 hours. The reaction mixture was quenched with water and extracted with ether. The organic extracts were dried (anhydrous magnesia sulphate), filtered and the solvent evaporated yielding 4-[bromo-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 299, 1.18 g) as a yellow oil: NMR: (CDCl3) 1.1(4H, m) 1.9(1H, m) 6.9(1H,s) 7.9(1H,m) 8.0(1H, s) 8.15(2H,m).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20](Cl)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1
Reactant: C1CCNC1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]nc2n1-c1ccc(N3CCCC3)nc1C(c1ccccc1Cl)=NC2

Procedure:
20 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were boiled with 60 ml. of pyrrolidine for 1 hour under reflux. Then the mixture was poured into 1 liter of water and acidified with glacial acetic acid whereupon the reaction product crystallized out. This was dissolved in alcohol, the alcoholic solution concentrated to about 70 ml. and ether added. The crystallized material was recrystallized from methanol. M.P. 228°-230° C.; Yield 8 grams.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][C:19]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:26]([Cl:35])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[NH2:18][C:19]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:31][CH2:30]2)[C:26]([Cl:35])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Reactant: COC(=O)c1cc(Cl)c(N2CCNCC2)cc1N
Product: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1N

Procedure:
3-(2-Methoxyphenyl)-5-methylisoxazole-4-carboxylic acid and methyl 2-amino-5-chloro-4-(piperazin-1-yl)benzoate (TFA salt) were coupled under the conditions described in Preparation M to give methyl 2-amino-5-chloro-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate. 1H-NMR (CDCl3, 400 MHz): δ 7.82 (1H, s), 7.60-7.47 (2H, m), 7.13-6.97 (2H, m), 6.01 (1H, s), 3.85 (3H, s), 3.84 (2H, s), 3.80 (3H, s), 3.25 (2H, s), 2.99 (2H, s), 2.58 (3H, s), 2.42 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-methylbenzenesulfonyl chloride according to METHOD A, giving 0.36 g (66%) of a pink solid; mp 173° C.; MS (Ionspray, [M+H]+) m/z 341.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:23]1[CH:27]=[C:26]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:25]=[N:24]1)[CH3:22]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([N:29]([CH2:28][C:26]1[CH:25]=[N:24][N:23]([CH2:21][CH3:22])[CH:27]=1)[C:30]1[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[CH:32][CH:31]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCc2c(OCc3ccccc3)cccc21
Product: CCn1cc(CN(C(=O)C2CCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 79.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 4-benzyloxyindan-1-carboxylic acid (0.54 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as starting materials, 4-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide (0.79 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:7]1)=[O:4].[N+](C1C=CC=CC=1)([O-])=O.[F:43]C(F)(F)C([O-])=O.[Na+].FOC(F)(F)F>FC(Cl)(Cl)Cl>[F:1][C:2]([F:32])([F:33])[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@:20]2([F:43])[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH2:7]1)=[O:4]
Reactant: C[C@]12CC[C@H](OC(=O)C(F)(F)F)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(F)(F)F)CC[C@@H]12
Reactant: O=C([O-])C(F)(F)F
Agent: FOC(F)(F)F
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: FC(Cl)(Cl)Cl
Product: C[C@]12CC[C@@]3(F)[C@@H](CC[C@H]4C[C@@H](OC(=O)C(F)(F)F)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)C(F)(F)F
Yield: 39.4 %

Procedure:
A well-stirred solution of 3β, 17β-di(trifluoroacetoxy)-5α-androstane (2.5 g, 5.15 mmole, prepared by treatment of 5α-androstane-3β,17β-diol with trifluoroacetic anhydride in pyridine), nitrobenzene (800 mg, 6.5 mmole) and sodium trifluoroacetate (10 g, 73.5 mmole) in fluorotrichloromethane (45 ml) was treated with trifluoromethyl hypofluorite (8.5 mmole) at -20° for 2.5 hours, air being admitted to the reaction vessel during this time. Thereafter the solution was purged with nitrogen and the solvent was removed in vacuo. The residue was dissolved in chloroform and the resulting solution was washed with aqueous sodium bicarbonate and water and was then dried, whereafter the product was chromatographed on silica gel (125 g). Elution with chloroform:hexane (3:7) gave unreacted starting material (308 mg), while subsequent elution with chloroform:hexane (7:13) gave 3β,17β-di(trifluoroacetoxy)-9α-fluoro-5α-androstane (1.02 g), which crystallized from hexane as prisms (917 mg) m.p. 140°-142°; [α] 24D - 22° (c 1.47, CHCl3). (Found C,55.10; H,5.78; F,26.35%;m/e 502. C33H29O4F7 requires C,54.97; H,5.82; F,26.47%; M+ 502).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[CH:21]1([NH:24][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and cyclopropylamine (19 mg, 0.32 mmol). The title compound was obtained as a solid (39 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.82 (1H, m), 8.37 (1H, s), 2.74 (1H, m), 0.69 (2H, m), 0.52 (2H, m). MS m/z: 388.02, 390.02 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:18]=[O:19]>O1CCCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[N:11][CH:10]=2)[CH2:15][CH:18]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2cnccc2CC1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-4-methylpyridine (step a, 1.47 g, 7.06 mmol) in tetrahydrofuran (50 ml) was cooled to -70° C. and treated with n-butyllithinum (6.2 ml, 2.5M in hexane, 15.5 mmol) at such a rate as to keep the temperature below -60° C. On complete addition the mixture was warmed to -20° C. and stirred for 30 minutes. The mixture was cooled to -30° C. and treated with dimethylformamide (0.66 ml, 8.47 mmol). The mixture was allowed to warm to 20° C., quenched with water (50 ml) and extracted with ethyl acetate (50 ml and 2×25 ml). The combined organic fractions were washed with saturated brine (50 ml), dried (Na2SO4), filtered and concentrated to residue in vacuo. The residue was purified by chromatography on silica gel (75% ethyl acetate/25% hexane) to afford the title compound as a colourless oil; yield: 1.26 g (81%) 1H NMR (CD2Cl2 /TMS): δ=1.6 (9H, s), 2.96 (1H, d, J=18 Hz), 3.35 (1H, dd, J=8 Hz & 18 Hz), 5.05 (1H, br.s), 5.98 (1H, br.s), 7.16 (1H, d, J=5 Hz), 8.15 (1H, d, J=5 Hz), 8.75 (1H, br.d).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:40]([C:35]3[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=3)([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[OH:41])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: O=C(c1cccnc1)c1ccc(Cl)c(Cl)c1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cccnc3)c3ccc(Cl)c(Cl)c3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (78.6 mg, 0.183 mmol, Intermediate 16) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (3,4-dichlorophenyl)(pyridin-3-yl)methanone (50.2 mg, 0.199 mmol, Intermediate 30: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 10 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 20 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes) to provide the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (d, J=2.0 Hz, 1H), 8.32 (dd, J=4.8, 1.4 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.81 (dd, J=2.5, 0.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.64-7.58 (m, 2H), 7.53-7.48 (m, 2H), 7.46 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.17 (dd, J=7.8, 4.7 Hz, 1H), 7.06 (dd, J=8.4, 2.2 Hz, 1H), 6.39 (dd, J=2.4, 1.9 Hz, 1H), 4.26 (s, 2H), 4.07 (s, 3H); MS m/e 601.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.ClC1C=CC(NN=C2CCCC(=O)C2)=CC=1>O.FC(F)(F)C(O)=O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Agent: O=C1CCCC(=NNc2ccc(Cl)cc2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
A suspension of p-chlorophenylhydrazine hydrochloride (8.06 g, 45 mmol) in water is added over a 10 min. period to a solution of 1,3-cyclohexanedione (5.05 g, 45 mmol) in water, stirred for 16 h and filtered. The filtercake is washed with water and air-dried. The thus-obtained cyclohexane-1,3-dione mono-(4-chlorophenyl)-hydrazone (45 mmol th.) is dissolved in trifluoroacetic acid (TFA) (30 mL), heated at 80° C. for 16 h, cooled to room temperature, poured into ice-water and filtered. The filtercake is air-dried and recrystallized from ethanol/water to afford the title product as a tan solid, 4.2 g (42% yield) identified by NMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17].[C-]#N.[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17]
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 40 %

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenylhydrazono) succinonitrile (0.296 g, 1 mmol), sodium cyanide (0.196 g, 4 equivalents), water (1 ml) and acetic acid (5 ml) were added successively to a tube, which was sealed and reacted at 20° C. for 40 hours. The mixture was added to saturated sodium bicarbonate solution, extracted (dichloromethane), washed (water), dried (magnesium sulfate) and evaporated to give a mixture which contained 40% of the desired title compound, NMR 3.1 (m, 2H), 4.5 (m, 1H), 5.89 (m, 1H), 6.94 (d, 1H), 7.71 (s, 2H), together with 60% of unchanged starting hydrazone.